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Meeting Abstracts  |   December 1999
Intrathecal Drug Therapy for Chronic Pain  : From Basic Science to Clinical Practice
Author Affiliations & Notes
  • Patrick M. Dougherty, Ph.D.
    *
  • Peter S. Staats, M.D.
  • *Associate Professor, Departments of Neuroscience and Neurosurgery. †Associate Professor, Department of Anesthesiology and Critical Care Medicine.
Article Information
Meeting Abstracts   |   December 1999
Intrathecal Drug Therapy for Chronic Pain  : From Basic Science to Clinical Practice
Anesthesiology 12 1999, Vol.91, 1891. doi:
Anesthesiology 12 1999, Vol.91, 1891. doi:
SYSTEMIC analgesics and conservative therapies are effective in controlling chronic pain for the majority of patients. However, many other patients, such as those with advanced head and neck carcinoma and those with neuropathic pain, require more aggressive therapy to directly modulate pain transmission in the central nervous system. Reversible methods of aggressive therapy in the spinal cord include electrical stimulation procedures and intrathecal delivery of analgesics by implanted pumps, both of which are finding ever-expanding roles in pain control. Of these, long-term intrathecal drug therapy is likely to show the largest near-term expansion because the numbers of agents approved for this route of administration are likely soon to increase substantially. Moreover, drug therapy itself will change as treatments using microsome drug encapsulation and novel suspension media are introduced. Further on the clinical horizon is intrathecal cell implantation for the relief of chronic pain. The goal of this review is to update the reader regarding each of these pending advances in intrathecal drug therapy for chronic pain.
Present and Future Intrathecal Analgesics 
Morphine is the only drug presently approved for long-term intrathecal treatment of pain by the United States Food and Drug Administration and by the major manufacturers of infusion pumps for use in their devices. Nevertheless, chronic pain conditions are not always adequately treated by intrathecal opioids alone. Opioids have many unwanted side effects and a significant stigma. Therefore, extensive basic animal and clinical research has focused on identifying alternative classes of analgesics and adjuvants to manage pain. 1 Many receptors and compounds that modulate pain transmission have been identified (Fig. 1). The analgesic properties of drugs active at a variety of these targets are being investigated, both alone and in combination, in humans (table 1). 3 Herein, we review the basic and clinical science of many of these compounds organized on the basis of their function in the spinal dorsal horn. Agents that nonspecifically alter transmission in the dorsal horn by interacting with the ion channels and second-messenger systems that generate action potentials, release synaptic neurotransmitters, and regulate cell excitability are discussed first. We progress to compounds that act on neurotransmitter receptor systems. Finally, we discuss compounds that act on peptide neuromodulator and novel trans-synaptic signal molecule receptor systems.
Fig. 1. Schematic diagram of the major neurochemicals involved in somatosensory transmission and processing in the spinal dorsal horn. The figure is organized with the pain signaling output neurons of the dorsal horn, the dorsal horn projection neurons, as the central cellular component. These cells are the source of all inputs for pain and temperature to the rostral central nervous system structures, such as the thalamus, brain stem, and hypothalamus, that in turn influence cortical and limbic brain structures necessary for conscious perception and appreciation of pain. The primary afferents that convey input from peripheral tissues to spinal interneurons and projection cells are shown entering at the right of the figure. The local circuit interneurons that influence the processing of sensory inputs to projection cells are represented by the cell profile at the bottom right. Meanwhile, the inputs to the spinal cord that have come from rostral central nervous system sensory modulatory sites are shown in the cellular component at the top of the figure, alongside the departing axon of the projection cell. The chemicals involved as neurotransmitters (transmitters) and neuromodulators (modulators) associated with each compartment are indicated in the boxes associated with each profile. Boxes at the bottom left list the nonspecific and trans-synaptic signals that provide additional sites for intervention. 
Fig. 1. Schematic diagram of the major neurochemicals involved in somatosensory transmission and processing in the spinal dorsal horn. The figure is organized with the pain signaling output neurons of the dorsal horn, the dorsal horn projection neurons, as the central cellular component. These cells are the source of all inputs for pain and temperature to the rostral central nervous system structures, such as the thalamus, brain stem, and hypothalamus, that in turn influence cortical and limbic brain structures necessary for conscious perception and appreciation of pain. The primary afferents that convey input from peripheral tissues to spinal interneurons and projection cells are shown entering at the right of the figure. The local circuit interneurons that influence the processing of sensory inputs to projection cells are represented by the cell profile at the bottom right. Meanwhile, the inputs to the spinal cord that have come from rostral central nervous system sensory modulatory sites are shown in the cellular component at the top of the figure, alongside the departing axon of the projection cell. The chemicals involved as neurotransmitters (transmitters) and neuromodulators (modulators) associated with each compartment are indicated in the boxes associated with each profile. Boxes at the bottom left list the nonspecific and trans-synaptic signals that provide additional sites for intervention. 
Fig. 1. Schematic diagram of the major neurochemicals involved in somatosensory transmission and processing in the spinal dorsal horn. The figure is organized with the pain signaling output neurons of the dorsal horn, the dorsal horn projection neurons, as the central cellular component. These cells are the source of all inputs for pain and temperature to the rostral central nervous system structures, such as the thalamus, brain stem, and hypothalamus, that in turn influence cortical and limbic brain structures necessary for conscious perception and appreciation of pain. The primary afferents that convey input from peripheral tissues to spinal interneurons and projection cells are shown entering at the right of the figure. The local circuit interneurons that influence the processing of sensory inputs to projection cells are represented by the cell profile at the bottom right. Meanwhile, the inputs to the spinal cord that have come from rostral central nervous system sensory modulatory sites are shown in the cellular component at the top of the figure, alongside the departing axon of the projection cell. The chemicals involved as neurotransmitters (transmitters) and neuromodulators (modulators) associated with each compartment are indicated in the boxes associated with each profile. Boxes at the bottom left list the nonspecific and trans-synaptic signals that provide additional sites for intervention. 
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Table 1. Human Intrathecal Analgesics 
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Table 1. Human Intrathecal Analgesics 
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Various animal models of nociception are used to approximate specific pain conditions in humans. For example, hot plate, tail flick, tail–paw pinch, and shock titration experiments assess analgesic effects on acute cutaneous thermal and mechanical pain. Intraplantar injections of formalin, zymosan, carrageenan or Freund's adjuvant are models of acute and sustained inflammatory pain. Intraperitoneal hypertonic saline, acetic acid, and colorectal distension model acute visceral pain. There are also a number of nerve injury models of human neuropathic pain. Despite these models, it is impossible to directly assess the effects of drugs in animals on the complex cognitive experience that humans know and can communicate as pain. Although we refer to certain drugs as showing “analgesic” properties in animals, it is more appropriate to state that these studies assess “antinociceptive” properties. This is because we know that particular stimuli activate nociceptors or produce nociceptive responses and that certain drugs block these activities. The effect of analgesics in animal studies therefore needs validation in humans before a given compound can enter widespread clinical use. Preclinical studies not only need to be designed as thorough, blinded, placebo-controlled studies, but also should evaluate drug toxicity and drug interaction effects. Therefore, our review is intended to update readers regarding the future of intrathecal drug therapy and not as an explicit charge to alter current therapies to include unproven experimental compounds.
Blockade of Ion Channels and Second-messenger Systems 
Propagation of bioelectric signals in the nervous system is crucially dependent on the movement of various ions and the activity of cellular enzymes and metabolites. The proteins that form ion channels and function as second-messenger enzymes can be blocked by numerous agents, and many of these have been studied as putative analgesics. However, because ion channels and second messengers are found in all neural elements, the effects of compounds acting at these sites are not specific to pain circuitry. Therefore, side effects are often encountered with these drugs that limit their usefulness when given alone. Nevertheless, many compounds in this category will be successful as analgesic adjuvants. The four ion channels involved in pain transmission, those for sodium, calcium, potassium, and chloride, are discussed individually. In contrast, the eight second-messenger enzymes involved in pain transmission (including adenylate and guanylate cyclase; phospholipases A3, D, and C; and protein kinases C, A, and G) have complex biochemical interrelations and therefore are discussed as a set.
Sodium Channels. 
Local anesthetics such as lidocaine and bupivacaine inactivate voltage-sensitive sodium channels (fig. 2). The opening of these channels is the primary event underlying the depolarization of nerve membranes and therefore is the key to propagation of neural impulses throughout the nervous system. Dorsal root ganglion neurons have multiple types of sodium currents that are mediated by at least one class of tetrodotoxin-sensitive channel and by as many as four tetrodotoxin-resistant sodium channels. 4 Sodium currents in dorsal horn neurons are mediated by at least three types of tetrodotoxin sensitive channels. 5 
Fig. 2. Summary of the two major classes of sodium channels involved in somatosensory transmission at spinal levels. Drugs that modify each channel are listed, with arrows indicating sites of action. The “X” indicates blockade of the channel. 4030W92 = 2,4-diamino-5-(2,3-dichlorophenyl)-6-fluoromethylpyrimidine.  34 
Fig. 2. Summary of the two major classes of sodium channels involved in somatosensory transmission at spinal levels. Drugs that modify each channel are listed, with arrows indicating sites of action. The “X” indicates blockade of the channel. 4030W92 = 2,4-diamino-5-(2,3-dichlorophenyl)-6-fluoromethylpyrimidine.  34
Fig. 2. Summary of the two major classes of sodium channels involved in somatosensory transmission at spinal levels. Drugs that modify each channel are listed, with arrows indicating sites of action. The “X” indicates blockade of the channel. 4030W92 = 2,4-diamino-5-(2,3-dichlorophenyl)-6-fluoromethylpyrimidine.  34 
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The effects of spinally delivered local anesthetics for short-term pain management have been studied in animals and humans for many years. 6 However, use of long-term intrathecal infusion of local anesthetics for pain relief in animals was first investigated in the early 1980s. 7 Since then, these compounds have been used in numerous experimental studies for long-term relief of somatic, visceral, 8 and neuropathic pain. 9–12 Although relief of experimental measures of pain was often profound in each of these studies, many side effects, including somatic and visceral motor impairment, were encountered.
Prolonged infusion of local anesthetics for postoperative pain in humans became widespread in the 1990s. 13–16 Many patients with cancer and chronic nonmalignant pain receive continuous infusions of intrathecal local anesthetics outside of the hospital. 17–20 Intrathecal local anesthetics combined with intrathecal opiates have provided pain relief in each of these conditions, but side effects are common. 17–20 These include delayed urinary retention, paresthesia, paresis–gait impairment, periods of orthostatic hypotension, bradypnea, and dyspnea. The percentages of patients affected by one or more of these side effects varied among studies, ranging from one third to two thirds of all subjects. 17–21 Additionally, tolerance often increased drug requirements to such a large extent that increases in drug concentration (limited by solubility) and increases in drug infusion rate (limited by pump design) did not permit administration of sufficient doses to produce pain relief. 22 Externalized epidural and intrathecal catheters were therefore necessary to maintain analgesia, increasing the risk of infection.
Future local anesthetics for treatment of chronic pain will probably be compounds active at C-fiber–specific sodium channels. 23,24 Tetrodotoxin-resistant sodium channels are concentrated in primary afferent C fibers of the mouse, the rat, and humans and present only at much lower concentrations in other dorsal root and autonomic ganglion neurons. 23–27 Tetrodotoxin-resistant sodium channels are the chief mediators of action potentials in nociceptive C primary afferents, 28 and algesic compounds, such as prostaglandins, specifically increase sodium currents through these channels. 29 Expression of tetrodotoxin-resistant channels increases during the development of nociceptive (inflammatory) pain but undergo down-regulation with development of neuropathic pain. 30–33 Finally, the usefulness and specificity of antagonists at these channels to pain signaling has been substantiated in an animal study with one recently developed compound. 34 Extension of these findings should soon follow, with novel antagonists to these channels based on the chemical structure of the anticonvulsants. 35 
Calcium Channels. 
Calcium ions are essential for regulation of neuronal excitability and for the release of neurotransmitter with synaptic depolarization. 36 At least four types of calcium channels, the L, N, T, and P types, have been identified in dorsal root ganglion and dorsal horn neurons (fig. 3). There are numerous chemical antagonists of L-type calcium channels, 36 whereas N-type calcium channels are blocked using toxins of Conus magnus  . 37 P channels are especially prevalent in Purkinje cells and are sensitive to venom toxins of the funnel-web spider (Agelenopsis aperta  ). 36 T channels are involved in the regulation of neuronal excitability and pacemaker activity. 38 T channels in dorsal root ganglia are also blocked by some conotoxins. 39 
Fig. 3. Summary of the four classes of calcium channels involved in sensory transmission at spinal levels. Drugs that modify each channel are listed, with arrows indicating the sites of action. The “X” indicates blockade of the channel. Some conotoxins block “P”-type channels, but these may not be involved in transmission of sensory information at spinal levels. 
Fig. 3. Summary of the four classes of calcium channels involved in sensory transmission at spinal levels. Drugs that modify each channel are listed, with arrows indicating the sites of action. The “X” indicates blockade of the channel. Some conotoxins block “P”-type channels, but these may not be involved in transmission of sensory information at spinal levels. 
Fig. 3. Summary of the four classes of calcium channels involved in sensory transmission at spinal levels. Drugs that modify each channel are listed, with arrows indicating the sites of action. The “X” indicates blockade of the channel. Some conotoxins block “P”-type channels, but these may not be involved in transmission of sensory information at spinal levels. 
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Mixed antinociceptive effects of intrathecal L-type calcium channel antagonists have been observed in animals. In one series, verapamil alone had little effect on tail-flick latency of rats, although it potentiated the effects of small doses of morphine. 38,40 In contrast, verapamil and diltiazem produced analgesia in the tail-flick and colorectal distension tests 41; and nifedipine prevented capsaicin-induced mechanical hyperalgesia. 42 N-type calcium channel antagonists have shown a clearer antinociceptive profile in animal studies. Intrathecal administration of conopeptides in rats relieved neuropathic pain, 37,43 attenuated both phases of the formalin test, 37 produced short-term thermal antinociception, 38 and prevented capsaicin-induced hyperalgesia. 42 However, pronounced motor disturbances persisted for 2 or 3 days after administration of high-dose conotoxin in rats. 43 
The analgesic properties of P-type calcium channel antagonists have been evaluated after intraspinal infusion of agatoxins. 42,44 Agatoxin did not affect the responses of rats to short-term noxious mechanical or heat stimuli or to spontaneous pain behaviors after intradermal injection of capsaicin or after joint inflammation. However, agatoxin prevented development of mechanical hyperalgesia after capsaicin and thermal hyperalgesia after joint inflammation. 42,44 Similar effects were reported on dorsal horn neurons after application of agatoxin to the surface of the spinal cord. 45 There was little effect on the responses of single dorsal horn neurons to pressure applied to the knee joint in normal animals. However, agatoxin markedly decreased the response to pressure in neurons from animals with inflamed knee joints. 45 
Both L- and N-type calcium channel antagonists have clinical analgesic properties. Patients who received epidural verapamil (in combination with bupivacaine) consumed smaller doses of analgesics postoperatively than patients treated with bupivacaine alone. 46 Similarly, an N-channel antagonist, conotoxin, was analgesic after intrathecal administration to patients with uncontrolled pain caused by malignant disease. 47 Verapamil did not produce any major side effects, whereas side effects similar to those of excessive lidocaine limited the usefulness of conotoxin. 47 
In summary, combinations of L-type calcium channel antagonists with standard analgesics such as morphine will probably find increasing clinical use in the near term. However, the future of calcium channel analgesics will probably follow the course observed in sodium channel research, with efforts to identify C-fiber–specific channel subtypes.
Potassium Channels. 
Potassium is the second main cation of the neuronal action potential. There are two large families of potassium channels: the voltage-gated channels and the inwardly rectifying channels. 48 The voltage-gated channels include the “A” fast-transient conductances sensitive to 4-aminopyridine, barium, and cobalt and the calcium-activated potassium channels sensitive to cobalt, manganese, and cadmium. 49 Dorsal root ganglion neurons are believed to have one to three types of voltage-gated channels and three or four types of delayed rectifier channels. 50,51 Opening of voltage-gated potassium channels allows outward positive current flow from neurons, such as during repolarization after an action potential. Blockade of these channels initially prolongs generation of action potentials. 52 Continued application, however, prevents repolarization and, therefore, ultimately produces a failure to generate action potentials. 52 
Although intrathecal administration of potassium channel antagonists has not been used to treat pain in either animals or humans, 4-aminopyridine is used for long-term intrathecal treatment of spasticity in multiple sclerosis. 53 One side effect of this treatment, paresthesia, is suggested to be caused by preferential blockade of nonmyelinated fibers, 54,55 which in turn suggests analgesic potential. However, a number of patients have also reported abdominal pain with these treatments that may relate to abnormal discharge patterns in primary afferent fibers. 55 Potassium channel agonists–antagonists are not likely to be used soon for the treatment of pain.
Chloride Channels. 
Three major classes of chloride channels have been identified. 56 The first class identified was the ligand-gated chloride channels, including those of the γ-aminobutyric acid type A (GABAA) and glycine receptors. The ligand-gated chloride channels are common in dorsal root ganglia and dorsal horn neurons. 57 The second class, also probably common at spinal levels, is the voltage-gated chloride channel. 58 The final chloride channel class is activated by cyclic adenosine monophosphate (cAMP) and may include only the cystic fibrosis transmembrane regulator. 59 Activation of chloride currents usually produces inward movement of chloride to cells that hyperpolarize neurons; facilitation of these hyperpolarizing currents underlies the mechanisms of many depressant drugs. An important exception at spinal levels, however, is that GABAAreceptors on primary afferent terminals gate a chloride channel that allows efflux of chloride, 60,61 with a net effect therefore of depolarizing primary afferent terminals.
Chloride channel antagonists, such as bicuculline and strychnine, have not been administered to relieve pain, but instead to produce an experimental pain state characterized by a pronounced opiate refractory allodynia. 62–64 These compounds were also used to exacerbate the anatomic consequences of nerve constriction injury. 65 Nevertheless, chloride channels may have paradoxic effects in some pain conditions. 66 As mentioned previously, C-fiber volleys depolarize primary afferent A fibers by activating outward chloride currents through GABAAreceptor channels. 60,61 This primary afferent depolarization was proposed as a means of limiting painful input to the dorsal horn, consistent with the gate-control theory of pain transmission. 67 However, new evidence suggests that the allodynia produced by intradermal injection of capsaicin is caused by an increased effectiveness of chloride currents evoked by A-fiber “touch”-type afferents on C-fiber nociceptors. 66 If substantiated, chloride channel antagonists may prove to be useful for treatment of chronic pain conditions that have touch-evoked nociceptive components.
Second-messenger Systems. 
Surface receptors affect neuronal activity either by direct gating of an ion channel or by activating biochemical cascades and, therefore, are often classified as either ionotropic or metabotropic, respectively (fig. 4). The transduction of metabotropic receptor activation to biochemical processes involves interactions with a family of so-called G-binding (guanosine triphosphate) proteins. 68–71 G proteins assemble as trimeric complexes composed of α, β, and γ subunits that associate physically to surface receptors. The β and γ subunits are constant in all complexes, whereas one of three differing isoforms of the α subunit confers functional specificity. 68–71 The α subunit is activated after ligand-receptor interaction by the addition of guanosine triphosphate, dissociates from the complex, and interacts with and modulates the function of numerous intracellular targets until the bound guanosine triphosphate is autohydrolyzed. 68–71 The αSsubunit increases conductance at L-type calcium channels, inactivates guanylate cyclase, and activates adenylate cyclase, thereby increasing cellular concentrations of cAMP. 68–70 The αIsubunit, in contrast, inactivates adenylate cyclase, thereby decreasing levels of cAMP; negatively modulates calcium channels; activates outward potassium currents; and activates guanylate cyclase, thereby increasing cellular cyclic guanosine monophosphate (cGMP). Finally, the αq,12subunits activate one of several phospholipase enzymes (e.g.  , phospholipase C, D, or A3), resulting in release of membrane phospholipid metabolites, including arachidonic acid, diacyl-glycerol, and inositol triphosphate.
Fig. 4. Schematic summary of the spinal second-messenger systems involved in pain transmission. The figure is organized in columns and rows. Filled rectangles represent surface drug receptors. Compounds that activate each receptor are listed at the side. G-labeled pentagons represent the G-protein β and γ subunits, whereas the circles labeled “q”, “s,” and “i” represent the three functionally distinct isoforms of the α subunit. Circles with arrows represent enzymes that generate secondary metabolites as a direct consequence of activity of the G-protein subunits. The products of these enzymes are listed in the center of the figure. Rectangles represent the final tier of enzymes activated in the cascade. The “+” indicates activation or positive modulation, whereas the “-” indicates inactivation or inhibition. *Indicates those targets for which antagonists were shown to produce antinociception. AC = adenylate cyclase; CamKII = calcium-calmodulin dependent protein kinase II; cAMP = cyclic adenosine monophosphate; cGMP = cyclic guanosine monophosphate; GC = guanylate cyclase; IP3= inositol triphosphate; NOS = nitric oxide synthase; PKA = protein kinase A; PKC = protein kinase C; PKG = protein kinase G; PL = phospholipase. 
Fig. 4. Schematic summary of the spinal second-messenger systems involved in pain transmission. The figure is organized in columns and rows. Filled rectangles represent surface drug receptors. Compounds that activate each receptor are listed at the side. G-labeled pentagons represent the G-protein β and γ subunits, whereas the circles labeled “q”, “s,” and “i” represent the three functionally distinct isoforms of the α subunit. Circles with arrows represent enzymes that generate secondary metabolites as a direct consequence of activity of the G-protein subunits. The products of these enzymes are listed in the center of the figure. Rectangles represent the final tier of enzymes activated in the cascade. The “+” indicates activation or positive modulation, whereas the “-” indicates inactivation or inhibition. *Indicates those targets for which antagonists were shown to produce antinociception. AC = adenylate cyclase; CamKII = calcium-calmodulin dependent protein kinase II; cAMP = cyclic adenosine monophosphate; cGMP = cyclic guanosine monophosphate; GC = guanylate cyclase; IP3= inositol triphosphate; NOS = nitric oxide synthase; PKA = protein kinase A; PKC = protein kinase C; PKG = protein kinase G; PL = phospholipase. 
Fig. 4. Schematic summary of the spinal second-messenger systems involved in pain transmission. The figure is organized in columns and rows. Filled rectangles represent surface drug receptors. Compounds that activate each receptor are listed at the side. G-labeled pentagons represent the G-protein β and γ subunits, whereas the circles labeled “q”, “s,” and “i” represent the three functionally distinct isoforms of the α subunit. Circles with arrows represent enzymes that generate secondary metabolites as a direct consequence of activity of the G-protein subunits. The products of these enzymes are listed in the center of the figure. Rectangles represent the final tier of enzymes activated in the cascade. The “+” indicates activation or positive modulation, whereas the “-” indicates inactivation or inhibition. *Indicates those targets for which antagonists were shown to produce antinociception. AC = adenylate cyclase; CamKII = calcium-calmodulin dependent protein kinase II; cAMP = cyclic adenosine monophosphate; cGMP = cyclic guanosine monophosphate; GC = guanylate cyclase; IP3= inositol triphosphate; NOS = nitric oxide synthase; PKA = protein kinase A; PKC = protein kinase C; PKG = protein kinase G; PL = phospholipase. 
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The metabolites generated by each of the G proteins, in turn, activate one of three types of protein kinases or increase intracellular calcium. Increases in diacylglycerol or arachidonic acid activate the protein kinase C family of enzymes. 72 There are at least 12 isoforms of protein kinase C, although three (α, β, and γ) subtypes predominate in the spinal cord. 70,72 Protein kinases A and G are those families of enzymes activated by cAMP and cyclic guanosine monophosphate (cGMP), respectively. The functions of protein kinases at the spinal level include regulation of tetrodotoxin-sensitive sodium channels in primary afferent fibers, 28 release of neurotransmitter, 72 and control of excitatory neurotransmitter currents in dorsal horn cells. 73 Intracellular calcium is released from internal stores by binding inositol triphosphate and is stimulated by the action of αSon L-type calcium channels. Increases of intracellular calcium activate the enzymes calmodulin, cam kinase II, and nitric oxide synthase.
The role of second-messenger systems on pain sensitivity has been evaluated in a number of studies. Levels of membrane-bound protein kinase C increase after nerve injury 74 and intraplantar injection of formalin. 75 Spinal infusion of phorbol esters to activate protein kinase C increases the behavioral response to intraplantar formalin 76 and increases the spontaneous and evoked activity of primate spinothalamic tract neurons. 77 In contrast, antagonists for protein kinase C decrease pain behavior after nerve injury, 74 intraplantar formalin, 75,76 intraspinal N  -methyl-D-aspartate (NMDA)78 and intradermal capsaicin. 79 Similarly, inhibition of phospholipase C 76 or phospholipase A 80 (needed for release of cofactors to protein kinase C) reduced hyperalgesia after intraplantar formalin and zymosan, respectively. Antagonists of protein kinases A and G 79 also decreased capsaicin-induced pain. Finally, animals engineered with defects in protein kinase C had less pain after nerve injury, 81 whereas those engineered with defects in protein kinase A had decreased responses to formalin, capsaicin, and hind-paw inflammation. 82 
In summary, many second-messenger systems may ultimately become targets for clinical pain treatment. However, the role of these systems in pain management is indirect through the action of various drugs that interact with surface receptors linked to G proteins. Receptors linked to GS(receptors associated with βγαSsubunits) include the β1-adrenergic, dopaminergic type 1, and adenosine type 2 receptors. Those that activate Gq,12(βγαq,12) include the serotonin 2c, α1-adrenergic; histamine; thromboxane A2; metabotropic glutamate; and muscarinic types 1, 3, and 5 receptors. Finally, GI-(βγαi)–linked receptors include adenosine 1; serotonin 1B; GABAB; muscarinic type 2; and μ-, δ-, and κ-opioid receptors. 68 As reviewed in the after-sections, neurotransmitter receptors linked to GSand Gq,12generally increase pain transmission, whereas GI-linked receptors inhibit pain signaling. 68–70,83 
Blockade or Facilitation of Neurotransmitter Function 
Neurotransmitters are the chemicals that mediate transmission of action potentials at synaptic junctions between neurons. There are four major groups of neurotransmitters in the spinal dorsal horn: excitatory amino acids, inhibitory amino acids, monoamines, and purines. All are relatively small molecular-weight compounds. Their rapid release and reuptake (degradation) yields a corresponding rapid time course in effects, usually measured in the range of milliseconds. Most pharmacologic agents act by either blocking or mimicking neurotransmitter actions.
Excitatory Amino Acids. 
The amino acids glutamate and aspartate are the main excitatory neurotransmitters of somatosensory transmission pathways. Glutamate and aspartate are present in peripheral nerves, dorsal root ganglia and axons, and cells of the dorsal horn. 2,84–87 
There are at least four distinct types of excitatory amino acid receptors named for the selective synthetic agonists that bind to them 88 (fig. 5). The sites that bind NMDA define the NMDA receptors. These have the highest affinity for the natural ligand aspartate and form an ion channel that is permeable to calcium (and sodium and potassium). 88 NMDA receptors are selectively blocked by a number of chemical antagonists, such as CPP. Ketamine and dextromethorphan are also NMDA antagonists; however, both act on nonexcitatory amino acid receptors. 88 Ketamine, for example, binds to ς opioid and serotonin receptors. 88 NMDA receptors are blocked at resting membrane potentials by magnesium. Relief of this blockade requires depolarization of the cell by other synaptic inputs, which means NMDA receptors function as detectors of temporally coincident synaptic events. 89 The combined features of calcium permeability and coincidence detection are thought to be the keys to NMDA-receptor mediation of heterosynaptic (Hebbian) plasticity in neural pathways, such as that underlying hippocampal long-term potentiation and dorsal horn neuron sensitization. 89,90 
Fig. 5. Schematic summary of the spinal excitatory amino acid (glutamate) receptors that participate in pain transmission. Excitatory amino acid receptor antagonists that modulate each receptor are listed, with arrows indicating the site of action. The boldface names and solid lines indicate the two classification schemes for these receptors. The “-” indicates antagonist effect. 
Fig. 5. Schematic summary of the spinal excitatory amino acid (glutamate) receptors that participate in pain transmission. Excitatory amino acid receptor antagonists that modulate each receptor are listed, with arrows indicating the site of action. The boldface names and solid lines indicate the two classification schemes for these receptors. The “-” indicates antagonist effect. 
Fig. 5. Schematic summary of the spinal excitatory amino acid (glutamate) receptors that participate in pain transmission. Excitatory amino acid receptor antagonists that modulate each receptor are listed, with arrows indicating the site of action. The boldface names and solid lines indicate the two classification schemes for these receptors. The “-” indicates antagonist effect. 
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Non-NMDA excitatory amino acid receptors include three distinct sites. The first of these selectively binds AMPA and the second selectively binds kainate. Glutamate has its higheset affinity for AMPA and kainate receptors. 91–93 Most AMPA and kainate receptors form monovalent cationic channels, although subtypes of each have been identified that are also permeable to calcium. 94,95 Although antagonists for these receptors, such as CNQX and DNQX, do not select between the AMPA and kainate binding sites, the receptors have differential sensitivity to antagonists of receptor desensitization. 96,97 Finally, the third non-NMDA site selectively binds ACPD and is blocked by 4C3HPG. The ACPD receptor, in contrast to the NMDA, AMPA, and kainte receptors, is a G-protein–linked complex that initiates inositol phospholipid metabolism when activated. This feature results in a second partitioning of excitatory amino acid receptors into ionotropic (NMDA, AMPA, kainate) and metabotropic (ACPD) subtypes.
All four excitatory amino acid receptors mediate somatosensory transmission in the dorsal horn. Intrathecal injection of NMDA, AMPA, and kainate produced nocifensive biting and scratching behavior, 98 whereas injection of ACPD increased the behavioral responses to intraplantar formalin. 99 Intrathecal injection of NMDA antagonists has little effect on the responses to acute nociceptive stimuli in normal animals but markedly decreases touch and heat hyperalgesia after peripheral inflammation or nerve injury. 100–103 Similar effects have been observed after intrathecal injection of magnesium sulfate. 104 In contrast, intrathecally administered AMPA and kainate receptor antagonists reduce behavioral responses to short-term nociceptive stimuli and after induction of hyperalgesia. 103,105,106 However, AMPA and kainate antagonists, unlike NMDA antagonists, impair motor function at analgesic doses. 103,105,106 Finally, metabotropic receptor antagonists had no effect in a model of postoperative pain 107 but reduced the behavioral responses to intraplantar formalin, 99 and treatment with metabotropic receptor antisense oligonucleotide increased tail-flick latency. 108 
Neurophysiology studies confirm the roles of excitatory amino acids in pain transmission. Ionotropic glutamate receptor agonists increase 109–114 and antagonists decrease the responses of dorsal horn neurons to somatosensory stimuli. 91,93,115–124 Non-NMDA–receptor antagonists decreased the transmission of both noxious and non-noxious information, whereas NMDA-receptor antagonists selectively attenuated responses to sustained noxious stimuli. 92,93 ACPD produced excitation of nociceptive neurons in monkeys and rats and a selective increase in responses to innocuous cutaneous stimuli. 125,126 The majority of synapses activated by primary afferent fibers on arrival to the dorsal horn are mediated by the “fast” ionotropic non-NMDA (AMPA and kainate) receptors. NMDA receptors are recruited with polysynaptic activation of intrinsic dorsal horn neurons and are essential for induction of hypersensitivity of dorsal horn cells after injury. Influx of calcium through the NMDA receptor is the crucial first step in initiation of hypersensitivity. 101 In turn, increased intracellular calcium increases resting membrane potential and membrane resistance and initiates changes in gene expression. Long-term maintenance of hypersensitivity requires coincident activation of neuropeptide receptors involving either GS- or GQ-mediated biochemical cascades. 127 Finally, ACPD receptors appear to affect global sensitivity of multirecetpive dorsal horn neurons to innocuous and noxious stimuli and, therefore, function to control the gain of these neurons to peripheral inputs. 126 
Clinical analgesia trials have been begun with NMDA antagonists. 128–130 Intrathecal ketamine has consistently produced analgesia at dosages of 50 mg and more, although this dosage is also analgesic when given systemically. 131–133 Limitations to intrathecal use of ketamine include its well-described psychotropic effects. 128 Additionally, vacuolar myelopathy has been reported in a patient who received intrathecal ketamine. 129 Although this neurotoxicity might be attributed to preservative in the preparation, 129 similar toxicity was observed in animals administered preservative-free ketamine. 134 Finally, a “pure” NMDA antagonist, CPP, relieved intractable neurogenic pain in a single patient trial, although psychotropic side effects were encountered. 135 In summary, studies in animals suggest that excitatory amino acid receptor antagonists have promise as future analgesics. However, preliminary clinical studies with these compounds indicate limitations.
Inhibitory Amino Acids. 
γ-Aminobutyric acid and glycine are the inhibitory amino acid neurotransmitters of the spinal dorsal horn. 136,137 Three types of GABA receptors and two glycine receptors have been identified, 138–140 although a fourth distinct GABA receptor may be expressed by human dorsal root ganglion neurons 141 (fig. 6). The GABAAreceptor is part of a chloride ionophore complex. 142,143 Selective GABAAagonists include muscimol; selective antagonists include gabazine. Barbiturates and alcohol modulate activity at this receptor by direct facilitation of inward chloride currents. 142,143 Benzodiazepines bind to a unique site on the GABAAreceptor complex that facilitates GABA receptor–agonist binding and, therefore, increases channel open time. 136,138,140 The GABABreceptor is a G-protein–linked complex that, when activated, typically increases outward potassium currents. 144 Baclofen is a selective GABABreceptor agonist and phaclofen is a selective antagonist. It has been suggested that the newly described GABACreceptor is directly associated with a potassium channel ionophore. Cis  -4-aminocrotonic acid is a selective GABACreceptor agonist, but there is no selective antagonist for these receptors.
Fig. 6. Summary of the spinal GABA receptors involved in pain transmission. Agonists and antagonists active at each receptor are listed, with arrows indicating the site of action. The “+” indicates agonist function and the “-” indicates antagonist function. 
Fig. 6. Summary of the spinal GABA receptors involved in pain transmission. Agonists and antagonists active at each receptor are listed, with arrows indicating the site of action. The “+” indicates agonist function and the “-” indicates antagonist function. 
Fig. 6. Summary of the spinal GABA receptors involved in pain transmission. Agonists and antagonists active at each receptor are listed, with arrows indicating the site of action. The “+” indicates agonist function and the “-” indicates antagonist function. 
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Glycine receptors include one subtype linked to a chloride ionophore and sensitive to the antagonist strychnine. The second is a strychnine-insensitive modulatory site on the NMDA-receptor complex antagonized by HA-966. 139,140 
Both GABAAand GABABagonists have analgesic properties after intrathecal administration in a number of pain models in animals. Muscimol and baclofen blocked both the allodynia produced by a long-term nerve constriction injury 145 and the biting and scratching behavior elicited by intrathecal injection of substance P. 146 Similarly, muscimol and baclofen each produced antinociception in phases 1 and 2 of the formalin model 147 and in the electrical current threshold test in rats 148 and monkeys. 149 Midazolam, similar to muscimol and baclofen, produced antinociception in the hot plate, tail-flick and electric current threshold test in rats. 150–154 Of note, the baclofen-induced increase of tail-flick latency and inhibition of hot plate responses were attenuated by pretreatment with pertussis toxin, 155 and the effects of midazolam were additive with that of morphine. 151 Therefore, GABABreceptors and opioid receptors probably access complementary G-protein systems (GI) in the dorsal horn.
GABAAand GABABreceptor antagonists enhance nociceptive behaviors after intrathecal injection in rats. 156 However, a long-term facilitation of the flexor withdrawal reflex was produced by intrathecal injection of the GABAAreceptor antagonist bicuculline but not by a GABABantagonist. 64 These results indicate that GABAAreceptors mediate a tonic inhibition, whereas GABABreceptors mediate a stimulus-driven inhibition of spinal pain-signaling (somatosensory) pathways.
Intrathecal administration of glycine in awake animals decreased responses to noxious heat 157 and inhibited substance P-induced biting and scratching. 146 Similarly, iontophoresis of glycine profoundly inhibited the responses of spinal neurons to all peripheral stimuli, 158,159 probably by a direct membrane hyperpolarization. 158 Strychnine facilitates flexor withdrawal 64 and produces morphine-insensitive allodynia in rats. 62,63 Finally, administration of the strychnine-insensitive glycine receptor antagonist HA-966 predictably results in effects similar to those of NMDA antagonists, including reduction of responses to noxious, but not non-noxious, stimuli. 160 
Although antinociception is well-demonstrated with intrathecal GABA agonists in animal studies, similar analgesic effects in humans have not been produced consistently. Intrathecal injection of the GABAAagonist midazolam was effective in treating chronic mechanical low back and postoperative pain. 161,162 Long-term midazolam treatment also successfully relieved chronic nonmalignant musculoskeletal and neurogenic pain without evidence of toxicity. 163 However, midazolam did not have an independent effect on pain of peripheral arteriopathy or in malignant disease. 163 
Intrathecally administered GABABagonists have also shown mixed results for pain relief. Intrathecal baclofen is approved by the Food and Drug Administration of the United States and is widely used for the relief of spasm in spinal cord injury, cerebral palsy, and multiple sclerosis. 164–171 Baclofen has also been used to relieve central poststroke and musculoskeletal pain 164,172 However, in other studies, baclofen was ineffective for neurogenic pain in patients with spinal cord injury 173 and had no effect on pinch-evoked or musculoskeletal pain. 174 
In summary, the usefulness of intrathecal GABA receptor analgesics in humans remains open to question. Basic science studies have emphasized that GABAAand GABABagonists have analgesic effects that are very modality specific. For example, muscimol, but not baclofen, antagonized the biting and scratching behavior elicited by intrathecal injection of the excitatory amino acid agonists NMDA, quisqualic acid, and kainate. 175 In contrast, baclofen, but not midazolam, attenuated formalin-evoked pain behaviors. 151 Future clinical studies with these compounds may show more consistent effects as the conditions most appropriate for each agonist subtype in humans are clarified.
The effects of intrathecally administered glycine or glycine antagonists, such as HA-966, in humans have not been reported.
Monoamine. 
Norepinephrine. 
Norepinephrine was first detected in fibers of the dorsal lateral spinal funiculus in the late 1960s. 176 Potential analgesic effects were not considered, however, until inhibition of dorsal horn neurons by microstimulation of norepinephrine-containing brain stem nuclei was shown in the late 1970s. 177 The native receptors for norepinephrine include two broad classes, the α- and β-adrenergic receptors, of which there are multiple subtypes (e.g.  , α1a, α1b2a2b1, β2).
α-Adrenergic receptors, in particular α2receptors, have antinociceptive properties in many models of acute pain in rats, cats, and monkeys. 178 This includes an increase in shock titration assay, 149 suppression of the flexion withdrawal reflex, 179 increase in tail-flick and hot plate latencies, 151,155,180–183 and inhibition of responses to colorectal distension 184 and noxious compression of skin. 185,186 α2Agonists also have antinociceptive properties in animal models of prolonged and chronic pain, including the formalin test, 187 experimental neuropathy, 188 spinal cord ischemia, 179 and autotomy. 189 
Epidural clonidine recently was approved for treatment of intractable pain, and intrathecal clinical trials are now being conducted. Intrathecal infusion of clonidine with hydromorphone or other opiates provided relief of intractable cancer pain. 190,191 Intrathecal clonidine was also effective for management of reflex sympathetic dystrophy and postoperative pain, 191,192,193 and prolonged the effects of local anesthetics and potentiated the effectiveness of other agents used in neuraxial delivery. 194 The interactions of clonidine with morphine and other opiates may be a result of combined effects of both agents in reducing calcium currents in presynaptic terminals. Alternatively, the effects of clonidine may be mediated, in part, by local release of acetylcholine. 191 
Alhough intrathecal clonidine has promise as an adjunctive analgesic compound, clinical use has been limited by a number of side effects, most particularly, hypotension and bradycardia. 195,196 Thus, α2-adrenergic compounds need further improvement before they can be used widely.
Dopamine. 
Dopamine is found in axon terminals in the superficial laminae of the dorsal horn. These terminals arise from cells at supraspinal levels that send axons to the spinal cord via  the dorsal lateral spinal funiculus. 197 Intrathecal injection of dopamine and dopamine receptor agonists increased tail-flick latency 198,199 and decreased hot plate and acetic acid writhing. 200 This effect was blocked by a type 2 dopamine but not by a type 1 receptor antagonist. 198,199 Interestingly, the analgesia of spinal apomorphine is reduced by naloxone 201 and dopamine-2 receptor agonists facilitated the motor effects of morphine, 202 suggesting reciprocal interactions between spinal opioid and dopamine receptor systems.
Patients with dysfunction of endogenous dopamine systems, such as Parkinson's disease, often have an accompanying pain syndrome. 203 However, no studies have evaluated the possible analgesic effects of dopamine in these or other patients.
Serotonin. 
Increases in serotonin, or 5-hydroxy-tryptamine, in the spinal dorsal horn after microstimulation of brain stem pain inhibitory nuclei suggest antinociceptive activity for this monoamine. 177,180,204 Serotonin is present in terminals in the dorsal horn, primarily in laminae I and II, the intermediolateral cell column, and the ventral horn. Serotonin colocalizes with several peptides, including enkephalin, somatostatin, calcitonin gene-related peptide, substance P, and the neurotransmitter GABA. There are at least three serotonin receptor classes in the dorsal horn termed 1, 2, and 3, each of which has multiple subtypes. 205 The effect of these receptors in control of pain remains unclear. Intrathecal serotonin produced antinociception in tail-flick, hot plate, paw pressure, intraplantar formalin, and shock titration experiments in mice and rats. 180,206–209 Yet, in other studies, serotonin facilitated input to dorsal horn cells from primary afferent C fibers and facilitated paw pressure and tail-flick responses. 205,209,210 Intrathecal studies with more selective serotonin receptor agonists have not clarified these discrepancies. For example, one group reported serotonin-1a receptor agonists inhibit hot plate responses, 211 whereas others reported a facilitation of tail flick. 210,212 Intrathecal-1b receptor agonists were analgesic in tail-flick and colorectal distension tests 210,212–214 but without effects on hot plate reponses. 211 Similarly, serotonin type 2 receptors enhanced nociceptive responses in some studies 215,216 and reduced responses in others 213,214 Intrathecal type 3 agonists were also pro-217 and antinociceptive. 208 Thus, serotonin modulates pain transmission; however the receptor mechanisms that govern these effects are poorly defined. Possible confounding factors in previous studies are that serotonin differentially regulates nociceptive stimuli of varying modality, 209 the distribution of serotonin receptor subtypes varies between spinal regions, 215 and the drugs available have been inadequately selective. Further study with more selective pharmacologic tools will be needed to resolve these issues before initiation of clinical studies.
Acetylcholine. 
Another potentially analgesic member of the monoamine family is acetylcholine. Cholinergic terminals are abundant in the dorsal horn, arising from brain stem raphe nuclei, 218 the nucleus ambiguous, the dorsal motor nucleus of the vagus, 177 and local dorsal horn neurons. 219 Spinal cholinergic receptors include nicotinic and muscarinic 1 and 2 subtypes. 220 Although intrathecal injections of acetylcholine had no effect on nociceptive responses of animals, injection of synthetic cholinergic agonists were antinociceptive in a number of behavioral paradigms. For example, carbachol and oxotremorine produced antinociception in tail-flick, hot plate, and acetic acid writhing tests. 183 These effects were additive to that of morphine, 151,221,222 were prevented by atropine and pirenzepine 223 but not by d  -tubocurarine, and were not reproduced with nicotine. 222 These results suggest that spinal muscarinic-1 and -2 receptors are antinociceptive but nicotinic receptors are not. This conclusion, however, may be premature based on recent studies with a novel nicotinic cholinergic agonist that had an excellent antinociceptive profile after systemic administration. 224 
Intrathecal injection of acetylcholinesterase inhibitors also produced analgesia in animal studies. 225 Although the analgesic effects of the cholinesterase inhibitors were transient, the effects were synergistic to those of clonidine and morphine, resulting in a profound and long-lasting analgesia. Side effects described as “abnormal behavior” were observed in these studies that were reduced with clonidine. 225 
Clinical studies of acetylcholinesterase inhibitors have begun. 226 Intrathecal administration of neostigmine produced antinociception to a cold stimulus in normal human volunteers 226,227 and relieved visceral and somatic postsurgical pain. 228,229 However, side effects included nausea, emesis, reversible lower extremity paresis, 226–230 tachycardia, hypertension, sedation, and anxiety. 226,227 Application of cholinesterase inhibitors with opiates did not increase the incidence of nausea or emesis, although postsurgical analgesia was produced at lower doses of each drug than when either was given alone. 231 In summary, cholinesterase inhibitors have promise as novel independent analgesics and as adjuvants to established analgesics such as morphine. However, a solution to the side effects of nausea and emesis may be needed before widespread use of these compounds.
Tricyclic Antidepressants. 
Tricyclic antidepressants have long been known to modulate pain transmission. This effect is believed to be a result of inhibition of reuptake and consequent increases in norepinephrine and serotonin. However, there is uncertainty regarding the mechanism of analgesia of tricyclics. For example, in vitro  studies have shown that tricyclics bind to the NMDA-receptor complex, 232,233 suggesting that the hyperalgesia and allodynia treated by tricyclics is caused by NMDA-receptor inhibition, rather than by increases in levels of serotonin or norepinephrine. Intrathecal injection of desiprimine or amitriptyline decreased NMDA-induced pain behaviors in a dose-dependent fashion. 234,235 These effects were unaffected by coadministration of phentolamine or methysergide, suggesting that monoamines were not involved. 235 Clinical application of intrathecal tricyclic antidepressants is not possible because preservative-free preparations are not available, toxicology has not been assessed, and motor weakness developed at high doses in rat experiments. 235 In that tricyclics are synergistic with opiates 236 and potently decrease inflammatory hyperalgesia, 235 further attention should be devoted to this potentially effective mode of pain control.
Purines. 
Evidence has accumulated during the past several years that adenosine and adenosine triphosphate are somatosensory neurotransmitters. 237 There are at least three types of adenosine receptors, termed 1–3, each with differing effects on target cells (fig. 7). Adenosine 1 receptors link to the GI-protein subunit and therefore inhibit target cells by decreasing cAMP 238,239 and facilitating currents at adenosine triphosphate–sensitive potassium channels. 240 In contrast, adenosine 2 receptors link to the Gs-protein subunit and therefore excite target cells by increasing the activity of adenyl cyclase. 238 Type 3 adenosine receptors are not present in the dorsal horn, but rather are expressed in dermal mast cells. 237 Activation of adenosine 3 receptors provokes pain as a result of mast cell degranulation and the release of serotonin and histamine. 241 
Fig. 7. Schematic summary of the spinal adenosine receptors involved in pain transmission. Subtype-selective agonists–antagonists have not yet been studied and therefore are not listed. 
Fig. 7. Schematic summary of the spinal adenosine receptors involved in pain transmission. Subtype-selective agonists–antagonists have not yet been studied and therefore are not listed. 
Fig. 7. Schematic summary of the spinal adenosine receptors involved in pain transmission. Subtype-selective agonists–antagonists have not yet been studied and therefore are not listed. 
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Adenosine produces pain when administered peripherally but produces analgesia when administered spinally. 237 For example, intrathecal adenosine produced antinociception in the rat tail-flick test. This effect was enhanced by supplemental calcium. 242 The mixed type1–type 2 receptor agonist 5′-N  -ethylcarboxamide adenosine produced analgesia in rats that was enhanced by clonidine. 243 Adenosine produced antinociception in the hot plate test in mice. 180 Intrathecal administration of type 1 receptor agonists decreased the discharges of deep dorsal horn cells to C-fiber volleys. 244 The antinociception produced by adenosine was inhibited by methylxanthines, confirming that adenylate cyclase is involved in these effects. Many reports cite a role for adenosine in morphine-produced antinociception that may be a result of a shared action on adenylate cyclase. 244–248 Adenosine and opiate-like substances may also mediate norepinephrine-produced antinociception. 246 
Four studies have addressed the role of adenosine in pain transmission in humans. Intravenous and subcutaneous administration of adenosine caused pain in healthy subjects, 237 but intravenous adenosine relieved neuropathic pain in one study. 249 Adenosine decreased spontaneous and touch-evoked pain in healthy volunteers after application of mustard oil 250 and relieved neuropathic allodynia. 251 No significant complications or side effects were reported, although one volunteer experienced transient lumbar pain with drug injection. 251,252 Further study with intrathecal adenosine and adenosine-receptor selective agonists should be of interest.
Blockade or Facilitation of Neuromodulator Receptors 
Neuromodulators are substances that adapt the action of neurotransmitters to varying biologic conditions. 49,253 Similar to transmitters, modulators are released at synapses and act on specific membrane receptor sites. Unlike transmitters, the time course of neuromodulator effects is long, with effects measured in seconds to minutes. The sites of action for neuromodulators are not necessarily confined to a single synapse. Modulators often spread from their site of release and through tissue after high-intensity stimulation to affect synapses at a distance. 254 The majority of neuromodulators are relatively large-molecular-weight peptides.
Opioid Receptors. 
The natural opioids include the peptides β-endorphin, leuenkephalin, and met-enkephalin and dynorphin derived from the proopiomelanocortin, proenkephalin,  and prodynorphin  genes, respectively. 255 The opioid peptides are found in axon terminals and cell bodies throughout the spinal dorsal horn, although mostly in the superficial laminae. 177 The nerve terminals containing opioid peptides arise from dorsal root ganglia, cells intrinsic to the dorsal horn, and cells of various brain stem nuclei that descend via  the dorsal lateral funiculus.
Opioid agonists exert their effects at μ, δ, and κ receptors. All three consist of seven transmembrane spanning G-protein–coupled complexes. 256,257 Dorsal horn opioid receptors are located presynaptically on capsaicin-sensitive small-diameter primary afferent nerve endings 258–260 and postsynaptically on dendrites and somata of intrinsic neurons. 177 Inhibition of transmitter release from primary afferent nerve terminals by suppression of voltage-gated calcium currents is one widely recognized mechanism for opioid-induced analgesia. 256,257 A second is direct inhibition of dorsal horn neurons by inhibition of adenyl cyclase and activation of outward potassium currents. 177,261 Synthetic opioid receptor–selective agonists include the nonpeptide compounds morphine (μ-agonist) and trans-3,4-dichloro-N  -methyl-N  -[2-(1-pyrrolidinyl)- cyclohexyl] benzeneacetamide (U50488, κ-agonist) and peptide analogs such as D-Pen2-D-Pen5-enkephalin (δ-agonist).
A number of studies in animals have established the analgesic effects of intrathecal morphine to short-term noxious stimuli. For example, intrathecal morphine increases shock-titration threshold in monkeys, 149 suppresses the responses of rats to colorectal distension, 262 decreases hyperalgesia in a model of postoperative pain, 263 and increases tail-flick and hot plate latencies in rat. 155 Intrathecal morphine also decreases the discharge of deep dorsal horn cells to C-fiber volleys. 244,264 These effects of morphine are mimicked by the natural μ-agonist β-endorphin. 265–267 Pertussis toxin blocks the effects of morphine and β-endorphin, confirming the role of G proteins in transduction after receptor activation. 155 
Intrathecal morphine also has analgesic effects in prolonged models of nociception, such as experimental arthritis 268 and intraplantar formalin. 269 However, intrathecal morphine is less effective in animal models of chronic neuropathic pain. For example, morphine had no effect on the onset of thermal hyperalgesia in sciatic experimental peripheral neuropathy. 270 Relief of neuropathic pain in rats has been observed only when morphine is coadministered with other compounds. 271 
Although intrathecal δ- and κ-opioid receptor agonists decreased the response to short-term noxious thermal stimuli, 264 these usually produce antinociception only in specific models of acute pain in animals. For example, δ-agonists produced marked analgesia in the colorectal distension and intraplantar formalin models, 272,262 whereas κ-agonists had only marginal effects. 262 Conversely, κ-agonists markedly reduced arthritis-induced pressure pain, whereas δ-agonists were ineffective. 268 Toxicity has not been reported after intrathecal enkephalin, but the κ-agonist dynorphin produced hindlimb paralysis in some studies. 273,274 A long-lasting tactile allodynia has also been reported after intrathecal dynorphin. 275 Interestingly, NMDA-receptor antagonists prevented dynorphin-induced paralysis and allodynia. This suggests not only that dynorphin may be neurotoxic when administered in the intrathecal space, but also that there are important functional interactions between dynorphin and the excitatory amino acids that contribute to this toxicity.
Intraspinal delivery of opioids for pain management in humans is relatively new; nevertheless, morphine is the gold standard for intrathecal analgesics. 276 Epidural and intrathecal opiates usually produce excellent analgesia, 277,278 and infusion pumps have been developed to provide continuous delivery of spinal opioids in patients with chronic pain. Intrathecal morphine has fewer side effects than do systemic opioids. 279–286 Only minor neurohistopathologic changes, including focal foreign body giant cells and small aggregates of lymphocytes and reactive microglia near the catheter site, have been observed after long-term infusion of morphine to cancer patients. 287 Nevertheless, complications are common, most notably, pruritis, respiratory depression, somnolence, and gastrointestinal and urinary dysfunction. 279–285,288 Additionally, development of tolerance often necessitates continued escalation of dose until the capacity of current infusion pumps is exceeded. Furthermore, some authors reported that continuous morphine infusion is ineffective for long-term management of chronic pain from nonmalignant causes 289 and that accumulation of morphine metabolites provokes development of a paradoxic hyperalgesia, allodynia and myoclonus. 290 
Other opioids have also been tested as intrathecal analgesics. Lipophilic agents, such as fentanyl, dilaudid, and sufentanil, that diffuse poorly in cerebrospinal fluid may have a role in well-localized pain syndromes when delivered by catheters to spinal levels corresponding to the affected areas. δ-Opioid and κ-opioid receptor agonists may be useful in pain syndromes that are little affected by μ-agonists such as morphine. Intrathecal β-endorphin produced postsurgical analgesia 291 and relief of intractable pain caused by disseminated cancer. 292,293 Intrathecal dynorphin produced analgesia for cancer pain patients without obvious toxicity. 294 Therefore, future studies with opioids will probably focus on improving effectiveness for neuropathic-related pains, perhaps with a focus on the usefulness of δ- and κ-agonists in these conditions, and to limit unwanted effects, such as tolerance.
Neurokinin Receptors. 
The neurokinin peptides include substance P and neurokinins A and B. 295–297 Substance P and neurokinin A are involved in transmission and modulation of nociceptive inputs, whereas a role for neurokinin B is poorly defined. Neurokinin peptides are located in primary afferents, dorsal roots, and cells and axon terminals in the spinal cord. The majority of neurokinin-containing terminals are from primary afferent fibers, whereas the remainders are from axons descending from various brain stem nuclei. 2 
There are at least three neurokinin receptors (1, 2, and 3) expressed in the dorsal horn 295 and on dorsal root ganglion neurons. 298 Although each peptide binds to all three receptors, substance P binds preferentially to the neurokinin-1 receptor, whereas neurokinin A and neurokinin B prefer type 2 and type 3 receptors, respectively. Neurokinin-1, and perhaps neurokinin-2, receptors are important in transmission of short-term nociceptive stimuli and induction of hypersensitivity after peripheral injury. 127,299–303 The transduction mechanisms of neurokinin-1 and -2 receptors involve metabolism of phosphatidyl inositol and increases of intracellular calcium levels. 2 
Evidence for substance P as a transmitter for nociceptive afferents was initially based on its excitation of nociceptive neurons in the dorsal horn of experimental animals in the late 1970s. 304,305 Subsequently, intrathecal administration of substance P was shown to produce a “caudally directed biting and scratching syndrome,” presumed to reflect nocifensive behavior. 306–308 Smaller intrathecal doses of substance P reduced thresholds to noxious heat stimuli. 306–308 The tachykinin peptides produce small but prolonged depolarizations of many dorsal horn neurons in vitro  309–311 and excite many nociceptive dorsal horn cells in vivo.  304,305,312–316 Tachykinin receptor antagonists decrease nociceptive responses in behavioral paradigms 317–321 and the responses of dorsal horn neurons to noxious stimuli. 301,315,322,323 Finally, animals with bioengineered disruptions of the tachykinin-1  gene, the source of substance P and neurokinin A, have increased baseline nociceptive thresholds and decreased responses to formalin and capsaicin, 324,325 whereas animals with bioengineered alterations of the neurokinin-1 receptor showed decreased ‘wind-up’. 326 Interestingly, animals given intrathecal injections of neurokinin-1 receptor antisense oligonucleotide did not show a decrease in receptor level or change in behavioral responses to formalin until also treated with intrathecal substance P. 327 
Human studies with intrathecal neurokinin receptor antagonists have not been reported, possibly because of the potential toxicity and rapid degradation of the peptide analog antagonists that were available. Newer nonpeptide antagonists have alleviated these previous concerns, and clinical trials for relief of depression 328 and postoperative pain have begun for orally active antagonists. 329 Intrathecal studies should follow soon.
Calcitonin Gene-related Peptide Receptors. 
Calcitonin gene-related peptide is found in many small dorsal root ganglion cells, in thinly myelinated (A-δ) and unmyelinated (C) axons, in axons of Lissauer's tract, and in terminals of these primary afferents in spinal laminae I, II, and V. 330 Although two types of calcitonin gene-related peptide, α and β, are present in dorsal root ganglion cells and as many as four types of G-protein–coupled receptors are present in the dorsal horn, the function of this neuropeptide is unknown. 330,331 The coexistence of calcitonin gene-related peptide and substance P within spinal cord terminals 332,333 and dorsal root ganglion neurons 334 suggests a functional relation between the two. The levels of calcitonin gene-related peptide in the dorsal horn change in parallel with those of substance P after acute knee joint inflammation 335 and after injury to peripheral nerve. 336 Noxious thermal, mechanical, and chemical stimuli provoke the corelease of calcitonin gene-related peptide with substance P in the substantia gelatinosa. 332,337,338 However, intrathecal administration of calcitonin gene-related peptide has mixed effects in models of nociception. Calcitonin gene-related peptide had no effect on nociceptive reflexes in one series of studies 333,339 but facilitated tail-flick reflex in another series. 340 Similarly, calcitonin gene-related peptide antagonized the effects of substance P in one series 341 but enhanced the effects of substance P by preventing degradation or increasing peptide release in others. 333,342 The effects of intrathecal injection of calcitonin gene-related peptide 8–37, a receptor antagonist, have been clearer. This compound produced a dose-dependent increase in paw-withdrawal latency of normal rats to paw pressure and radiant heat. 339 Additionally, calcitonin gene-related peptide 8–37reversed hyperalgesia produced by thermal 343 and nerve injury. 344 These effects were suggested to be a result of antagonism at endogenous opioid receptors. 344,345 In summary, the role of calcitonin gene-related peptide in dorsal horn somatosensory processing necessitates further definition before its usefulness for treatment of human pain can be evaluated.
Somatostatin Receptors. 
Terenius 346 first suggested an antinociceptive role for somatostatin in the spinal cord. Somatostatin is detected in primary afferent axons terminating in the dorsal horn, spinal interneurons, and terminals of axons from descending pathways. 347 There are at least five distinct somatostatin receptors, designated by numbers 1–5, encoded by separate genes. 348 This may be an underestimate, however, because subtypes of the somatostatin-2 receptor (A and B) have been identified. All receptors identified to date are G-protein coupled and widely expressed throughout the central nervous system. 348 Somatostatin is specifically increased in the dorsal horn after noxious thermal but not after noxious mechanical stimulation. 349,350 Similarly, intrathecal injection of somatostatin, or somatostatin analogs, produced analgesia to thermal but not mechanical stimuli. 351–357 Evidence of neurotoxicity, including gait disturbance, paralysis, pyknotic dorsal horn neurons, and posterior column demyelination, are common after intrathecal somatostatin in cats and rats. 358–360 
Despite the neurotoxicity observed in animals, two clinical trials with intrathecal somatostatin have been conducted in cancer patients 361,362 In the first study, six of eight patients had good-to-excellent pain relief, although tachyphylaxis or short-term tolerance after a short period of infusion necessitated increased dosing. Postmortem observations revealed histopathologic changes in two of eight patients. 361 Although these changes were attributed to progression of disease, a direct neurotoxic effect of somatostatin cannot be discounted because of the animal data. 358 Another similar study used octreotide, a synthetic analogue of somatostatin, because of its longer half-life and lack of associated neurodegenerative effects. 362 Two patients with nonmalignant pain were treated successfully with continuous intrathecal infusion of octreotide for 5 yr, although additional opioids were necessary. When blinded to the drug, each patient preferred octreotide to placebo. 362 Thus, although a number of factors limit the use of somatostatin, derivatives of this peptide may ultimately have clinical usefulness.
Other Neuromodulators. 
A large number of neuropeptides and neuropeptide receptors have been identified in the dorsal horn of animals and humans for which a clear role in nociceptive processing has yet to be established. Neuropeptide Y, for example, is colocalized in GABA-containing cells of the dorsal horn. 363 The peptide and its receptors concentrate in the superficial layers of the dorsal horn, where afferent information is modulated, 364 and neuropeptide Y decreases transmitter release from primary afferent fibers. 365 Galanin and its binding sites also concentrate in the superficial layers of the dorsal horn. 366 Galanin antagonizes many effects of substance P and calcitonin gene-related peptide. 341,367 The levels of neuropeptide Y and galanin substantially increase after peripheral nerve injury. 368 
Other neuropeptides and neuropeptide receptors found in the dorsal horn include angiotensin II, 369,370 bombesin, 371 corticotropin releasing hormone, 370 vasopressin, oxytocin, 372 vasoactive intestinal polypeptide, 373 and cholecystokinin. Of this group, bombesin produces a caudally directed biting and scratching behavior similar to that of substance P after intrathecal injection 374; vasoactive intestinal polypeptide is directly excitatory to dorsal horn neurons 375; and cholecystokinin may act as a natural opiate-receptor antagonist.
In summary, there are many peptides in the dorsal horn for which function is poorly defined. However, it appears that several of these limit the signaling of nociceptive information, whereas others promote this signaling. Eventually, agonists for some, such as neuropeptide Y and galanin, and antagonists for others, such as bombesin and vasoactive intestinal polypeptide, may prove useful for the clinical treatment of pain.
Modulation of Trans-synaptic Signal Molecules. 
The trans-synaptic signal molecules are the newest class of substances to be identified. Similar to neuromodulators, these substances have relatively slow onset and a prolonged duration of effect. In addition, these substances often have effects that are remote from their site of release. The trans-synaptic molecules differ from neuromodulators, however, in that they do not necessarily have either a discrete neuronal locus for release or a specific neuronal target site of action, but rather may also have non-neuronal (glial) sites of release and effect. 376–379 Members of this family include the prostaglandins, leukotrienes, nitric oxide, and carbon monoxide.
Prostaglandins and Leukotrienes. 
Prostaglandins and leukotrienes are synthesized from arachidonic acid by the fatty acid cyclooxygenase and lipoxygenase pathways. 380 Prostaglandins and leukotrienes both have important roles in the sensitization of peripheral primary afferent fibers 381–383 and the generation of primary hyperalgesia. 384 It is the prostaglandins, however, that play the more important role in dorsal horn (central) mechanisms of pain transmission. 385 Influx of calcium to neurons and glia through NMDA and voltage-gated ion channels activated by nociceptive inputs activates phospholipase A2and releases arachidonic acid. 379,386,387 Arachidonic acid is then metabolized in the central nervous system by the enzyme cyclooxygenase type 2 and in peripheral tissues by cyclooxygenase type 1 to form prostaglandins. 378,385 Effects of prostaglandins on pain transmission are mediated by increases in neuronal levels of calcium and cAMP, 386 thereby increasing excitability and the release of excitatory neurotransmitters and neuromodulators. 388,389 
Effectiveness of intraspinal cyclooxygenase inhibitors has been evaluated in two animal models of sustained pain. 390–392 Intrathecal ketorolac, aspirin, and indomethacin had limited effects on the short-term phase reaction to formalin, but markedly attenuated the delayed second phase. 390,392 Interestingly, ketorolac produced a synergistic antinociceptive effect with morphine and an α2-adrenergic agonist, suggesting complementary but unshared cellular mechanisms between these receptor systems. 390 Ketorolac probably decreases activation of GSby prostaglandins, whereas the opioids and α2-adrenergic agonists activate GI, resulting in inhibition of spinal adenylate cyclase. 386 Finally, intrathecal administration of a cyclooxygenase type 2 antagonist decreased thermal hyperalgesia after paw inflammation. 391 In summary, intrathecal cyclooxygenase inhibitors are effective in reducing moderate levels of pain but not completely effective against more severe pain. This reduced effectiveness compared with analgesics, such as morphine, may reflect the observation that not all prostaglandins provoke pain, but rather some prostaglandins appear to limit pain. 393 Future directions in prostanoid research will probably focus on the design of antagonists that selectively reduce synthesis of pain-provoking prostanoids, such as the prostaglandin E2, while sparing formation of pain-limiting prostanoids, such as prostaglandin F2. 393,394 
Nitric Oxide and Carbon Monoxide. 
Nitric oxide and carbon monoxide have recently been recognized as novel neurotransmitter substances. 71,395–397 Nitric oxide is synthesized from L-arginine by activation of the enzyme nitric oxide synthase. Nitric oxide synthase is activated by increases in intracellular calcium after opening of NMDA receptors and neurokinin-1 receptor-mediated release of inositol triphosphate. 398 Free nitric oxide diffuses to nearby and distant cells, penetrates the cell membranes, and increases the function of guanylate cyclase and protein kinase G, thereby influencing gene regulation. 395,396 Although less studied, carbon monoxide appears to function identically to nitric oxide in many neural systems. 397 
The role of nitric oxide in nociceptive transmission has been tested in several animal studies. Levels of nitric oxide synthase increase in the dorsal root ganglion and dorsal horn of rats with paw inflammation and neuropathic pain. 399,400 Nitric oxide is involved in the development of wind-up and several models of hyperalgesia. 78,399,401–403 Intrathecal administration of arginine analogs, which inhibit nitric oxide synthesis as false substrates, produced a dose-dependent reduction in hyperalgesia as a result of intraplantar formalin and nerve injury. 401–403 Recently, a possible role of carbon monoxide in nociceptive transmission was evaluated. Intrathecal zinc protoporphyrin IX, which binds and neutralizes carbon monoxide, produced a blockade of spinal nociceptive transmission. 404 Thus, both substances may have future roles in the management of pain. However, no clinical trials have assessed the analgesic or potential neurotoxic effects 395,397 of nitric oxide or carbon monoxide inhibitors.
Future Methods of Drug Delivery 
Many of the compounds reviewed herein may have more widespread clinical use in the near future. Further on the treatment horizon will be the introduction of novel drug delivery strategies. For example, analgesics encapsulated in liposomes for prolongation of pharmacologic effects will become available. Two compounds, tetracaine and meperidine, produce prolonged analgesia in the mouse after liposome encapsulation. 405,406 Initial attempts have been made to develop slowly degradable polymers that contain local anesthetics or opioids to provide prolonged, sustained release of analgesics. 407 For example, epidurally implanted biodegradable polymers that contain local anesthetics yielded an 8- to 10-fold increase in duration of neural blockade. 408 Similarly, a hydromorphone-containing polymer delivered a constant amount of drug over 30–90 days both in vitro  and in animal models, without an early drug spike. 409 Although these preparations have not been studied extensively with intrathecal administration, the implications are obvious.
Still further on the horizon looms the possibility of long-term pain relief using intrathecal cell implantation. Antinociceptive effects were produced in rats by intrathecal transplantation of catecholamine-producing B16 melanoma cells. 410 Analgesia has also been produced by intrathecal transplantation of adrenal medullary chromaffin cells that secrete opioid peptides and catecholamines. 411 
Conclusion 
We are entering an exciting era in the therapy of chronic pain conditions as basic science provides many new intrathecal compounds and drug delivery systems to meet the needs of clinical practice. The only compound approved by the Food and Drug Administration for long-term intrathecal treatment of pain is morphine. All other compounds that we discussed are experimental, and issues regarding long-term toxicity and drug interactions are not resolved. Nevertheless, it is likely that many new compounds and treatment approaches will ultimately have a clinical niche and, as a consequence, alter and improve the treatment of chronic pain.
References 
References 
Staats PS, Mitchell VD: Future directions for intrathecal therapies. Prog Anesthesiol 1997; 19: 367–82
Rustioni A, Weinberg RJ: Somatosensory system, Handbook of Chemical Neuroanatomy, Integrated Systems of the CNS, Part II. Edited by Bjorklund A, Hokfelt T, Swanson LW. Amsterdam, Elsevier Science Publishers, 1989, pp 219–321
Paice JA, Renn RD, Shott SD: Intraspinal morphine for chronic pain: A retrospective multicenter study. J Pain Symptom Manag 1996; 11: 71–80
Rush AM, Brau ME, Elliott AA, Elliott JR: Electrophysiological properties of sodium current subtypes in small cells from adult rat dorsal root ganglia. J Physiol 1998; 511: 771–89
Safronov BV, Wolff M, Vogel W: Functional distribution of three types of Na+ channel on soma and processes of dorsal horn neurones of rat spinal cord. J Physiol 1997; 503: 371–85
Young ER, MacKenzie TA: The pharmacology of local anesthetics—A review of the literature. J Can Dent Assoc 1992; 58: 34–42
Feldman HS, Covino BG: A chronic model for investigation of experimental spinal anesthesia in the dog. A NESTHESIOLOGY 1981; 54: 148–52
Maves TJ, Gebhart GF: Antinociceptive synergy between intrathecal morphine and lidocaine during visceral and somatic nociception in the rat. A NESTHESIOLOGY 1992; 76: 91–9
Chaplan SR, Bach FW, Shafer SL, Yaksh TL: Prolonged alleviation of tactile allodynia by intravenous lidocaine in neuropathic rats. A NESTHESIOLOGY 1995; 83: 775–85
Luo L, Wiesenfeld-Hallin Z: Effects of intrathecal local anesthetics on spinal excitability and on the development of autotomy. Pain 1995; 63: 173–9
Ossipov MH, Suarez LJ, Spaulding TC: A comparison of the antinociceptive and behavioral effects of intrathecally administered opiates, alpha-2-adrenergic agonists, and local anesthetics in mice and rats. Anesth Analg 1988; 67: 616–24
Yashpal K, Katz J, Coderre TJ: Effects of preemptive or postinjury intrathecal local anesthesia on persistent nociceptive responses in rats. Confounding influences of peripheral inflammation and the general anesthetic regimen. A NESTHESIOLOGY 1996; 84: 1119–25
Dahm P, Nitescu P, Appelgren L, Curelaru I: Efficacy and technical complications of long-term continuous intraspinal infusions of opioid and/or bupivacaine in refractory nonmalignant pain: A comparison between the epidural and the intrathecal approach with externalized or implanted catheters and infusion pumps. Clin J Pain 1998; 14: 4–16
Lubenow TR, Faber LP, McCarthy RJ, Hopkins EM, Warren WH, Ivankovich AD: Postthoracotomy pain management using continuous epidural analgesia in 1,324 patients. Ann Thoracic Surg 1994; 58: 924–30
Shafer AL, Donnelly AJ: Management of postoperative pain by continuous epidural infusion of analgesics. Clin Pharmacol 1991; 10: 745–64
Rapp SE, Ready LB, Greer BE: Postoperative pain management in gynecology onocology patients utilizing epidural opiate analgesia and patient-controlled analgesia. Gynecol Onocol 1989; 35: 341–4
Hardy PAJ, Wells JCD: Continuous intrathecal lignocaine infusion analgesia: A case report of a nine-week trial. Palliat Med 1989; 3: 23–5
Berde CB, Sethna NF, Conrad LS, Hershenson MB, Shillito J: Subarachnoid bupivacaine analgesia for seven months for a patient with a spinal cord tumor. A NESTHESIOLOGY 1990; 72: 1094–6
Sjoberg M, Appelgren L, Einarsson S, Hultman E, Linder LE, Nitescu P, Curelaru I: Long-term intrathecal morphine and bupivacaine in refractory cancer pain: I. Results from the first series of 52 patients. Acta Anaesth Scand 1991; 35: 30–43
Appelgren L, Janson M, Nitescu P, Curelaru I: Continuous intracisternal and high cervical intrathecal bupivicaine analgesia in refractory head and neck pain. A NESTHESIOLOGY 1996; 84: 256–72
Krames ES, Lanning RM: Intrathecal infusional analgesia for nonmalignant pain: Analgesic efficacy of intrathecal opioid with or without bupivacaine. J Pain Symptom Manag 1993; 8: 539–48
Kowal A, Staats PS: Intractable Pain: A new technique for attack in patients with an implanted intrathecal infusion pump. Regional Anesthesia 1997; 22: 584
Arbuckle JB, Docherty RJ: Expression of tetrodotoxin-resistant sodium channel in capsaicin-sensitive dorsal root ganglion neurons of adult rats. Neurosci Lett 1995; 185: 70–3
Akopian AJ, Silvilati L, Wood JN: A tetrodotoxin-resistant voltage gated channel expressed by sensory neurons. Nature 1996; 379:
Dib-Hajj SD, Tyrrell L, Black JA, Waxman SG: NaN, a novel voltage-gated Na channel, is expressed preferentially in peripheral sensory neurons and down-regulated after axotomy. Proc Natl Acad Sci U S A 1998; 95: 8963–8
Sangameswaran L, Fish LM, Koch BD, Rabert DK, Delgado SG, Ilnicka M, Jakeman LB, Novakovic S, Wong K, Sze P, Tzoumaka E, Stewart GR, Herman RC, Chan H, Eglen RM, Hunter JC: A novel tetrodotoxin-sensitive, voltage-gated sodium channel expressed in rat and human dorsal root ganglia. J Biol Chem 1998; 272: 14805–9
Souslova VA, Fox M, Wood JN, Akopian AN: Cloning and characterization of a mouse sensory neuron tetrodotoxin-resistant voltage-gated sodium channel gene, SCN10a. Genomics 1997; 41: 201–9
Gold MS, Levine JD, Correa AM: Modulation of TTX-RINa by PKC and PKA and their role in PGE2-induced sensitization of rat sensory neurons in vitro. J Neurosci 1998; 18: 10345–55
Gold MS, Reichling DB, Shuster MJ, Levine JD: Hyperalgesic agents increase a tetrodotoxin-resistant Na+ current in nociceptors. Proc Natl Acad Sci U S A 1996; 93: 1108–12
Tanaka M, Cummins TR, Ishikawa K, Dib-Hajj SD, Black JA, Waxman SG: SNS Na+ channel expression increases in dorsal root ganglion neurons in the carrageenan inflammatory pain model. Neuroreport 1998; 9: 967–72
Okuse K, Chaplan SR, McMahon SB, Luo ZD, Calcutt NA, Scott BP, Akopian AN, Wood JN: Regulation of expression of the sensory neuron-specific sodium channel SNS in inflammatory and neuropathic pain. Mol Cell Neurosci 1997; 10: 196–207
Oaklander AL, Belzberg AJ: Unilateral nerve injury down-regulates mRNA for Na+ channel SCN10A bilaterally in rat dorsal root ganglia. Brain Res Mol Brain Res 1997; 52: 162–5
Novakovic SD, Tzoumaka E, McGivern JG, Haraguchi M, Sangameswaran L, Gogas KR, Eglen RM, Hunter JC: Distribution of the tetrodotoxin-resistant sodium channel PN3 in rat sensory neurons in normal and neuropathic conditions. J Neurosci 1998; 18: 2174–87
Trezise DJ, John VH, Xie XM: Voltage- and use-dependent inhibition of Na+ channels in rat sensory neurones by 4030W92, a new antihyperalgesic agent. Br J Pharmacol 1998; 124: 953–63
Rush AM, Elliott JR: Phenytoin and carbamazepine: Differential inhibition of sodium currents in small cells from adult rat dorsal root ganaglia. Neurosci Lett 1997; 226: 95–8
Lynch C, Pancrazio JJ: Snails, spiders, and stereospecificity — Is there a role for calcium channels in anesthetic mechanisms? A NESTHESIOLOGY 1994; 81: 1–5
Bowersox SS, Gadbois T, Singh T, Pettus M, Wang YX, Luther RR. Selective N-type neuronal voltage-sensitive calcium channel blocker, SNX-111, produces spinal antinocicepion in rat models of acute, persistent and neuropathic pain. J Pharmacol Exp Ther 1996; 279: 1243–9
Omote K, Kawamata M, Satoh O, Iwasaki H, Namiki A. Spinal antinociceptive action of an N-type voltage-dependent calcium channel blocker and the synergistic interaction with morphine. A NESTHESIOLOGY 1996; 84: 636–43
Todorovic SM, Lingle CJ: Pharmacological properties of T-type Ca2+ current in adult rat sensory neurons: Effects of anticonvulsant and anesthetic agents. J Neurophysiol 1998; 79: 240–52
Omote K, Sonoda H: Potentiation of antinociceptive effects of morphine by calcium-channel blockers at the level of the spinal cord. A NESTHESIOLOGY 1993; 79: 746–52
Hara K, Saito Y, Kirihara Y, Sakura S, Kosaka Y: Antinociceptive effects of intrathecal L-type calcium channel blockers on visceral and somatic stimuli in the rat. Anesth Analg 1998; 87: 382–7
Sluka KA: Blockade of calcium channels can prevent the onset of secondary hyperalgesia and allodynia induced by intradermal injection of capsaicin in rats. Pain 1997; 71: 157–64
Malmberg AB, Yaksh TL: Voltage-sensitive calcium channels in spinal nociceptive processing: Blockade of N- and P-type channels inhibits formalin-induced nociception. J Neurosci 1994; 14: 4882–90
Sluka KA: Blockade of N- and P/Q-type calcium channels reduces the secondary heat hyperalgesia induced by acute inflammation. J Pharmacol Exp Ther 1998; 287: 232–7
Nebe J, Vanegas H, Neugebauer V, Schaible HG: Omega-agatoxin IVA, a P-type calcium channel antagonist, reduces nociceptive processing in spinal cord neurons with input from the inflamed but not the normal knee joint—an electrophysiological study in the rat in vivo. Eur J Neurosci 1997; 9: 2193–201
Choe H, Kim JS, Ko SH, Kim DC, Han YJ, Song HS: Epidural verapamil reduces analgesic consumption after lower abdominal surgery. Anesth Analg 1998; 86: 786–90
Brose WG, Cherukuri S, Longton WC, Gaeta RR, Presley R: Safety and efficacy of intrathecal SNX-111, a novel analgesic, in the management of intractable neuropathic and nociceptive pain in humans: Preliminary results. Am Pain Soc Abstracts 1995; A–116
Jan LY, Jan YN: Structural elements involved in specific K+ channel functions. Ann Rev Physiol 1992; 54: 537–5
Cooper JR, Bloom FE, Roth RH: The biochemical basis of neuropharmacology. New York, Oxford University Press, 1991.
Safronov BV, Bischoff U, Vogel W: Single voltage-gated K+ channels and their functions in small dorsal root ganglion neurones of rat. J Physiol 1996; 493: 408
Gold MS, Shuster MJ, Levine JD: Characterization of six voltage-gated K+ currents in adult rat sensory neurons. J Neurophysiol 1996; 75: 2629–46
Shi R, Blight AR: Differential effects of low and high concentrations of 4-aminopyridine on axonal conduction in normal and injured spinal cord. Neuroscience 1997; 77: 553–62
Schwid SR, Petrie MD, McDermott MP, Tierney DS, Mason DH, Goodman AD: Quantitative assessment of sustained-release 4-aminopyridine for symptomatic treatment of multiple sclerosis. Neurology 1997; 48: 817–21
Bowe CM, Kocsis JD, Targ EF, Waxman SG: Physiological effects of 4-aminopyridine on demyelinated mammalian motor and sensory fibers. Ann Neurol 1987; 22: 264–8
Lees G: The effects of anticonvulsants on 4-aminopyridine-induced bursting: In vitro studies on rat peripheral nerve and dorsal roots. Br J Pharmacol 1996; 117: 573–9
Jentsch TJ, Gunther W: Chloride channels: An emerging molecular picture. BioEssays 1997; 19: 117–26
Grenningloh G, Rienitz A, Schmitt B, Methfessel C, Zensen M, Beyreuther K, Gundelfinger ED, Betz H: The strychinine-binding subunit of the glycine receptor shows homology with nicotinic acetylcholine receptors. Nature 1987; 328: 215–20
Jentsch TJ, Günther W, Püsch M, Schwappach B: Properties of voltage-gated chloride channels of the CLC gene family. J Physiol 1995; 482: 19S–25S
Riordan JR, Rommens JM, Kerem B-S, Alon N, Rozmahel R, Grzelczak Z, Zielenski J, Lok S, Plavsic N, Chou J-L, Drumm ML, Iannuzzi C, Collins FS, Tsui LC: Identification of the cyctic fibrosis gene: Cloning and characterization of complementary DNA. Science 1989; 245: 1066–73
Schmidt RF, Senges J, Zimmermann M: Presynaptic depolarization of cutaneous mechanoreceptor afferents after mechanical skin stimulation. Exp Brain Res 1967; 3: 234–47
Eccles JC, Schmidt RF, Willis WD: The location and the mode of action of the presynaptic inhibitory pathways on to group I afferent fibers from muscle. J Neurophysiol 1963; 26: 506–22
Yaksh TL: Behavioral and autonomic correlates of the tactile evoked allodynia produced by spinal glycine inhibition: effects of modulatory receptor systems and excitatory amino acid antagonists. Pain 1989; 37: 111–23
Sherman SE, Loomis CW: Morphine insensitive allodynia is produced by intrathecal strychnine in the lightly anesthetized rat. Pain 1994; 56: 17–29
Sivilotti L, Woolf CJ: The contribution of GABAA and glycine receptors to central sensitization: Disinhibition and touch-evoked allodynia in the spinal cord. J Neurophysiol 1994; 72: 169–79
Sugimoto T, Bennett GJ, Kajander KC: Transsynaptic degeneration in the superficial dorsal horn after sciatic nerve injury: Effects of a chronic constriction injury, transection, and strychnine. Pain 1990; 42: 205–13
Cervero F, Laird JMA: Mechanisms of touch-evoked pain (allodynia): A new model. Pain 1996; 68: 13–23
Melzack R, Wall PD: Pain mechanisms: A new theory. Science 1965; 150: 971–9
Linden J, Auchampach JA, Jin X, Figler RA: The structure and function of A1 and A2B adenosine receptors. Life Sci 1998; 62: 1519–24
Manji HK, Potter WZ, Lenox RH: Signal transduction pathways. Molecular targets for lithium's actions. Arch Gen Psychiat 1995; 52: 531–43
Pacheco MA, Jope RS: Phosphoinositide signaling in human brain. Prog Neurobiol 1996; 50: 255–73
Vincent SR: Nitric oxide: A radical neurotransmitter in the central nervous system. Prog Neurobiol 1994; 42: 129–60
Majewski H, Kotsonis P, Iannazzo L, Murphy TV, Musgrave IF: Protein kinase C and transmitter release. Clin Exp Pharmacol Physiol 1997; 24: 619–23
Berthele A, Schadrack J, Zieglgänsberger W: Involvement of glutamatergic neurotransmission and protein kinase C in spinal plasticity and the development of chronic pain. Prog Brain Res 1996; 110: 193–206
Mayer DJ, Mao J, Price DD: The association of neuropathic pain, morphine tolerance and dependence, and the translocation of protein kinase C. NIDA Research Monograph 1995; 147: 269–98
Yashpal K, Pitcher GM, Parent A, Quirion R, Coderre TJ: Noxious thermal and chemical stimulation induce increases in 3H-phorbol 12,13-dibutyrate binding in spinal cord dorsal horn as well as persistent pain and hyperalgesia, which is reduced by inhibition of protein kinase C. J Neurosci 1995; 15: 3263–72
Coderre TJ: Contribution of protein kinase C to central sensitization and persistent pain following tissue injury. Neurosci Lett 1998; 140: 181–4
Palecek J, Paleckova V, Dougherty PM, Willis WD: The effect of phorbol esters on the responses of primate spinothalamic neurons to mechanical and thermal stimuli. J Neurophysiol 1994; 71: 529–37
Meller ST, Dykstra C, Gebhart GF: Acute thermal hyperalgesia in the rat is produced by activation of N-methyl-D-aspartate receptors and protein kinase C and production of nitric oxide. Neuroscience 1996; 71: 327–35
Sluka KA, Willis WD: The effects of G-protein and protein kinase inhibitors on the behavioral responses of rats to intradermal injection of capsaicin. Pain 1997; 71: 165–78
Meller ST: Thermal and mechanical hyperalgesia. A distinct role for different excitatory amino acid receptors and signal transduction pathways? Am Pain Soc J 1998; 3: 215–31
Malmberg AB, Chen C, Tonegawa S, Basbaum AI: Preserved acute pain and reduced neuropathic pain in mice lacking PKC gamma. Science 1997; 278: 279–83
Malmberg AB, Brandon EP, Idzera RL, Liu H, McKnight GS, Basbaum AI: Diminished inflammation and nociceptive pain with preservation of neuropathic pain in mice with a targeted mutation of the type I regulatory subunit of cAMP-dependent protein kinase. J Neurosci 1997; 17: 7462–70
Duggan AW, Griersmith BT: Methyl xanthines, adenosine 3′,5′-cyclic monophosphate and the spinal transmission of nociceptive information. Br J Pharmacol 1979; 67: 51–7
Graham LT Jr, Shank RP, Werman R, Aprison MH: Distribution of some synaptic transmitter suspects in cat spinal cord: Glutamic acid, aspartic acid, gamma-aminobutyric acid, glycine and glutamine. J Neurochem 1967; 14: 465–72
Westlund KN, McNeill DL, Coggeshall RE: Glutamate immunoreactivity in rat dorsal root axons. Neurosci Lett 1989; 96: 13–7
Westlund KN, McNeil DL, Patterson JT, Coggeshall RE: Aspartate immunoreactive axons in normal rat L4 dorsal roots. Brain Res 1989; 489: 347–51
Carlton SM, LaMotte CC, Honda CN, Surmeier DJ, Delanerolle N, Willis WD: Ultrastructural analysis of terminals contacting functionally identified primate spinothalamic tract neurons. J Comp Neurol 1989; 281: 555–66
Monaghan DT, Bridges RJ, Cotman CW: The excitatory amino acid receptors: Their classes, pharmacology, and distinct properties in the function of the central nervous system. Ann Rev Pharmacol Toxicol 1989; 29: 365–402
Mayer ML, Westbrook GL: The physiology of excitatory amino acids in the vertebrate central nervous system. Prog Neurobiol 1987; 28: 197–276
Cotman CW, Monaghan DT: Excitatory amino acid neurotransmission: NMDA receptors and Hebb-type synaptic plasticity. Ann Rev Neurosci 1988; 11: 61–80
Davies J, Watkins JC: Actions of D and L forms of 2-amino-5-phosphonovalerate and 2- amino-4-phosphonobutyrate in the cat spinal cord. Brain Res 1982; 235: 378–86
Davies J: A reappraisal of the role of NMDA and non-NMDA receptors in neurotransmission in the cat dorsal horn, Frontiers in Excitatory Amino Acid Research. Edited by Cavalhiero EA, Lehman J, Turski L. New York, Alan R. Liss, 1988, pp 355–62
Dougherty PM, Palecek J, Paleckova V, Sorkin LS, Willis WD: The role of NMDA and non-NMDA excitatory amino acid receptors in the excitation of primate spinothalamic tract neurons by mechanical, thermal, chemical, and electrical stimuli. J Neurosci 1992; 12: 3025–41
Hollmann M, Hartley M, Heinemann S: Ca++ permeability of KA-AMPA-gated glutamate receptor channels depends on subunit composition. Science 1991; 252: 851–3
Pellegrini-Giampietro DE, Gorter JA, Bennett MVL, Zukin RS: The GluR2 (GluR-B) hypothesis: Ca2+-permeable AMPA receptors in neurological disorders. Trends Neurosci 1997; 20: 464–70
Partin KM, Patneau DK, Winters CA, Mayer ML, Buonanno A: Selective modulation of desensitization at AMPA versus kainate receptors by cyclothiazide and concanavalin A. Neuron 1993; 11: 1069–82
Dougherty PM, Mittman S, Lenz FA: Facilitation of responses to AMPA but not kainate by cyclothiazide in primate somatosensory thalamus. Neurosci Lett 1998; 245: 1–4
Aanonsen LM, Wilcox GL: Nociceptive action of excitatory amino acids in the mouse: Effects of spinally administered opioids, phencyclidine and sigma agonists. J Pharmacol Exp Therap 1987; 243: 9–19
Fisher K, Coderre TJ: The contribution of metabotropic receptors (mGluRs) to formalin-induced nociception. Pain 1996; 68: 255–63
Chapman V, Dickenson AH: The combination of NMDA antagonists and morphine produces profound antinociception in the rat dorsal horn. Brain Res 1992; 573: 321–3
Ma QP, Woolf CJ: Noxious stimuli induce an N-methyl-D-aspartate receptor dependent hypersensitivity of the flexion withdrawal reflex to touch: Implications for the treatment of mechanical allodynia. Pain 1995; 61: 383–90
Yamamoto T, Yaksh TL: Spinal pharmacology of thermal hyperesthesia induced by constriction injury of sciatic nerve. Excitatory amino acids. Pain 1992; 51: 121–8
Lufty K, Cai SX, Woodward RM, Weber E: Antinociceptive effects of NMDA and non-NMDA receptor antagonists in the tail flick test in mice. Pain 1997; 70: 31–40
Chanimov M, Cohen ML, Grinspun Y, Herbert M, Reif R, Kaufman I, Bahar M: Neurotoxicity after spinal anaesthesia induced by serial intrathecal injections of magnesium sulphate. An experimental study in a rat model. Anaesthesia 1997; 52: 223–8
Nishiyama T, Yaksh TL, Weber E: Effects of intrathecal NMDA and non-NMDA antagonists on acute thermal nociception and their interaction with morphine. A NESTHESIOLOGY 1998; 89: 715–22
Zahn PK, Umali E, Brennan TJ: Intrathecal non-NMDA excitatory amino acid receptor antagonists inhibit pain behaviors in a rat model of postoperative pain. Pain 1998; 74: 213–23
Zahn PK, Brennan TJ: Intrathecal metabotropic glutamate receptor antagonists do not decrease mechanical hyperalgesia in a rat model of postoperative pain. Anesth Analg 1998; 87: 1354–9
Young MR, Blackburn-Munro G, Dickinson T, Johnson MJ, Anderson H, Nakalembe I, Fleetwood-Walker SM: Antisense ablation of type I metabotropic glutamate receptor mGluR1 inhibits spinal nocicpetive transmission. J Neurosci 1998; 18: 10180–8
Aanonsen LM, Lei S, Wilcox GL: Excitatory amino acid receptors and nociceptive neurotransmission in rat spinal cord. Pain 1990; 41: 309–21
Curtis DR, Hosli L, Johnston GAR, Johnston IH: The hyperpolarization of spinal motoneurones by glycine and related amino acids. Exp Brain Res 1968; 5: 235–58
Willcockson WS, Chung JM, Hori Y, Lee KH, Willis WD: Effects of iontophoretically released amino acids and amines on primate spinothalamic tract cells. J Neurosci 1984; 4: 732–40
Schneider SP, Perl ER: Selective excitation of neurons in the mammalian spinal dorsal horn by aspartate and glutamate in vitro: Correlation with location and excitatory input. Brain Res 1985; 360: 339–43
King AE, Thompson SWN, Urban L, Woolf CJ: An intracellular analysis of amino acid induced excitations of deep dorsal horn neurones in the rat spinal cord slice. Neurosci Lett 1988; 89: 286–92
Dougherty PM, Willis WD: Modification of the responses of spinothalamic tract neurons to mechanical stimulation by excitatory amino acids and an antagonist. Brain Res 1991; 542: 15–22
Dougherty PM, Sluka KA, Sorkin LS, Westlund KN, Willis WD: Neural changes in acute arthritis in monkeys: I. Parallel enhancement of spinothalamic tract neurons to mechanical stimulation and excitatory amino acids. Brain Res Rev 1992; 17: 1–13
Dougherty PM, Willis WD: Enhanced responses of spinothalamic tract neurons to excitatory amino acids accompany the generation of capsaicin-induced hyperalgesia in the monkey. J Neurosci 1992; 12: 883–94
Salt TE, Hill RG: Pharmacological differentiation between responses of rat medullary dorsal horn neurons to noxious mechanical and noxious thermal cutaneous stimuli. Brain Res 1983; 263: 167–71
Schouenborg J, Sjolund BH: First-order nociceptive synapses in rat dorsal horn are blocked by an amino acid antagonist. Brain Res 1986; 379: 394–8
Davies SN, Lodge D: Evidence for involvement of N-methylaspartate receptors in ‘wind- up’ of class 2 neurones in the dorsal horn of the rat. Brain Res 1987; 424: 402–6
Childs AM, Evans RH, Watkins JC: The pharmacological selectivity of three NMDA antagonists. Eur J Pharmacol 1988; 145: 81–6
Dickenson AH, Sullivan AF: Differential effects of excitatory amino acid antagonists on dorsal horn nociceptive neurones in the rat. Brain Res 1990; 506: 31–9
Gerber G, Randic M: Excitatory amino acid-mediated components of synaptically evoked input from dorsal roots to deep dorsal horn neurons in the rat spinal cord slice. Neurosci Lett 1989; 106: 211–9
Haley JE, Sullivan AF, Dickenson AH: Evidence for spinal N-methyl-D-aspartate receptor involvement in prolonged chemical nociception in the rat. Brain Res 1990; 518: 218–26
Headley PM, Parsons CG, West DC: The role of N-methylaspartate receptors in mediating responses of rat and cat spinal neurones to defined sensory stimuli. J Physiol 1987; 385: 169–88
Young MR, Fleetwood-Walker SM, Dickinson T, Blackburn-Munro G, Sparrow H, Birch PJ, Bountra C: Behavioural and electrophysiological evidence supporting a role for group I metabotropic glutamate receptors in the mediation of nociceptive inputs to the rat spinal cord. Brain Res 1997; 777: 161–9
Palecek J, Paleckova V, Dougherty PM, Willis WD: The effect of trans-ACPD, a metabotropic excitatory amino acid receptor agonist, on the responses of primate spinothalamic tract neurons. Pain 1994; 56: 261–9
Dougherty PM, Mittman S, Sorkin LS: Hyperalgesia and amino acids. Receptor selectivity based on stimulus intensity and a role for peptides. Am Pain Soc J 1994; 3: 240–8
Reich DL, Silvay G: Ketamine: an update on the first twenty-five years of clinical experience. Can J Anaesth 1989; 36: 186–97
Karpinski N, Dunn J, Hansen L, Masliah E: Subpial vacuolar myelopathy after intrathecal ketamine: A report of a case. Pain 1997; 73: 103–5
Hawksworth C, Serpell M: Intrathecal anesthesia with ketamine. Reg Anesth Pain Med 1998; 23: 283–8
Eide PK, Stubhaug A, Oye I, Breivik H: Continuous subcutaneous administration of the N-methyl-D-aspartic acid (NMDA) receptor antagonist ketamine in the treatment of post-herpetic neuralgia. Pain 1995; 61: 221–8
Nikolajsen L, Hansen CL, Nielsen J, Keller J, Arendt-Nielsen L, Jensen TS: The effect of ketamine on phantom pain: A central neuropathic disorder maintained by peripheral input. Pain 1996; 67: 69–77
Andersen OK, Felsby S, Nicolaisen L, Bjerring P, Jensen TS, Arendt-Nielsen L: The effect of ketamine on stimulation of primary and secondary hyperalgesic areas induced by capsaicin - a double-blind, placebo-controlled, human experimental study. Pain 1996; 66: 51–62
Ahuja BR: Analgesic effect of intrathecal ketamine in rats. Br J Anaesth 1983; 55: 991–5
Kristensen JD, Svensson B, Gordh T Jr: The NMDA-receptor antagonist CPP abolishes neurogenic ‘wind-up pain’ after intrathecal administration in humans. Pain 1992; 51: 249–53
Aprison MH, Shank RP, Davidoff RA: A comparison of the concentration of glycine, a transmitter suspect, in different areas of the brain and spinal cord in seven different vertebrates. Comp Biochem Physiol 1969; 28: 1345–55
Rizzoli AA: Distribution of glutamic acid, aspartic acid, gamma-aminobutyric acid and glycine in six areas of cat spinal cord before and after transection. Brain Res 1968; 11: 11–18
Bowery N: GABAb receptors and their significance in mammalian pharmacology. Trends Pharmacol Sci 1989; 10: 401–6
Akagi H, Miledi R: Heterogeneity of glycine receptors and their messenger RNAs in rat brain and spinal cord. Science 1988; 242: 270–3
Monaghan DT, Olverman HJ, Nguyen L, Watkins JC, Cotman CW: Two classes of N-methyl-D-aspartate recognition sites: Differential distribution and differential regulation by glycine. Proc Natl Acad Sci U S A 1988; 85: 9836–40
Valeyev AY, Hackman JC, Wood PM, Davidoff RA: Pharmacologically novel GABA receptor in human dorsal root ganglion neurons. J Neurophysiol 1996; 76: 3555–8
Johnston GAR: GABA-A receptor pharmacology. Pharmacol Ther 1996; 69: 173–98
Rabow LE, Russek SJ, Farb DH: From ion currents to genomic analysis: Recent advances in GABAA receptor research. Synapse 1995; 21: 189–274
Bowery NG: GABA-B receptor pharmacology. Ann Rev Pharmacol Toxicol 1993; 33: 109–47
Hwang JH, Yaksh TL: The effect of spinal GABA receptor agonists on tactile allodynia in a surgically-induced neuropathic pain model in the rat. Pain 1997; 70: 15–22
Beyer C, Banas C, Gonzalez-Flores O, Komisaruk BR: Blockage of substance P-induced scratching behavior in rats by the intrathecal administration of inhibitory amino acid agonists. Pharmacol Biochem Behav 1989; 34: 491–5
Dirig DM, Yaksh TL: Intrathecal baclofen and muscimol, but not midazolam, are antinociceptive using the rat-formalin model. J Pharmacol Exp Ther 1995; 275: 219–27
Nadeson R, Guo Z, Porter V, Gent JP, Goodchild CS: Gamma-aminobutyric acid A receptors and spinally mediated antinociception in rats. J Pharmacol Exp Ther 1996; 278: 620–6
Yaksh TL, Reddy SV: Studies in the primate on the analgetic effects associated with intrathecal actions of opiates, alpha-adrenergic agonists and baclofen. A NESTHESIOLOGY 1981; 54: 451–67
Edwards M, Serrao JM, Gent JP, Goodchild CS: On the mechanism by which midazolam causes spinally mediated analgesia. A NESTHESIOLOGY 1990; 73: 273–7
Plummer JL, Cmielewski PL, Gourlay GK, Owen H, Cousins MJ: Antinociceptive and motor effects of intrathecal morphine combined with intrathecal clonidine, noradrenaline, carbachol or midazolam in rats. Pain 1992; 49: 145–52
Aran S, Hammond DL: Antagonism of baclofen-induced antinociception by intrathecal administration of phaclofen or 2-hydroxy-saclofen, but not delta-aminovaleric acid in the rat. J Pharmacol Exp Ther 1991; 257: 360–8
Hammond DL, Moy ML: Actions of 4-amino-3-(5-methoxybenz(b)furan-2-yl) butanoic acid and 4-amino-3-benzo(b)furan-2-yl butanoic acid in the rat spinal cord. Eur J Pharmacol 1992; 229: 227–34
Wilson PR, Yaksh TL: Baclofen is antinociceptive in the spinal intrathecal space of animals. Eur J Pharmacol 1978; 51: 323–30
Hoehn K, Reid A, Sawynok J: Pertussis toxin inhibits antinociception produced by intrathecal injection of morphine, noradrenaline and baclofen. Eur J Pharmacol 1988; 146: 65–72
Satoh O, Omote K: Roles of monoaminergic, glycinergic and GABAergic inhibitory systems in the spinal cord in rats with peripheral mononeuropathy. Brain Res 1996; 728: 27–36
Simpson RK Jr, Gondo M, Robertson CS, Goodman JC: Reduction in thermal hyperalgesia by intrathecal administration of glycine and related compounds. Neurochem Res 1997; 22: 75–9
Curtis DR, Hosli L, Johnston GAR, Johnston IH: Glycine and spinal inhibition. Brain Res 1967; 5: 112–4
Werman R, Davidoff RA, Aprison MH: Inhibitory action of glycine on spinal neurons in the cat. J Neurophysiol 1968; 31: 81–95
Lufty K, Woodward RM, Keana JF, Weber E: Inhibition of clonic seizure-like excitatory effects induced by intrathecal morphine using two NMDA receptor antagonists: MK-801 and ACEA-1011. Eur J Pharmacol 1994; 252: 261–6
Serrao JM, Marks RL, Morley SJ, Goodchild CS: Intrathecal midazolam for the treatment of chronic mechanical low back pain: A controlled comparison with epidural steroid in a pilot study. Pain 1992; 48: 5–12
Valentine JM, Lyons G, Bellamy MC: The effect of intrathecal midazolam on post-operative pain. Eur J Anesthesiol 1996; 13: 589–93
Borg PA, Krijnen HJ: Long-term intrathecal administration of midazolam and clonidine. Clin J Pain 1996; 12: 63–8
Albright AL, Ceervi A, Singletary J: Intrathecal baclofen for spasticity in cerebral palsy. JAMA 1991; 265: 1418–22
Albright AL, Barron WB, Fasick MP, Polinko P, Janosky J: Continuous intrathecal baclofen infusion for spasticity of cerebral origin. JAMA 1993; 270: 2475–7
Penn RD, Savoy SM, Corcos DM, Latash M, Gottlieb G, Parke B, Kroin JS: Intrathecal baclofen for severe spinal spasticity. New England J Med 1989; 320: 1517–21
Penn RD: Intrathecal baclofen for spasticity of spinal origin: Seven years of experience. J Neurosurg 1992; 6: 115–8
Stewart-Wynne EG, Silbert PL, Buffery S, Perlman D, Tan E: Intrathecal baclofen for severe spasticity: Five years experience. Clin Exp Neurol 1991; 28: 244–55
Parke B, Penn RD, Savoy SM, Corcos DM: Functional outcome after delivery of intrathecal baclofen. Arch Phys Med Rehab 1989; 70: 30–2
Broseta J, Garcia-March G, Sanchez-Ledesma MJ, Anaya J, Silva I: Chronic intrathecal baclofen administration in severe spasticty. Stereotact Funct Neurosurg 1990; 54/55: 147–53
Armstrong RW, Steinbok P, Farrell K: Continuous intrathecal baclofen tratement of severe spasms in two children with spinal cord injury. Dev Med Child Neurol 1992; 34: 731–8
Amano K, Kawamura H, Tanikawa T, Kawabatake H, Notani M, Iseki H, Shiwaku T, Nago T, Iwata Y, Taira T, Umezawa Y, Simizu T, Kitamura K: Long-term follow-up study of rostral mesencephalic reticulotomy for pain relief- report of 34 cases. Appl Neurophysiol 1986; 49: 105–11
Loubser PG, Akman NM: Effects of intrathecal baclofen on chronic spinal cord injury pain. J Pain Symptom Manag 1996; 12: 241–7
Herman RM, D'Luzansky SC, Ippolito R: Intrathecal baclofen suppresses central pain in patients with spinal lesions. A pilot study. Clin J Pain 1992; 8: 338–45
Aanonsen LM, Wilcox GL: Muscimol, gamma-aminobutyric acid-A receptors and excitatory amino acids in the mouse spinal cord. J Pharmacol Exp Therap 1989; 248: 1034–8
Dahlstrom A, Fuxe K: Evidence for the existence of monoamine neurons in the central nervous system: II. Experimentally induced changes in the intra- neuronal amine levels of bulbospinal neuron systems. Acta Physiol Scand 1965; 64: 1–36
Willis WD, Coggeshall RE: Sensory Mechanisms of the Spinal Cord. New York, Plenum Press, 1991
Yaksh TL, Noueihed R: The physiology and pharmacology of spinal opiates. Ann Rev Pharmacol Toxicol 1985; 25: 433–62
Hao J-X, Yu W, Xu XJ, Wiesenfeld-Hallin Z: Effects of intrathecal vs. systemic clonidine in treateing chronic allodynia-like response in spinally injured rats. Brain Res 1996; 736: 28–34
DeLander GE, Hopkins CJ: Interdependence of spinal adenosinergic, serotonergic and noradrenergic systems mediating antinociception. Neuropharmacology 1987; 26: 1791–4
Monroe PJ, Smith DL, Kirk HR, Smith DJ: Spinal noradrenergic imidazoline receptors do not mediate the antinociceptive action of intrathecal clonidine in the rat. J Pharmacol Exp Ther 1995; 273: 1057–62
Aran S, Proudfit HK: Antinociceptive interactions between intrathecally administered alpha noradrenergic agonists and 5′-N-ethylcarboxamide adenosine. Brain Res 1990; 519: 287–93
Gordh T Jr, Jansson I, Hartvig P, Gillberg PG, Post C: Interactions between noradrenergic and cholinergic mechanisms involved in spinal nociceptive processing. Acta Anaesth Scand 1989; 33: 39–47
Danzebrink RM, Gebhart GF: Antinociceptive effects of intrathecal adrenoceptor agonists in a rat model of visceral nociception. J Pharmacol Exp Ther 1990; 253: 698–705
Murata K, Nakagawa I, Kumeta Y, Kitahata LM, Collins JG: Intrathecal clonidine suppresses noxiously evoked activity of spinal wide dynamic range neurons in cats. Anesth Analg 1989; 69: 185–191
Sullivan AF, Dashwood MR, Dickenson AH: Alpha 2-adrenoceptor modulation of nociception in rat spinal cord: Location, effects and interactions with morphine. Eur J Pharmacol 1987; 138: 169–77
Kanui TI, Tjolsen A, Lund A, Mjellem-Joly N, Hole K: Antinociceptive effects of intrathecal administration of alpha-adrenergic antagonists and clonidine in the formalin test in the mouse. Neuropharmacology 1993; 32: 367–71
Yaksh TL, Pogrel JW, Lee YW, Chaplan SR: Reversal of nerve ligation-induced allodynia by spinal alpha-2 adrenoceptor agonists. J Pharmacol Exp Ther 1995; 272: 207–14
Puke MJ, Xu XJ, Wiesenfeld-Hallin Z: Intrathecal administration of clonidine suppresses autotomy, a behavioral sign of chronic pain in rats after sciatic nerve section. Neurosci Lett 1991; 133: 199–202
Coombs DW, Saunders RL, Fratkin JD, Jensen LE, Murphy CA: Continuous intrathecal hydromorphone and clonidine for intractable cancer pain. J Neurosurg 1986; 64: 890–4
Eisenach JC, DuPen S, Dubois M, Miguel R, Allin D: Epidural clonidine analgesia for intractable cancer pain. Pain 1995; 61: 391–9
Rauck RL, Eisenach JC, Jackson K, Young LD, Southern J: Epidural clonidine treatment for refractory reflex sympathetic dystrophy. A NESTHESIOLOGY 1993; 79: 1163–9
Grace D, Bunting H, Milligan KR, Fee JPH: Post-operative analgesia after co-administration of clonidine and morphine by the intrathecal route in a patient undergoing hip replacement. Anesth Analg 1995; 80: 86–91
Lee YW, Yaksh TL: Analysis of drug interaction between intrathecal clonidine and MK801 in peripheral neuropathic pain rat model. A NESTHESIOLOGY 1995; 82: 741–8
Klimscha W, Chiari A, Krafft P, Plattner O, Taslimi R, Mayer N, Weinstabl C, Schneider B, Zimpfer M: Hemodynamic and analgesic effects of clonidine added repetitively to continuous epidural and spinal blocks. Anesth Analg 1995; 80: 322–7
Filos KS, Goudas LC, Patroni O, Palyzou V: Hemodynamic and analgesic profile after intrathecal clonidine in humans. A NESTHESIOLOGY 1994; 81: 591–601
Jensen TS, Schroder HD, Smith DF: The role of spinal pathways in dopamine mediated alteration in the tail-flick reflex in rats. Neuropharmacology 1984; 23: 149–53
Liu QS, Qiao JT, Dafny N: D2 dopamine receptor involvement in spinal dopamine-produced antinociception. Life Sci 1992; 51: 1485–92
Barasi S, Duggal KN: The effect of local and systemic application of dopaminergic agents on tail flick latency in the rat. Eur J Pharmacol 1985; 117: 287–94
Jensen TS, Yaksh TL: Effects of an intrathecal dopamine agonist, apomorphine, on thermal and chemical evoked noxious responses in rats. Brain Res 1984; 296: 285–93
Kang YM, Hu WM, Qiao JT: Endogenous opioids and ATP-sensitive potassium channels are involved in the mediation of apomorphine-induced antinociception at the spinal level: A behavioral study in rats. Brain Res Bull 1998; 46: 225–8
Hasegawa Y, Kurachi M, Otomo S: Dopamine D2 receptors and spinal cord excitation in mice. Eur J Pharmacol 1990; 184: 207–12
Stein WM, Read S: Chronic pain in the setting of Parkinson's disease and depression. J Pain Symptom Manag 1997; 14: 255–8
Basbaum A: Anatomical substrates for the descending control of nociception, Brain Stem Control of Spinal Mechanisms. Edited by Sjolund B, Bjorklund A. Amsterdam, Elsevier Biomedical Press, 1982, pp 119–33
Fozard JR: 5-HT: The enigma variations. Trends Pharmacol Sci 1987; 8: 501–6
Minor BG, Post C, Archer T: Blockade of intrathecal 5-hydroxytryptamine-induced antinociception in rats by noradrenaline depletion. Neurosci Lett 1985; 54: 39–44
Richardson BP, Engel G, Donatsch P, Stadler PA: Identification of serotonin M-receptor subtypes and their specific blockade by a new class of drugs. Nature 1985; 316: 126–31
Bardin L, Jourdan D, Alloui A, Lavarenne J, Eschalier A: Differential influence of two serotonin 5-HT3 receptor antagonists on spinal serotonin-induced analgesia in rats. Brain Res 1997; 765: 267–72
Bardin L, Bardin M, Lavarenne J, Eschalier A: Effect of intrathecal serotonin on nociception in rats: Influence of the pain test used. Exp Brain Res 1997; 113: 81–7
Ali Z, Wu G, Kozlov A, Barasi S: The actions of 5-HT1 agonists and antagonists on nociceptive processing in the rat spinal cord: Results from behavioural and electrophysiological studies. Brain Res 1994; 661: 83–90
Mjellem N, Lund A, Eide PK, Storkson R, Tjolsen A: The role of 5-HT1A and 5-HT1B receptors in spinal nociceptive transmission and in the modulation of NMDA induced behavior. Neuroreport 1992; 3: 1061-4
Alhaider AA, Wilcox GL: Differential roles of 5-hydroxytryptamine 1A and 5-hydroxytryptamine 1B receptor subtypes in modulating spinal nociceptive transmission in mice. J Pharmacol Exp Ther 1993; 265: 378–85
Danzebrink RM, Gebhart GF: Intrathecal coadministration of clonidine with serotonin receptor agonists produces supra-additive visceral antinociception in the rat. Brain Res 1991; 555: 35–42
Sawynok J, Reid A: Noradrenergic mediation of spinal antinociception by 5-hydroxytryptamine: Characterization of receptor subtypes. Eur J Pharmacol 1992; 223: 49–56
Kjorsvik A, Storkson R, Tjolsen A, Hole K: Differential effects of activation of lumbar and thoracic 5-HT2A/2C receptors on nociception in rats. Pharmacol Biochem Behav 1997; 56: 523–7
Mjellem N, Lund A, Hole K: Different functions of spinal 5-HT1A and 5-HT2 receptor subtypes in modulating behavior induced by excitatory amino acid receptor agonists in mice. Brain Res 1993; 626: 78–82
Ali Z, Wu G, Kozlov A, Barasi S: The role of 5HT3 in nociceptive processing in the rat spinal cord: Results from behavioural and electrophysiological studies. Neurosci Lett 1996; 208: 203–7
Bowker RM, Westlund KN, Sullivan MC, Wilber JF, Coulter JD: Descending serotonergic, peptidergic and cholinergic pathways from the raphe nuclei: A multiple transmitter complex. Brain Res 1983; 288: 33-48
Aquilonius S, Eckernas S, Gillberg P: Topographic localization of choline acetyltransferase within the human spinal cord and a comparison with some other species. Brain Res 1981; 211: 329–40
Urban L, Willets J, Murae K, Randic M: Cholinergic effects on spinal dorsl horn neurons in vitro: An intracellular study. Brain Res 1989; 500: 12–20
Abram SE, O'Connor TC: Characteristics of the analgesic effects and drug interactions of intrathecal carbachol in rats. A NESTHESIOLOGY 1995; 83: 844–9
Yaksh TL, Dirksen R, Harty GJ: Antinociceptive effects of intrathecally injected cholinomimetic drugs in the rat and cat. Eur J Pharmacol 1985; 117: 81–8
Gillberg PG, Gordh T Jr, Hartvig P, Jansson I, Pettersson J, Post C: Characterization of the antinociception induced by intrathecally administered carbachol. Pharmacol Toxicol 1989; 64: 340–3
Bannon AW, Decker MW, Holladay MW, Curzon P, Donnelly-Roberts D, Puttfarcken PS, Bitner RS, Diaz A, Dickenson AH, Porsolt RD, Williams M, Arneric SP: Broad-spectrum, non-opioid analgesic activity by selective modulation of neuronal nicotinic acetylcholine receptors. Science 1998; 279: 77–81
Abram SE, Winne RP: Intrathecal acetyl cholinesterase inhibitors produce analgesia that is synergistic with morphine and clonidine in rats. Anesth Analg 1995; 81: 501–7
Hood DD, Eisenach JC, Tuttle R: Phase I safety assessment of intrathecal neostigmine methylsulfate in humans. A NESTHESIOLOGY 1995; 82: 331–43
Hood DD, Mallak KA, Eisenach JC, Tong C: Interaction between intrathecal neostigmine and epidural clonidine in human volunteers. A NESTHESIOLOGY 1996; 85: 315–25
Lauretti GR, Hood DD, Eisenach JC, Pfeifer BL: A multi-center study of intrathecal neostigmine for analgesia following vaginal hysterectomy. A NESTHESIOLOGY 1998; 89: 913–8
Lauretti GR, Mattos AL, Reis MP, Prado WA: Intrathecal neostigmine for postoperative analgesia after orthopedic surgery. J Clin Anesth 1997; 9: 473–7
Eisenach JC, Hood DD, Curry R: Phase I human safety assessment of intrathecal neostigmine containing methyl- and propylparabens. Anesth Analg 1997; 85: 842–6
Lauretti GR, Reis MP, Prado WA, Klamt JG: Dose-response study of intrathecal morphine versus intrathecal neostigmine, their combination, or placebo for postoperative analgesia in patients undergoing anterior and posterior vaginoplasty. Anesth Analg 1996; 82: 1182–7
Boireau A, Bordier F, Durand G, Doble A: The antidepressant metapramine is a low-affinity antagonist at N-methyl-D-aspartic acid receptors. Neuropharmacology 1996; 35: 1703–7
Watanabe Y, Saito H, Abe K: Tricyclic antidepressants block NMDA receptor-mediated synaptic responses and induction of long-term potentiation in rat hippocampal slices. Neuropharmacology 1993; 32: 479–86
Mjellem N, Lund A, Hole K: Reduction of NMDA-induced behavior after acute and chronic administration of desiprimine in mice. Neuropharmacology 1993; 32: 591–5
Eisenach JC, Gebhart GF: Intrathecal amitriptyline acts as an N-methyl-D-aspartate receptor antagonist in the presence of inflammatory hyperalgesia in rats. A NESTHESIOLOGY 1995; 83: 1046–54
Eisenach JC, Gebhart GF: Intrathecal amitriptyline-antinociceptive interactions with intravenous morphine and intrathecal clonidine, neostigmine, and carbamylcholine in rats. A NESTHESIOLOGY 1995; 83: 1036–45
Sawynok J: Adenosine receptor activation and nociception. Eur J Pharmacol 1998; 347: 1–11
Taiwo YO, Levine JD: Further confirmation of the role of adenyl cyclase and of cAMP-dependent protein kinase in primary afferent hyperalgesia. Neuroscience 1991; 44: 131–5
Sawynok J, Reid A: Role of G-proteins and adenylate cyclase in antinociception produced by intrathecal purines. Eur J Pharmacol 1988; 156: 25–34
Li J, Perl ER: Adenosine inhibition of synaptic transmission in the substantia gelatinosa. J Neurophysiol 1994; 72: 1611–21
Sawynok J, Zarrindast MR, Reid AR, Doak GJ: Adenosine A3 receptor activation produces nociceptive behaviour and edema by release of histamine and 5-hydroxytryptamine. Eur J Pharmacol 1997; 333: 1–7
Sawynok J, Reid A, Isbrucker R: Adenosine mediates calcium-induced antinociception and potentiation of noradrenergic antinociception in the spinal cord. Brain Res 1990; 524: 187–195
Aran S, Proudfit HK: Antinociception produced by interactions between intrathecally administered adenosine agonists and norepinephrine. Brain Res 1990; 513: 255–63
Reeve AJ, Dickenson AH: Electrophysiological study on spinal antinociceptive interactions between adenosine and morphine in the dorsal horn of the rat. Neurosci Lett 1995; 194: 81–4
Zarrindast MR, Nikfar S: Different influences of adenosine receptor agonists and antagonists on morphine antinociception in mice. Gen Pharmacol 1994; 25: 139–42
Yang SW, Zhang ZH, Chen JY, Xie YF, Qiao JT, Dafny N: Morphine and norepinephrine-induced antinociception at the spinal level is mediated by adenosine. Neuroreport 1994; 5: 1441–4
Suh HW, Song DK, Kim YH: Differential effects of adenosine receptor antagonists injected intrathecally on antinociception induced by morphine and beta-endorphin administered intracerbroventricularly in the mouse. Neuropeptides 1997; 31: 339–44
Zarrindast MR, Iraie F, Heidari MR, Mohagheghi-Badi M: Effect of adenosine receptor agonists and antagonists on morphine-induced catalepsy in mice. Eur J Pharmacol 1997; 338: 11–6
Sollevi A, Belfrage M, Lundeberg T, Segerdahl M, Hansson P: Systemic adenosine infusion: A new treatment modality to alleviate neuropathic pain. Pain 1995; 61: 155–8
Rane K, Segerdahl M, Goiny M, Sollevi A: Intrathecal adenosine administration: A phase 1 clinical safety study in healthy volunteers, with additional evaluation of its influence on sensory thresholds and experimental pain. A NESTHESIOLOGY 1998; 89: 1108–15
Karlsten R, Gordh T Jr: An A1-selective adenosine agonist abolishes allodynia elicited by vibration and touch after intrathecal injection. Anesth Analg 1995; 80: 847
Dow RS: Action potentials of cerebellar cortex in response to local electrical stimulation. J Neurophysiol 1949; 12: 245–56
Bloom FE: Neurohumoral transmission and the central nervous system, Goodman and Gilman's The Pharmacological Basis of Therapeutics. Edited by Gilman AG, Goodman LS, Rall TW, Murad F. New York, MacMillan Publishing Company, 1985, pp 236–59
Duggan AW, Hope PJ, Jarrott B, Schaible HG, Fleetwood-Walker SM: Release, spread and persistence of immunoreactive neurokinin A in the dorsal horn of the cat following noxious cutaneous stimulation. Studies with antibody microprobes. Neuroscience 1990; 35: 195–202
Akil H, Watson SJ, Young E, Lewis ME, Khachaturian H, Walker JM: Endogenous opioids: Biology and function. Ann Rev Neurosci 1984; 7: 223–55
Satoh M, Minami M: Molecular pharmacology of the opioid receptors. Pharmacol Ther 1995; 68: 343–65
Reisine T: Opiate Receptors. Neuropharmacology 1995; 34: 463–72
Dado RJ, Law PY, Loh HH, Elde R: Immunofluorescent identification of a delta-opioid receptor on primary afferent nerve terminals. Neuroreport 1993; 5: 341–4
Ji R-R, Zhang Q, Law P-Y, Low HH, Elde R, Hokfelt T: Expression of μ-, δ-, and κ-opioid receptor-like immunoreactivities in rat dorsal root ganglia after carrageenan-induced inflammation. J Neurosci 1995; 15: 8156–66
Bartho L, Stein C, Herz A: Involvement of capsaicin-sensitive neurones in hyperalgesia and enhanced opioid antinociception in inflammation. Naunyn-Schmied Arch Pharmacol Exp Pathol 1990; 342: 666–70
Simon EJ, Hiller JM: The opiate receptors. Ann Rev Pharmacol Toxicol 1978; 18: 371–94
Harada Y, Nishioka K, Kitahata LM, Nakatani K, Collins JG: Contrasting actions of intrathecal U50,488, morphine, or [D-Pen2,D-Pen5] enkephalin or intravenous U50,488 on the viscermotor response to colorectal distension in the rat. A NESTHESIOLOGY 1995; 83: 336–43
Brennan TJ, Umali EF, Zahn PK: Comparison of pre- versus post-incision administration of intrathecal bupivacaine and intrathecal morphine in a rat model of postoperative pain. A NESTHESIOLOGY 1997; 87: 1517–28
Omote K, Kitahata LM, Collins JG, Nakatani K, Nakagawa I: The antinociceptive role of mu- and delta-opiate receptors and their interactions in the spinal dorsal horn of cats. Anesth Analg 1990; 71: 23–8
Yaksh TL, Gross KE, Li CH: Studies on the intrathecal effect of beta-endorphin in primate. Brain Res 1982; 241: 261–9
Kuraishi Y, Satoh M, Harada Y, Akaike A, Shibata T, Takagi H: Analgesic action of intrathecal and intracerebral beta-endorphin in rats: Comparison with morphine. Eur J Pharmacol 1980; 67: 143–6
Tseng LF, Collins KA: The tail-flick inhibition induced by beta-endorphin administered intrathecally is mediated by activation of kappa- and mu-opioid receptors in the mouse. Eur J Pharmacol 1992; 214: 59–65
Nagasaka H, Awad H, Yaksh TL: Peripheral and spinal actions of opioids in the blockade of the autonomic response evoked by compression of the inflamed knee joint. A NESTHESIOLOGY 1996; 85: 808-16
Yamamoto T, Yaksh TL: Comparison of the antinociceptive effects of pre- and posttreatment with intrathecal morphine and MK801, an NMDA antagonist, on the formalin test in the rat. A NESTHESIOLOGY 1992; 77: 757–63
Yamamoto T, Nozaki-Taguchi N: Clonidine, but not morphine, delays the development of thermal hyperesthesia induced by sciatic nerve constriction injury in the rat. A NESTHESIOLOGY 1996; 85: 835–45
Nichols ML, Lopez Y, Ossipov MH, Bian D, Porreca F: Enhancement of the antiallodynic and antinociceptive efficacy of spinal morphine by antisera to dynorphin A (1-13) or MK-801 in a nerve-ligation model of peripheral neuropathy. Pain 1997; 69: 317–22
Hammond DL, Wang H, Nakashima N, Basbaum AI: Differential effects of intrathecally administered delta and mu opioid receptor agonists on formalin-evoked nociception and on the expression of Fos-like immunoreactivity in the spinal cord of the rat. J Pharmacol Exp Ther 1998; 284: 378–87
Herman BH, Goldstein A: Antinociception and paralysis induced by intrathecal dynorphin A. J Pharmacol Exp Ther 1985; 232: 27–32
Faden AI, Jacobs TP: Dynorphin induces partially reversible paraplegia in the rat. Eur J Pharmacol 1983; 91: 321–4
Vanderah TW, Laughlin T, Lashbrook JM, Nichols ML, Wilcox GL, Ossipov MH, Malan TP Jr, Porreca F: Single intrathecal injections of dynorphin A or des-Tyr-dynorphins produce long-lasting allodynia in rats: Blockade by MK-801 but not naloxone. Pain 1996; 68: 275–81
Yaksh TL: Spinal opiate analgesia: Characteristics and principles of action. Pain 1981; 11: 293–346
Behar M, Magora F, Olshwang D: Epidural morphine treatment of pain. Lancet 1979; 1: 527–8
Coombs DW, Saunders RL, Gaylor MS: Continuous epidural analgesia via implanted morphine resevoir. Lancet 1981; 2: 425–6
Winkelmuller M, Winkelmuller W: Long-term effect of continuous intrathecal opioid treatment in chronic pain of nonmalignant etiology. J Neurosurg 1996; 85: 458–67
Shetter AG, Hadley MN, Wilkinson E: Administration of intraspinal morphine sulfate for the treatment of intractable cancer pain. Neurosurgery 1986; 18: 740–7
Coombs DW, Saunders RL, Gaylor MS, Block AR, Colton T, Harbaugh R, Pagneau MG, Mroz W: Relief of continuous chronic pain by intraspinal narcotic infusion via an implanted resevoir. JAMA 1983; 250: 2336–9
Auld AW, Maki-Jokela A, Murdoh DM: Intraspinal narcotic analgesia in the treatment of chronic pain. Spine 1985; 10: 777–81
Krames ES, Gershow J, Kenefick T, Lyons A, Taylor P, Wilkie D: Continuous infusion of spinally administered narcotics for the relief of pain due to malignant disorders. Cancer 1985; 56: 696–702
Hassenbusch SJ, Pillay PK, Maginec M, Currie K, Bay JW, Covington EC, Tomaszewski MZ: Constant infusion of morphine for intractable cancer pain using an implanted pump. J Neurosurg 1990; 73: 405–9
Penn RD, Paice JA: Chronic intrathecal morphine for intractable pain. J Neurosurg 1987; 67: 182–6
Gestin Y, Vainio A, Perurier AM: Long-term intrathecal infusion of morphine in the home care of patients with advanced cancer. Acta Anaesth Scand 1997; 41: 12–7
Wagemans MF, van der Valk P, Spoelder EM, Zuurmond WW, de Lange JJ: Neurohistopathological findings after continuous intrathecal administration of morphine or a morphine/bupivacaine mixture in cancer pain patients. Acta Anaesth Scand 1997; 41: 1033–8
Alhashemi JA, Crosby ET, Grodecki W, Duffy PJ, Hull KA, Gallant C: Treatment of intrathecal morphine-induced pruritis following caesarean section. Can J Anaesth 1997; 44: 1060–5
Yoshida GM, Nelson RW, Capen DA, Nagelberg S, Thomas JC, imoldi RL, Haye W: Evaluation of continuous intraspinal narcotic nalgesia for chronic pain from benign causes. Am J Orthop 1996; 5: 693–4
Sjogren P, Thunedborg LP, Christrup L, Hansen SH, Franks J: Is development of hyperalgesia, allodynia and myoclonus related to morphine metabolism during long-term administration? Six case histories. Acta Anaesth Scand 1998; 42: 1070–5
Oyama T, Matsuki A, Taneichi T, Ling N, Guillemin R: Beta-endorphin in obstetric analgesia. Am J Obstet Gynecol 1980; 37: 613–6
Oyama T, Jin T, Yamaya R, Ling N, Guillemin R: Profound analgesic effects of beta-endorphin in man. Lancet 1980; 1: 122–4
Wen HL, Mehal ZD, Ong BH, Ho WK: Treatment of pain in cancer patients by intrathecal administration of dynorphin. Peptides 1987; 8: 191–3
Wen HL, Mehal ZD, Ong BH, Ho WK, Wen DY: Intrathecal administration of beta-endorphin and dynorphin-(1-13) for the treatment of intractable pain. Life Sci 1985; 37: 1213–20
Nakanishi S: Substance P precursor and kininogen: Their structures, gene organizations and regulation. Physiol Rev 1987; 7: 1117–42
Maggio JE: Tachykinins. Ann Rev Neurosci 1988; 11: 13–28
Helke CJ, Krause JE, Mantyh PW, Couture R, Bannon MJ: Diversity in mammalian tachykinin peptidergic neuron: Multiple peptides, receptors, and regulatory mechanisms. FASEB J 1990; 4: 1606–1615
Brechenmacher C, Larmet Y, Feltz P, Rodeau JL: Cultured rat sensory neurones express functional tachykinin receptor subtypes 1, 2 and 3. Neurosci Lett 1998; 241: 159–62
Xu XJ, Maggi CA, Wiesenfeld-Hallin Z: On the role of NK2 tachykinin receptors in the mediation of the spinal reflex excitibility in the rat. Neuroscience 1991; 44: 483–90
Xu XJ, Dalsgaard CJ, Wiesenfeld-Hallin Z: Spinal substance P and N-methyl-D-aspartate receptors are coactivated in the induction of central sensitization of the nociceptive flexor reflex. Neuroscience 1992; 51: 641–8
Dougherty PM, Palecek J, Paleckova V, Willis WD: Neurokinin 1 and 2 antagonists attenuate the responses and NK1 antagonists prevent the sensitization of primate spinothalamic tract neurons after intradermal capsaicin. J Neurophysiol 1994; 72: 1464–75
Dougherty PM, Palecek J, Zorn S, Willis WD: Combined application of excitatory amino acids and substance P produces long-lasting changes in responses of primate spinothalamic tract neurons. Brain Res Rev 1993; 18: 227–46
Dougherty PM, Willis WD: Enhancement of spinothalamic neuron responses to chemical and mechanical stimuli following combined micro-iontophoretic application of N-methyl-D-aspartic acid and substance P. Pain 1992; 47: 85–93
Henry JL, Krnjevic K, Morris ME: Substance P and spinal neurones. Can J Physiol Pharmacol 1975; 53: 423–32
Krnjevic K: Effects of substance P on central neurons in cats, Substance P. Edited by VonEuler US, Pernow B. New York, Raven Press, 1977, pp 217–30
Hylden JLK, Wilcox GL: Pharmacological characterization of substance P-induced nociception in mice: Modulation by opioid and nordrenergic agonists at the spinal level. J Pharmacol Exp Therap 1983; 226: 398–404
Frenk H, Bossut D, Urca G, Mayer DJ: Is substance P a primary afferent neurotransmitter for nociceptive input? I. Analysis of pain-related behaviors resulting from intrathecal administration of substance P and 6 excitatory compounds. Brain Res 1988; 455: 223–31
Cridland RA, Henry JL: Comparison of the effects of substance P, neurokinin A, physalaemin and eledoisin in facilitating a nociceptive reflex in the rat. Brain Res 1986; 381: 93–9
Urban L, Randic M: Slow excitatory transmission in rat dorsal horn: Possible mediation by peptides. Brain Res 1984; 290: 336–41
Murase K, Ryu PD, Randic M: Substance P augments a persistent slow inward calcium-sensitive current in voltage-clamped spinal dorsal horn neurons of the rat. Brain Res 1986; 365: 369–76
Randic M, Hecimovic H, Ryu PD: Substance P modulates glutamate-induced currents in acutely isolated rat spinal dorsal horn neurones. Neurosci Lett 1990; 117: 74–80
Randic M, Miletic V: Effect of substance P in cat dorsal horn neurones activated by noxious stimuli. Brain Res 1977; 128: 164–9
Zieglgansberger W, Tulloch IF: Effects of substance P on neurones in the dorsal horn of the spinal cord of the cat. Brain Res 1979; 166: 273–82
Willcockson WS, Chung JM, Hori Y, Lee KH, Willis WD: Effects of iontophoretically released peptides on primate spinothalamic tract cells. J Neurosci 1984; 4: 741–50
Fleetwood-Walker SM, Mitchell R, Hope PJ, El-Yassir N, Molony V, Bladon CM: The involvement of neurokinin receptor subtypes in somatosensory processing in the superficial dorsal horn of the cat. Brain Res 1990; 519: 169–82
Kellenstein DE, Price DD, Hayes RL, Mayer DJ: Evidence that substance P selectively modulates C-fiber-evoked discharges of dorsal horn nociceptive neurons. Brain Res 1990; 526: 291–8
Piercey MF, Moon MW, Blinn JR, Dobry-Schreur PJK: Analgesic activities of spinal cord substance P antagonists implicate substance P as a neurotransmitter of pain sensation. Brain Res 1986; 385: 74–85
Brugger F, Evans RH, Hawkins NS: Effects of N-methyl-D-aspartate antagonists and spantide on spinal reflexes and responses to substance P and capsaicin in isolated spinal cord preparations from mouse and rat. Neuroscience 1990; 36: 611–22
Yashpal K, Radhakrishnan V, Henry JL: NMDA receptor antagonists block the facilitation of the tail flick reflex in the rat induced by intrathecal administration of substance P and noxious cutaneous stimulation. Neurosci Lett 1997; 128: 269–72
Murray CW, Cowan A, Larson AA: Neurokinin and NMDA antagonists (but not a kainic acid antagonist) are antinociceptive in the mouse formalin model. Pain 1991; 44: 179–85
Picard P, Boucher S, Regoli D, Gitter BD, Howbert JJ, Couture R: Use of non-peptide tachykinin receptor antagonists to substantiate the involvement of NK1 and NK2 receptors in a spinal nociceptive reflex in the rat. Eur J Pharmacol 1993; 232: 255–61
Radhakrishnan V, Henry JL: Novel substance P antagonist, CP-96345, blocks responses of cat dorsal horn neurons to noxious cutaneous stimulation and substance P. Neurosci Lett 1991; 132: 39–43
Urban L, Maggi CA, Nagy I, Dray A: The selective NK2 receptor antagonist MEN 10376 inhibits synaptic excitation of dorsal horn neurons evoked by C-fibre activation in the in vitro rat spinal cord. Neuropeptides 1992; 22: 68
Zimmer A, Zimmer AM, Baffi J, Usdin T, Reynolds K, Konig M, Palkovits M, Mezey E: Hypoalgesia in mice with a targeted deletion of the tachykinin 1 gene. Proc Natl Acad Sci U S A 1998; 95: 2630–5
Cao YQ, Mantyh PW, Carlson EJ, Gillespie AM, Epstein CJ, Basbaum AI: Primary afferent tachykinins are required to experience moderate to intense pain. Nature 1998; 392: 390–4
DeFelipe C, Herrero JF, O'Brien JA, Palmer JA, Doyle CA, Smith AJ, Laird JM, Belmonte C, Cervero F, Hunt SP: Altered nociception, analgesia and aggression in mice lacking the receptor for substance P. Nature 1998; 392: 334–5
Hua XY, Chen P, Polgar E, Nagy I, Marsala M, Phillips E, Wollaston L, Urban L, Yaksh TL, Webb M: Spinal neurokinin NK1 receptor down-regulation and antinociception: Effects of spinal NK1 receptor antisense oligonucleotides and NK1 receptor occupancy. J Neurochem 1998; 70: 688–98
Kramer MS, Cutler N, Feighner J, Shrivastava R, Carman J, Sramek JJ, Reines SA, Liu G, Snavely D, Wyatt-Knowles E, Hale JJ, Mills SG, MacCoss M, Swain CJ, Harrison T, Hill RG, Hefti F, Scolnick EM, Cascieri MA, Chicchi GG, Sadowski S, Williams AR, Hewson L, Smith D, Carlson EJ, Hargreaves RJ, Rupniak NMJ: Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science 1998; 281: 1640–5
Dionne RA, Max MB, Gordon SM, Parada S, Sang C, Gracely RH, Sethna NF, MacLean DB: The substance P receptor antagonist CP-99,994 reduces acute postoperative pain. Clin Pharmacol Ther 1998; 64: 562–8
Skofitsch G, Jacobowitz DM: Calcitonin- and calcitonin gene-related peptide: Receptor binding in the central nervous system, Handbook of Chemical Neuroanatomy, Volume 11: Neuropeptide Receptors in the CNS. Edited by Bjorklund A, Hokfelt T, Kuhar MJ. Amsterdam, Elsevier Science, 1992, pp 97–144
Amara SG, Jonas V, Rosenfeld MG, Ong ES, Evans RM: Alternative RNA processing of calcitonin gene expression generates mRNAs encoding different polypeptide products. Nature 1982; 298: 240–4
Franco-Cereceda A, Henke H, Lundberg JM, Petermann JB, Hokfelt T, Fischer JA: Calcitonin gene-related peptide (CGRP) in capsaicin-sensitive substance P-immunoreactive sensory neurons in animals and man: Distribution and release by capsaicin. Peptides 1987; 8: 399–410
Wiesenfeld-Hallin Z, Hokfelt T, Lundberg JM, Forssman WO, Reinecke M, Tschopp FA, Fischer JA: Immunoreactive calcitonin gene-related peptide and substance P coexist in sensory neurons to the spinal cord and interact in spinal behavioral responses of the rat. Neurosci Lett 1984; 52: 199–204
Cameron AA, Leah JD, Snow PJ: The coexistence of neuropeptides in feline sensory neurons. Neuroscience 1988; 27: 969–79
Sluka KA, Dougherty PM, Sorkin LS, Willis WD, Westlund KN: Neural changes in acute arthritis in monkeys: III. Changes in substance P, calcitonin gene-related peptide and glutamate in the dorsal horn of the spinal cord. Brain Res Rev 1992; 17: 29–38
Cameron AA, Cliffer KD, Dougherty PM, Garrison CJ, Willis WD, Carlton SM: Time course of degenerative and regenerative changes in the dorsal horn in a rat model of peripheral neuropathy. J Comp Neurol 1997; 379: 428–42
Morton CR, Hutchison WD: Release of sensory neuropeptides in the spinal cord: Studies with calcitonin gene-related peptide and galanin. Neuroscience 1989; 31: 807–15
Saria A, Gamse R, Petermann J, Fischer JA, Theodorsson-Norheim E, Lundberg JM: Simultaneous release of several tachykinins and calcitonin gene-related peptide from rat spinal cord slices. Neurosci Lett 1986; 63: 310–4
Yu LC, Hansson P, Lundeberg T: The calcitonin gene-related peptide antagonist CGRP8–37 increases the latency to withdrawal responses in rats. Brain Res 1994; 223–30
Cridland RA, Henry JL: Effects of intrathecal administration of neuropeptides on a spinal nociceptive reflex in the rat: VIP, galanin, CGRP, TRH, somatostatin and angiotensin II. Neuropeptides 1988; 11: 23–32
Cridland RA, Henry JL: Intrathecal administration of CGRP in the rat attenuates a facilitation of the tail flick reflex induced by either substance P or noxious cutaneous stimulation. Neurosci Lett 1989; 102: 241–6
Oku R, Satoh M, Fujii N, Otaka A, Yajima H, Takagi H: Calcitonin gene-related peptide promotes mechanical nociception by potentiating release of substance P from the spinal dorsal horn in rats. Brain Res 1987; 403: 350–4
Lofgren O, Yu LC, Theodorsson E, Hansson P, Lundeberg T: Intrathecal CGRP(8-37) results in a bilateral increase in hindpaw withdrawal latency in rats with a unilateral thermal injury. Neuropeptides 1997; 31: 601–7
Yu LC, Hansson P, Lundeberg T: The calcitonin gene-related peptide antagonist CGRP8–37 increases the latency to withdrawal responses bilaterally in rats with unilateral experimental mononeuropathy, an effect reversed by naloxone. Neuroscience 1996; 71: 523–31
Menard DP, van Rossum D, Kar S, StPierre S, Sutak M, Jhamandas K, Quirion R: A calcitonin gene-related peptide receptor antagonist prevents the development of tolerance to spinal morphine analgesia. J Neurosci 1996; 16: 2342–51
Terenius L: Somatostatin and ACTH are peptides with partial antagonist-like selectivity for opiate receptors. Eur J Pharmacol 1976; 38: 211–3
Krantic S, Quirion R, Uhl G: Somatostatin receptors, Handbook of Chemical Neuroanatomy, Volume 11: Neuropeptide Receptors in the CNS. Edited by Bjorklund A, Hokfelt T, Kuhar MJ. Amsetrdam, Elsevier Science, 1992, pp 321–46
Schonbrunn A, Gu YZ, Dournard P, Beaudet A, Tannenbaum GS, Brown PJ: Somatostatin receptor subtypes: Specific expression and signaling properties. Metabolism 1996; 45: 8–11
Morton CR, Hutchison WD, Hendry IA, Duggan AW: Somatostatin: Evidence for a role in thermal nociception. Brain Res 1989; 488: 89–96
Kuraishi Y, Hirota N, Sato Y, Hino Y, Satoh M, Takagi H: Evidence that substance P and somatostatin transmit separate information related to pain in the spinal dorsal horn. Brain Res 1985; 325: 294–8
Tiseo PJ, Adler MW, Liu-Chen LY: Differential release of substance P and somatostatin in the rat spinal cord in response to noxious cold and heat; effect of dynorphin A (1-17). J Pharmacol Exp Ther 1990; 252: 539–45
Chapman V, Dickenson AH: The effects of sandostatin and somatostatin on nociceptive transmission in the dorsal horn of the rat spinal cord. Neuropeptides 1992; 23: 147–52
Traub RJ, Brozoski D: Anti-somatostatin antisera, but neither a somatostatin agonist (octreotide) nor antagonist (CYCAM), attenuates hyperalgesia in the rat. Peptides 1996; 17: 769–73
Sandkuhler J, Fu QG, Helmchen C: Spinal somatostatin superfusion in vivo affects activity of cat nociceptive dorsal horn neurons: Comparison with spinal morphine. Neuroscience 1990; 34: 565-76
Wiesenfeld-Hallin Z: Substance P and somatostatin modulate spinal cord excitability via physiologically different sensory pathways. Brain Res 1986; 372: 172–5
Ohno H, Kuraishi Y, Minami M, Satoh M: Modality-specific antinociception produced by intrathecal injection of anti-somatostatin antiserum in rats. Brain Res 1988; 474: 197–200
Randic M, Miletic V: Depressant action of methionine-enkephalin and somatostatin in cat dorsal horn neurones activated by noxious stimuli. Brain Res 1978; 152: 196–202
Spampinato S, Romualdi P, Candeletti S, Cavicchini E, Ferri S: Distinguishable effects of intrathecal dynorphins, somatostatin, neurotensin and s-calcitonin on nociception and motor function in the rat. Pain 1988; 35: 95–104
Gaumann DM, Grabow TS, Yaksh TL, Casey SJ, Rodriguez M: Intrathecal somatostatin, somatostatin analogs, substance P analog and dynorphin A cause comparable neurotoxicity in rats. Neuroscience 1990; 39: 761–74
Gaumann DM, Yaksh TL, Post C, Wilcox GL, Rodriguez M: Intrathecal somatostatin in cat and mouse studies on pain, motor behavior, and histopathology. Anesth Analg 1989; 68: 623–32
Mollenholt P, Rawal N, Gordh T Jr, Olsson Y: Intrathecal and epidural somatostatin for patients with cancer. A NESTHESIOLOGY 1994; 81: 534–42
Paice JA, Penn RD, Kroin JS: Intrathecal octreotide for relief of intractable nonmalignant pain: 5-year experience with two cases. Neurosurgery 1996; 38: 203–7
Rowan S, Todd AJ, Spike RC: Evidence that neuropeptide Y is present in GABAergic neurons in the superficial dorsal horn of the rat spinal cord. Neuroscience 1993; 53: 537–45
Quirion R, Martel J-C: Brain neuropeptide Y receptors. Distribution and possible relevance to function, Handbook of Chemical Neuroanatomy, Volume 11: Neuropeptide Receptors in the CNS. Edited by Bjorklund A, Hokfelt T, Kuhar MJ. Amsterdam, Elsevier Science, 1992, pp 247–88
Walker MW, Ewald DA, Perney TM, Miller RJ: Neuropeptide Y modulates neurotransmitter release and Ca++ currents in rat sensory neurons. J Neurosci 1988; 8: 2438–46
Melander T, Kohler C, Nilsson S, Fisone G, Bartfai T, Hokfelt T: 125I-Galanin binding sites in the rat central nervous system, Handbook of Chemical Neuroanatomy, Volume 11: Neuropeptide Receptors in the CNS. Edited by Bjorklund A, Hokfelt T, Kuhar MJ. Amsterdam, Elsevier Science, 1992, pp 187–222
Wiesenfeld-Hallin Z, Xu XJ, Villar MJ, Hokfelt T: The effect of intrathecal galanin on the flexor reflex in rat: Increased depression after sciatic nerve section. Neurosci Lett 1989; 105: 149–54
Melander T, Hokfelt T, Rokaeus A: Distribution of galanin-like immunoreactivity in the rat CNS. J Comp Neurol 1986; 248: 475–517
Oldfield BJ, Allen AM, Hards DK, Kerrigan S, McKinley MJ, Mendelsohn FAO: The distribution of angiotensin II receptors in the spinal cord of the sheep. Neurosci Lett 1989; S34: S130
Allen AM, Paxinos G, Song KF, Mendelsohn FAO: Localization of angiotensin receptor binding sites in the rat brain., Handbook of Chemical Neuroanatomy, Volume 11: Neuropeptide Receptors in the CNS. Edited by Bjorklund A, Hokfelt T, Kuhar MJ: Amsterdam, Elsevier Science, 1992, pp 1–37
Moody TW, Wada E, Battey J: Bombesin/GRP receptors, Handbook of Chemical Neuroanatomy, Volume 11: Neuropeptide Receptors in the CNS. Edited by Bjorklund A, Hokfelt T, Kuhar MJ. Amsterdam, Elsevier Science, 1992, pp 55–96
Tribollet E: Vasopression and oxytocin receptors in the rat brain, Handbook of Chemical Neuroanatomy, Volume 11: Neuropeptide Receptors in the CNS. Edited by Bjorklund A, Hokfelt T, Kuhar MJ. Amsterdam, Elsevier Science, 1992, pp 289–320
Magistretti PJ, Martin J-L, Hof PR, Palacios JM: Vasoactive intestinal peptide (VIP) receptors, Handbook of Chemical Neuroanatomy, Volume 11: Neuropeptide Receptors in the CNS. Edited by Bjorklund A, Hokfelt T, Kuhar MJ. Amsterdam, Elsevier Science, 1992, pp 347–97
Bishop JF, Moody TW, O'Donohue TL: Peptide transmitters of primary sensory neurons: Similar actions of tachykinins and bombesin-like peptides. Peptides 1986; 7: 835–42
Jeftinija S, Murase K, Nedeljkov V, Randic M: Vasoactive intestintal polypeptide excites mammalian dorsal horn neurons both in vivo and in vitro. Brain Res 1982; 243: 158–64
Watkins LR, Martin D, Ulrich P, Tracey KJ, Maier SF: Evidence for the involvement of spinal cord glia in subcutaneous formalin induced hyperalgesia in the rat. Pain 1997; 71: 225–35
Simmons ML, Murphy S: Induction of nitric oxide synthase in glial cells. J Neurochem 1992; 59: 897–905
Vane JR, Bakhle YS, Botting RM: Cyclooxygenases 1 and 2. Ann Rev Pharmacol Toxicol 1998; 38: 97–120
Marriott DR, Wilkin GP, Wood JN: Substance P-Induced release of prostaglandins from astrocytes: Regional specialisation and correlation with phosphoinositol metabolism. J Neurochem 1991; 56: 259–65
Moncada S, Flower RJ, Vane JR: Prostaglandins, prostacylcin, thromboxane A2, and leukotrienes, Goodman and Gilman's The Pharmacological Basis of Therapeutics. Edited by Gilman AG, Goodman LS, Rall TW, Murad F. New York, MacMillan Publishing Company, 1985, pp 660–73
Levine JD, Lam D, Taiwo YO, Donatoni P, Goetzl EJ: Hyperalgesic properties of 15-lipoxygenase products of arachidonic acid. Proc Natl Acad Sci U S A 1986; 83: 5331–4
Martin H, Basbaum A, Kwiat G, Goetzl E, Levine J: Leukotiene and prostaglandins sensitization of cutaneous high-threshold C- and A-delta mechanonociceptors in hairy skin of rat hindlimbs. Neuroscience 1987; 22: 651–9
Madison S, Whitsel EA, Suarez-Roca H, Maixner W: Sensitizing effects of leukotriene B4 on intradermal primary afferents. Pain 1992; 49: 99–104
Bisgaard H, Kristensen JK: Leukotriene B4 produces hyperalgesia in humans. Prostaglandins 1985; 30: 791–7
Yaksh TL, Dirig DM, Malmberg AB: Mechanism of action of nonsteroidal anti-inflammatory drugs. Cancer Invest 1998; 16: 509–27
McCormack K: Non-steroidal anti-inflammatory drugs and spinal nociceptive processing. Pain 1994; 59: 9–43
Yaksh TL, Malmberg AB: Spinal actions of NSAIDS in blocking spinally mediated hyperalgesia: The role of cyclooxygenase products. Agents and Actions Suppl 1993; 41: 89–100
Vasko MR: Prostaglandin-induced neuropeptide release from spinal cord, Progress in Brain Research. Edited by Nyberg F, Sharma HS, Wiesenfeld-Hallin Z. Amsterdam, Elsevier Science BV, 1995, pp 368–80
Malmberg AB, Hamberger A, Hedner T: Effects of prostaglandin E2 and capsaicin on behavior and cerebrospinal fluid amino acid concentrations of unanesthetized rats: A microdialysis study. J Neurochem 1995; 65: 2193
Malmberg AB, Yaksh TL: Pharmacology of the spinal action of ketorolac, morphine, ST-91, U50488H, and L-PIA on the formalin test and an isobolographic analysis of the NSAID interaction. A NESTHESIOLOGY 1993; 79: 211–3
Yamamoto T, Nozaki-Taguchi N: Role of spinal cyclooxygenase (COX)-2 on thermal hyperalgesia evoked by carageenan injection in the rat. Neuroreport 1997; 8: 2179–82
Malmberg AB, Yaksh TL: Hyperalgesia mediated by spinal glutamate or substance P receptor blocked by spinal cyclooxygenase inhibition. Science 1992; 257: 1276–9
Poddubiuk ZM, Kleinrok Z: A comparison of the central actions of prostaglandins A2, E1, E2, F1, and F2 in the rat. Psychopharmacology 1976; 50: 95–102
Eisenach JC: Aspirin, the miracle drug: Spinally, too? A NESTHESIOLOGY 1993; 79: 211–3
Schuman EM, Madison DV: Nitric oxide and synaptic function. Ann Rev Neurosci 1994; 17: 153–83
Zhuo M, Small SA, Kandell ER, Hawkins RD: Nitric oxide and carbon monoxide produce long-term enhancement of synaptic transmission in the hippocampus by an activity-dependent mechanism. Science 1993; 260: 1946–9
Synder SH, Jaffrey SR, Zakhary R: Nitric oxide and carbon monoxide: Parallel roles as neural messengers. Brain Res Rev 1998; 26: 167–75
Aimar P, Pasti L, Carmignoto G, Merighi A: Nitric oxide-producing islet cells modulate the release of sensory neuropeptides in the rat substantia gelatinosa. J Neurosci 1998; 18: 10375–88
Choi Y, Raja SN, Moore LC, Tobin JR: Neuropathic pain in rats is associated with altered nitric oxide synthase activity in neural tissue. J Neurol Sci 1996; 138: 14–20
Gordh T, Sharma HS, Alm P, Westman J: Spinal nerve lesion induces upregulation of neuronal nitric oxide synthase in the spinal cord. An immunohistochemical investigation in the rat. Amino Acids 1998; 14: 105–12
Meller ST, Pechman PS, Gebhart GF, Maves TJ: Nitric oxide mediates the thermal hyperalgesia produced in a model of neuorpathic pain in the rat. Neuroscience 1992; 50: 7–10
Yamamoto T, Shimoyama N, Mizuguchi T: Nitric oxide synthase inhibitor blocks spinal sensitization induced by formalin injection into the rat paw. Anesth Analg 1993; 77: 886–90
Yaksh TL, Malmberg AB: Spinal nitric oxide synthesis inhibition blocks NMDA-induced thermal hyperalgesia and produces antinociception in the formalin test in rats. Pain 1993; 54: 291–300
Yamamoto T, Nozaki-Taguchi N: Zinc protoporphyrin IX, an inhibitor of the enzyme that produces carbon monoxide, blocks spinal nociceptive transmission evoked by formalin injection in the rat. Brain Res 1995; 704: 256–62
Langerman L, Golomb E, Benita S: Significant prolongation of the pharmacologic effect of tetracaine using a lipid solution of the agent. A NESTHESIOLOGY 1991; 74: 105–7
Langerman L, Golomb E, Benita S: Prolongation of the pharmacologic effect of meperidine by the use of a lipid solution of it. A NESTHESIOLOGY 1991; 72: 635–8
Masters DB, Berde CB, Dutta S, Turek T, Langer R: Sustained local anesthetic release from bioerodible polymer matrices: A potential method for prolonged regional analgesia. Pharmacol Res 1993; 10: 1527–32
Sato S, Baba Y, Tajima K, Kimura T, Tsuji MH, Kohda Y, Sato Y: Prolongation of epidural anesthesia in the rabbitt with the use of a biodegradable coploymer paste containing lidocaine. Anesth Analg 1995; 80: 97–101
Lesser GL, Grossman SA, Leong KW, Lo H, Eller S: In vitro and in vivo studies of subcutaneous hydromorphone implants designed for the treatement of cancer pain. Pain 1996; 65: 265–72
Wu HH, Lester BR, Wilcox GL: Antinociception following implantation of mouse B16 melanoma cells in mouse and rat spinal cord. Pain 1994; 56: 203–10
Pappas GD, Lazorthes Y, Bes JC, Tafani M, Winnie AP: Relief of intractable cancer pain by human chromaffin cell transplants: Experience at two medical centers. Neurolog Res 1997; 19: 71–7
Fig. 1. Schematic diagram of the major neurochemicals involved in somatosensory transmission and processing in the spinal dorsal horn. The figure is organized with the pain signaling output neurons of the dorsal horn, the dorsal horn projection neurons, as the central cellular component. These cells are the source of all inputs for pain and temperature to the rostral central nervous system structures, such as the thalamus, brain stem, and hypothalamus, that in turn influence cortical and limbic brain structures necessary for conscious perception and appreciation of pain. The primary afferents that convey input from peripheral tissues to spinal interneurons and projection cells are shown entering at the right of the figure. The local circuit interneurons that influence the processing of sensory inputs to projection cells are represented by the cell profile at the bottom right. Meanwhile, the inputs to the spinal cord that have come from rostral central nervous system sensory modulatory sites are shown in the cellular component at the top of the figure, alongside the departing axon of the projection cell. The chemicals involved as neurotransmitters (transmitters) and neuromodulators (modulators) associated with each compartment are indicated in the boxes associated with each profile. Boxes at the bottom left list the nonspecific and trans-synaptic signals that provide additional sites for intervention. 
Fig. 1. Schematic diagram of the major neurochemicals involved in somatosensory transmission and processing in the spinal dorsal horn. The figure is organized with the pain signaling output neurons of the dorsal horn, the dorsal horn projection neurons, as the central cellular component. These cells are the source of all inputs for pain and temperature to the rostral central nervous system structures, such as the thalamus, brain stem, and hypothalamus, that in turn influence cortical and limbic brain structures necessary for conscious perception and appreciation of pain. The primary afferents that convey input from peripheral tissues to spinal interneurons and projection cells are shown entering at the right of the figure. The local circuit interneurons that influence the processing of sensory inputs to projection cells are represented by the cell profile at the bottom right. Meanwhile, the inputs to the spinal cord that have come from rostral central nervous system sensory modulatory sites are shown in the cellular component at the top of the figure, alongside the departing axon of the projection cell. The chemicals involved as neurotransmitters (transmitters) and neuromodulators (modulators) associated with each compartment are indicated in the boxes associated with each profile. Boxes at the bottom left list the nonspecific and trans-synaptic signals that provide additional sites for intervention. 
Fig. 1. Schematic diagram of the major neurochemicals involved in somatosensory transmission and processing in the spinal dorsal horn. The figure is organized with the pain signaling output neurons of the dorsal horn, the dorsal horn projection neurons, as the central cellular component. These cells are the source of all inputs for pain and temperature to the rostral central nervous system structures, such as the thalamus, brain stem, and hypothalamus, that in turn influence cortical and limbic brain structures necessary for conscious perception and appreciation of pain. The primary afferents that convey input from peripheral tissues to spinal interneurons and projection cells are shown entering at the right of the figure. The local circuit interneurons that influence the processing of sensory inputs to projection cells are represented by the cell profile at the bottom right. Meanwhile, the inputs to the spinal cord that have come from rostral central nervous system sensory modulatory sites are shown in the cellular component at the top of the figure, alongside the departing axon of the projection cell. The chemicals involved as neurotransmitters (transmitters) and neuromodulators (modulators) associated with each compartment are indicated in the boxes associated with each profile. Boxes at the bottom left list the nonspecific and trans-synaptic signals that provide additional sites for intervention. 
×
Fig. 2. Summary of the two major classes of sodium channels involved in somatosensory transmission at spinal levels. Drugs that modify each channel are listed, with arrows indicating sites of action. The “X” indicates blockade of the channel. 4030W92 = 2,4-diamino-5-(2,3-dichlorophenyl)-6-fluoromethylpyrimidine.  34 
Fig. 2. Summary of the two major classes of sodium channels involved in somatosensory transmission at spinal levels. Drugs that modify each channel are listed, with arrows indicating sites of action. The “X” indicates blockade of the channel. 4030W92 = 2,4-diamino-5-(2,3-dichlorophenyl)-6-fluoromethylpyrimidine.  34
Fig. 2. Summary of the two major classes of sodium channels involved in somatosensory transmission at spinal levels. Drugs that modify each channel are listed, with arrows indicating sites of action. The “X” indicates blockade of the channel. 4030W92 = 2,4-diamino-5-(2,3-dichlorophenyl)-6-fluoromethylpyrimidine.  34 
×
Fig. 3. Summary of the four classes of calcium channels involved in sensory transmission at spinal levels. Drugs that modify each channel are listed, with arrows indicating the sites of action. The “X” indicates blockade of the channel. Some conotoxins block “P”-type channels, but these may not be involved in transmission of sensory information at spinal levels. 
Fig. 3. Summary of the four classes of calcium channels involved in sensory transmission at spinal levels. Drugs that modify each channel are listed, with arrows indicating the sites of action. The “X” indicates blockade of the channel. Some conotoxins block “P”-type channels, but these may not be involved in transmission of sensory information at spinal levels. 
Fig. 3. Summary of the four classes of calcium channels involved in sensory transmission at spinal levels. Drugs that modify each channel are listed, with arrows indicating the sites of action. The “X” indicates blockade of the channel. Some conotoxins block “P”-type channels, but these may not be involved in transmission of sensory information at spinal levels. 
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Fig. 4. Schematic summary of the spinal second-messenger systems involved in pain transmission. The figure is organized in columns and rows. Filled rectangles represent surface drug receptors. Compounds that activate each receptor are listed at the side. G-labeled pentagons represent the G-protein β and γ subunits, whereas the circles labeled “q”, “s,” and “i” represent the three functionally distinct isoforms of the α subunit. Circles with arrows represent enzymes that generate secondary metabolites as a direct consequence of activity of the G-protein subunits. The products of these enzymes are listed in the center of the figure. Rectangles represent the final tier of enzymes activated in the cascade. The “+” indicates activation or positive modulation, whereas the “-” indicates inactivation or inhibition. *Indicates those targets for which antagonists were shown to produce antinociception. AC = adenylate cyclase; CamKII = calcium-calmodulin dependent protein kinase II; cAMP = cyclic adenosine monophosphate; cGMP = cyclic guanosine monophosphate; GC = guanylate cyclase; IP3= inositol triphosphate; NOS = nitric oxide synthase; PKA = protein kinase A; PKC = protein kinase C; PKG = protein kinase G; PL = phospholipase. 
Fig. 4. Schematic summary of the spinal second-messenger systems involved in pain transmission. The figure is organized in columns and rows. Filled rectangles represent surface drug receptors. Compounds that activate each receptor are listed at the side. G-labeled pentagons represent the G-protein β and γ subunits, whereas the circles labeled “q”, “s,” and “i” represent the three functionally distinct isoforms of the α subunit. Circles with arrows represent enzymes that generate secondary metabolites as a direct consequence of activity of the G-protein subunits. The products of these enzymes are listed in the center of the figure. Rectangles represent the final tier of enzymes activated in the cascade. The “+” indicates activation or positive modulation, whereas the “-” indicates inactivation or inhibition. *Indicates those targets for which antagonists were shown to produce antinociception. AC = adenylate cyclase; CamKII = calcium-calmodulin dependent protein kinase II; cAMP = cyclic adenosine monophosphate; cGMP = cyclic guanosine monophosphate; GC = guanylate cyclase; IP3= inositol triphosphate; NOS = nitric oxide synthase; PKA = protein kinase A; PKC = protein kinase C; PKG = protein kinase G; PL = phospholipase. 
Fig. 4. Schematic summary of the spinal second-messenger systems involved in pain transmission. The figure is organized in columns and rows. Filled rectangles represent surface drug receptors. Compounds that activate each receptor are listed at the side. G-labeled pentagons represent the G-protein β and γ subunits, whereas the circles labeled “q”, “s,” and “i” represent the three functionally distinct isoforms of the α subunit. Circles with arrows represent enzymes that generate secondary metabolites as a direct consequence of activity of the G-protein subunits. The products of these enzymes are listed in the center of the figure. Rectangles represent the final tier of enzymes activated in the cascade. The “+” indicates activation or positive modulation, whereas the “-” indicates inactivation or inhibition. *Indicates those targets for which antagonists were shown to produce antinociception. AC = adenylate cyclase; CamKII = calcium-calmodulin dependent protein kinase II; cAMP = cyclic adenosine monophosphate; cGMP = cyclic guanosine monophosphate; GC = guanylate cyclase; IP3= inositol triphosphate; NOS = nitric oxide synthase; PKA = protein kinase A; PKC = protein kinase C; PKG = protein kinase G; PL = phospholipase. 
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Fig. 5. Schematic summary of the spinal excitatory amino acid (glutamate) receptors that participate in pain transmission. Excitatory amino acid receptor antagonists that modulate each receptor are listed, with arrows indicating the site of action. The boldface names and solid lines indicate the two classification schemes for these receptors. The “-” indicates antagonist effect. 
Fig. 5. Schematic summary of the spinal excitatory amino acid (glutamate) receptors that participate in pain transmission. Excitatory amino acid receptor antagonists that modulate each receptor are listed, with arrows indicating the site of action. The boldface names and solid lines indicate the two classification schemes for these receptors. The “-” indicates antagonist effect. 
Fig. 5. Schematic summary of the spinal excitatory amino acid (glutamate) receptors that participate in pain transmission. Excitatory amino acid receptor antagonists that modulate each receptor are listed, with arrows indicating the site of action. The boldface names and solid lines indicate the two classification schemes for these receptors. The “-” indicates antagonist effect. 
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Fig. 6. Summary of the spinal GABA receptors involved in pain transmission. Agonists and antagonists active at each receptor are listed, with arrows indicating the site of action. The “+” indicates agonist function and the “-” indicates antagonist function. 
Fig. 6. Summary of the spinal GABA receptors involved in pain transmission. Agonists and antagonists active at each receptor are listed, with arrows indicating the site of action. The “+” indicates agonist function and the “-” indicates antagonist function. 
Fig. 6. Summary of the spinal GABA receptors involved in pain transmission. Agonists and antagonists active at each receptor are listed, with arrows indicating the site of action. The “+” indicates agonist function and the “-” indicates antagonist function. 
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Fig. 7. Schematic summary of the spinal adenosine receptors involved in pain transmission. Subtype-selective agonists–antagonists have not yet been studied and therefore are not listed. 
Fig. 7. Schematic summary of the spinal adenosine receptors involved in pain transmission. Subtype-selective agonists–antagonists have not yet been studied and therefore are not listed. 
Fig. 7. Schematic summary of the spinal adenosine receptors involved in pain transmission. Subtype-selective agonists–antagonists have not yet been studied and therefore are not listed. 
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Table 1. Human Intrathecal Analgesics 
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Table 1. Human Intrathecal Analgesics 
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