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Special Articles  |   August 1999
Pain  : The Past, Present, and Future of Anesthesiology?
Author Notes
  • (Cousins) Professor and Head, Department of Anaesthesia & Pain Management.
  • Received from the University of Sydney Pain Management & Research Centre, Royal North Shore Hospital, New South Wales, Australia. Submitted for publication October 13, 1998. Accepted for publication March 15, 1999. Presented at the annual meeting of the American Society of Anesthesiologists, San Diego, California, October 20, 1997.
  • Address reprint requests to Dr. Cousins: Department of Anaesthesia & Pain Management, University of Sydney Pain Management & Research Centre, Royal North Shore Hospital, New South Wales 2065, Australia. Address electronic mail to:
Article Information
Special Articles
Special Articles   |   August 1999
Pain  : The Past, Present, and Future of Anesthesiology?
Anesthesiology 8 1999, Vol.91, 538-551. doi:
Anesthesiology 8 1999, Vol.91, 538-551. doi:
I WOULD first like to thank American Society of Anesthesiologists (ASA) President Phillip Bridenbaugh for inviting me to deliver this lecture; we have been professional colleagues and close friends for nearly 25 yr.
My address is entitled "Pain: The Past, Present, and Future of Anesthesiology?." It is appropriate to use this topic in this lecture series in memory of E. A. Rovenstine, or Rovie as he was affectionately known. Many know that he is credited with reporting in 1941 the use of suprascapular nerve block to relieve chronic shoulder pain, which is believed to be one of the earliest applications of nerve block for the relief of chronic pain. Perhaps fewer know that in 1948, nearly 50 yr ago, he published a paper with E. M. Papper that said "events in the changing medical world have made it imperative that we accept the challenge of pain occurring outside the surgical amphitheater. Such a concept fully justifies an anesthesia clinic on the therapy of pain." [dagger]
Papper seems to have carried this theme onward quite a long way, because at the age of 72 yr, in 1990, he published his PhD thesis entitled "Anesthesia, Pain and Suffering in the Romantic Era," [1 ] which was the era including the late 1700s and the first half of the 1800s. In his thesis, he says "attention to individuality by the romantic poets, essayists, and philosophers was crucial to preparing the way for change in clinical medicine designed to relieve pain and suffering and to prevent it where possible." He went on to say, "this required the production of an environment in which anesthesia could be accepted." I was fortunate last month to participate in the 150th anniversary of the discovery of chloroform for the relief of pain associated with childbirth. I would now like to return briefly to that environment surrounding the dramatic events of the first half of the 1800s with the discovery of ether for surgical anesthesia in 1846 and the discovery of chloroform in 1847 for relief of the pain of childbirth.
First, from the Paramount film The Great Discovery. The scene is the "Ether Dome" of the Massachusetts General Hospital in Boston; the surgeon, Mr. Warren, is addressing an audience of Boston physicians. A previous demonstration of nitrous oxide anesthesia by Horace Wells had been a dismal failure and was derided by the Boston physicians present as being outright dangerous.
Mr. Warren: We are gathered here today for you to witness while I perform an experiment in which I have confidence or at least a grain of hope. We will try a method advocated by a young dentist of this city, Dr. Morton. Well, sir, your patient is ready.
Dr. Morton: Thank you, sir, so am I.
Dr. Morton to patient Abbott: Don't be afraid. Just breathe in deeply. That's right. Keep on breathing.
Some time later, Dr. Morton: Mr. Warren, your patient is ready.
Mr. Warren: Thank you. Will he feel this?
Dr. Morton: He won't feel anything.
Mr. Warren: Now the next one [referring to request for instruments during the surgery].
Mr. Warren:[At the end of the surgery: Can you hear me, Abbott?
Abbott: Yes, sir.
Mr. Warren: Did you feel any pain?
Abbott: Huh?
Mr. Warren: I said, did you feel any pain?
Abbott: When?
Mr. Warren [to Boston physicians audience]: Gentlemen this is no humbug.
Now we travel to Edinburgh to revisit the discovery of chloroform for the relief of pain associated with childbirth. The following is taken from a video made for the University of Edinburgh to celebrate the 150th anniversary of the discovery of chloroform anesthesia-analgesia:
In a boxbed above his father's shop, James Young Simpson was born in 1811. In 1846, Robert Liston amputated a thigh in London using ether. Simpson immediately traveled down to visit his old professor of surgery before trying it himself in Edinburgh. The following year a contemporary from student days came back on a visit to Edinburgh; David Waldie of the Apothecaries Hall of London told Simpson he had discovered how to stabilize chloroform. He believed it might prove superior to ether. He offered to send some to Simpson. Simpson was joined at home by his two assistants Mathew Duncan and George Keith. Simpson had the chloroform. They set about trying it out. All three inhaled and all three passed out. It was the 4th of November 1847. Four days later, Simpson tried chloroform clinically for the first time, bringing Wilhelmina Carstairs into the world on the 8th of November. Many considered anesthetics as unnatural and morally wrong. Even the Professor of Surgery James Syme, while recognizing the benefits, initially opposed its use. For the rest of their lives, the two men had an acrimonious relationship. But Simpson gradually won the argument, especially after Queen Victoria's use of chloroform for the birth of her 8th child Prince Leopold on April 7th, 1853. The London Times in 1853 asked: 'Where would we have been without anesthetics? We place Simpson at the top of the list for true credit'.
The huge change in attitude that followed Queen Victoria's decision can be gauged from the following quotation from a leading article in the Lancet in 1853:
A very extraordinary report has obtained general circulation connected with the recent accouchement of her most gracious Majesty Queen Victoria. It has always been understood by the profession that the births of Royal children in all instances have been unattended by any peculiar or untoward circumstances. Intense astonishment, therefore, has been excited throughout the profession by the rumour that her Majesty during her last labour was placed under the influence of chloroform, an agent which has unquestionably caused instantaneous death in a considerable number of cases. Doubts on this subject cannot exist. In several of the fatal examples persons in their usual health expired while the process of inhalation was proceeding, and the deplorable catastrophes were clearly and indisputably referrible (sic) to the poisonous action of the chloroform, and to that cause alone.
These facts being perfectly well known to the medical world, we could not imagine that anyone had incurred the awful responsibility of advising the administration of chloroform to her Majesty during a perfectly natural labour with a seventh child. [It was, as a matter of fact, the eighth child]. On inquiry, therefore, we were not all surprised to learn that in her late confinement the Queen was not rendered insensible by chloroform or by any other anaesthetic agent. We state this with feelings of the highest satisfaction. In no case could it be justifiable to administer chloroform in perfectly ordinary labour; but the responsibility of advocating such a proceeding in the case of the Sovereign of these realms would, indeed, be tremendous. [2 ]
It is quite clear from these events that the introduction of ether for surgery and chloroform for childbirth really took place with considerable opposition and even denial from very prominent figures of that era, including surgeons, obstetricians, gynecologists, physicians and internists, and, indeed, society at large; nevertheless, this changed forever the pain and suffering associated with surgical procedures and childbirth.
What about Rovenstine's admonition that we should extend pain relief outside the operating theater? Sadly, if we look at pain relief, the possible versus reality, we are still not in a similar era for pain relief compared with the era for anesthesia that followed the discovery of ether and chloroform. For example, postsurgical, post-trauma, and cancer pain can now be relieved in more than 90% of patients, yet worldwide 50% or fewer patients have access to this type of relief. The situation is even worse in chronic, noncancer pain, for which, despite the fact that recent advances now make it possible to relieve pain in perhaps 70–80% of the patients, fewer than 10% of patients with these difficult problems obtain pain relief. It is interesting to note that 10–20 yr ago the possibility of pain relief in this group was probably less than 10%. So there has been a very large potential advance.
Patients with severe chronic pain represent a massive medical, economic, and societal problem. The patient's perspective, which is often expressed to me, is that they would be better off with cancer, because at least people would then believe that they had some easily recognizable cause for their pain. Indeed, there is a lack of a societal, humanitarian approach that one could liken to the lack of acceptance of childbirth pain relief in 1847. So we still face a very important challenge in changing not only societal but also medical attitudes toward, and practices for, the relief of chronic pain. There is also a lack of government focus on the huge economic costs and pitiful clinical resources, despite the fact that many hospitals are developing multidisciplinary pain management centers. They are doing this with great difficulty, and some are losing the battle rather sadly. And finally, there has been no discrete specialty status for this field. I am encouraged by the fact that in America, and now in Australia and in the United Kingdom, there is specialty training and specialty accreditation in this field. The Australian and New Zealand College of Anaesthetists has formed a Faculty of Pain Medicine that oversees training and an examination leading to a Fellowship in Pain Medicine. The Board of the Faculty of Pain Medicine is composed of representatives of the Australian and New Zealand College of Anaesthetists, The Royal Australasian College of Physicians, The Royal Australasian College of Surgeons, The Australian and New Zealand College of Psychiatrists, and the Faculty of Rehabilitation Medicine, Royal Australasian College of Physicians.
For those who do not practice in the field of pain medicine, I would like you, for just 1 min, to try to climb into the skin of a patient with severe unrelenting pain that continues day after day, night after night. This is a rather chilling description written by the psychologist LaShan. [3 ]
Terrible things being done, worse threatened. Outside forces in control. Will is helpless. No time limit set. Cannot predict when it will end. Pain is alien and meaningless. Consciousness turned inward. Time perspective lost. Relationships weakened.
I wonder what this suggests to you when you contemplate those words. Torture? For the patient with severe, unrelieved pain and the physician who has the ability to relieve that pain, but does not, is that "torture by omission"?
It is appropriate now to regard chronic pain as the silent epidemic. The dollar costs now exceed the combined cost of the acquired immune deficiency syndrome, cancer, and heart disease. Patients with chronic pain often suffer silently. Relatives and others are silent; they hope it won't happen to them. Society is silent; mostly it is unaware of this enormous human and financial cost. Politicians are silent because the costs are overwhelming. Finally, there is a huge gap between knowledge and practice, and this gap is, in fact, widening as the knowledge increases almost exponentially.
Chronic pain will be regarded as the disease of the 21st century. In a recent address, the Federal Minister for Health in Australia said, "the major costs in healthcare in Australia are common diseases-pain, asthma, diabetes, and the savings in best practice and treatment of these diseases could be about 25%." You will notice that he has used the word disease to refer to chronic pain. With best practice, savings in Australia could be about $4.8 billion annually, and you can multiple that by 15 times for the United States. In Australia, you may be aware that there has been much debate about the need for euthanasia legislation. Sadly, however, the focus in this debate has only been on patients with incurable cancer. And yet there is an enormous number of patients with severe noncancer pain, and many of these face a lifetime of unrelenting, excruciating pain. Many of these patients, and I see them weekly in our clinic, are, in fact, contemplating suicide. These are patients who would actively seek euthanasia if it was available and they felt that they had no other option. Yet pain relief and associated symptom control does restore a patient's will to live. Thus, the relief of chronic pain should be the priority in any debate that occurs in association with euthanasia.
To illustrate the plight of patients with chronic pain, consider a patient with a causalgia. This is a very severe form of pain associated with nerve injury. Such patients have a condition called allodynia. In other words, simply touching the skin causes pain. Opening the door to come into a room will cause this patient to withdraw the hand in the expectation of pain.
I would now like you to meet two further patients, both of whom very deliberately planned suicide because of their severe, unrelieved pain. The first is a specialist obstetrician who developed multiple sclerosis and was told by his neurologist "multiple sclerosis does not cause pain, you've got nothing to worry about, just get on with life." The second is a survivor of multiple back operations who decided that she could not survive the pain of her inoperable spinal stenosis. The following is taken from a video derived from a feature program on Australian National Television:
Patient Nic: I went blind and then went into bankruptcy in the middle of this incredible pain, which was like the worst form of torture I ask anyone to endure.
TV Presenter: It sounds like living hell and it was. Nic went from being a successful obstetrician with a thriving practice in Sydney to an incapacitated wreck who couldn't move out of the house.
Nic: My wife knew it was getting worse and did not know what to do about it.
Nic's Wife: It was just very distressing.
TV Presenter: After the insertion of a battery-driven pump into Nic's body that permanently pushes the drugs through a tube and into his spine, Nic's pain was greatly relieved. For Nic and his partner, Barbara, life only gets better.
TV Presenter: At 72 years of age, Lorraine thought her life was over as well. She had had three major back operations in 4 years. Her spine had degenerated to such a degree that further surgery for her spinal stenosis was pointless.
Lorraine: So, no matter how hard I tried, I simply could not walk and I found that I was always going back to bed. Even bed wasn't comfortable. The pain got to a stage where it was so bad I did not know how I was going to continue to live with it.
TV Presenter: Lorraine was bedridden for 8 months. She received the same treatment as Nic. A pump inserted into her body that delivers morphine and clonidine into the spine. Now only three weeks later…
Lorraine: It has given me quality of life. It has actually given me my life back. I am joining the world again. Of course, these are anecdotes and they do not prove the efficacy of the treatments used. However, they do give us an insight into the degree of suffering of patients with severe, intractable pain. Both patients had contemplated suicide and would have availed themselves of euthanasia, had it been legally available.
The situation illustrated by these patients points to the need for a different approach, an approach that sees pain relief as a basic human right. Now if one examines the human rights documents that exist in the world today, the first was the Bill of Rights of the United Kingdom in 1689, which had its antecedents in the Magna Carta of 1215. This was followed in 1789 by components of the Constitution and its Amendments in the United States. In France, in 1789, the concept of Liberty, Equality, and Fraternity also embodied specific human rights. In 1948, the United Nations Declaration of Human Rights said that "all persons are equal in dignity and rights and have the right to life, liberty and security." One can obtain that document incidentally on the Internet, and you will find that it is implied that, with appropriate medical care, one is able to achieve the aim of some quality of life. Interestingly, the United Nations Declaration does not mention pain relief as being a human right. However, I ask you just to ponder what would be your priority list for basic human rights. Would you consider freedom from hunger, which has been discussed so extensively? Freedom from thirst? Peace without political or other persecution? Freedom of speech, press, religion, assembly, mobility? The availability of unpolluted food, water, and air supply? Certainly, these are all important. However, they are difficult to enjoy if one has unrelenting, severe pain. I put it to you that the relief of severe, unrelenting pain would come at the top of a list of basic human rights. These concepts, I think, really have their antecedents in the pioneering work of John J. Bonica; his monumental text, The Management of Pain, was first published in the 1950s and then again in its second edition in 1990 immediately before his death. [4 ] He developed the multidisciplinary approach to pain management and founded the International Association for the Study of Pain. However, we are now at a stage when it will be our responsibility to take this concept to society, and this will not be an easy task.
I now return to the earlier theme that chronic pain is a disease entity. There is ample documentation now that persistent pain, even in the subacute phase after surgery, and in association with childbirth, can cause severe psychological and even psychiatric effects, which might be persistent. [5 ] There is also some extraordinary emerging evidence that persisting pain causes persisting physical effects involving pathophysiology of the nervous system itself. [6 ] We are used to the concept that severe pain may interfere with breathing and may stress the cardiovascular system. We are not at all used to the idea that severe pain may cause alterations in the nervous system itself: There may be spinal dorsal horn neuroanatomic reorganizations, so that the wiring in the spinal cord actually changes with time in association with severe pain; there are genetic changes in the dorsal horn of the spinal cord that change the dorsal horn neuronal response to nociception, increasing the response, which then remains increased; finally, there may even be the death of neurons in the spinal cord, and unfortunately these are inhibitory neurons. [7 ] The end result of all of this is what we see in the patient and what you saw graphically illustrated in the two patients described before-physical and mental deactivation.
Another illustration of pain as a disease is a patient who had what used to be called a reflex sympathetic dystrophy, now called complex regional pain syndrome type 1. The patient had an extraordinarily red and swollen foot. It was not possible to use any sheets covering her, because sheets touching the foot would cause her excruciating pain. Edema in her foot and leg became so great that large bubbles developed that would burst like a balloon. Now, extraordinarily, the only way to relieve these clinical signs and to relieve the severe pain was to use a high spinal anesthetic with an intrathecal catheter and to maintain a T4 level block, with the patient in an intensive care unit. Yet, when that was done, the swelling disappeared completely and the hyperalgesia disappeared. Such improvements are difficult to maintain, of course, with these severe neuropathic pain problems. Nevertheless, this short-term response shows what an absolute lie is the contention by some that reflex sympathetic dystrophy is a purely psychological problem.
Now let us turn to consider some of these persistent changes in the nervous system that can occur in association with long-standing, severe pain. I will take just a few examples. First, however, I would like to comment that when one reads the abstracts of the 1997 Annual Scientific Meeting of the ASA, in the section that deals with the neurosciences, it is astounding to see how much high-quality work is being done in the field of pain medicine. I could have chosen from any one of these abstracts for my illustrations in this lecture.
I take this opportunity to mention to you that the work that I will present now comes from a group of about 45 basic and clinical research workers of the Pain Management and Research Centre, University of Sydney, Royal North Shore Hospital, Sydney, Australia.
I would like to start with some comments on responses in association with injury of any type at the periphery: It could be surgery, it could be road trauma, it could be a mass of cancer cells invading, or it could be a degenerative process such as osteoarthritis. We now know that when the injury process occurs, there is sensitization of the nociceptors. It involves a wide variety of transmitters. The end result is primary hyperalgesia, an increased response to any sort of noxious stimulus in this area. Figure 1depicts this in more detail. Nociceptors are bathed in an "inflammatory soup" of various cytokines; adhesion factors; platelet activation factors; various algesic substances such as histamines, serotonin, and importantly substance P, which can set off vicious circles of activity; and arachidonic acid cascade products, including prostaglandins. [8 ] However, I will focus on one aspect of this response to injury, namely the sympathetic nerve activity that once was thought to be capable of sensitizing directly at the periphery by the release of norepinepherine (Figure 1). I would like to acknowledge that Figure 1was drawn by another colleague of mine who goes back nearly 25 yr, Mr. Allan Bentley, who has been the illustrator for all three volumes of the text Neural Blockade and has illustrated, in fact, most of my lectures. Allan Bentley is here today and I would like to thank you very much, Allan, for all of your help over these years.
Figure 1. Local tissue factors and peripheral pain receptors. The physical stimuli of trauma, the chemical environment (e.g., H+), algesic substances (e.g., serotonin [5-HT], bradykinin [BK]), and microcirculatory changes may all modify peripheral receptor activity. Substance P (SP) released by the axon reflex is an important peripheral pain transmitter. Efferent sympathetic activity may increase the sensitivity of receptors by means of norepinephrine (NA) release. Histamine, complement, and arachidonic cascade metabolites (e.g., prostaglandin E2[PgE], leukotriene B4[LTB4]) all may contribute to inflammation and increase the sensitivity of peripheral nociceptors, together with cytokines (e.g., tumor necrosis factor [TNF] and interleukin 1 [IL-1]), adhesion molecules (e.g., intercellular adhesion molecule [ICAM], endothelial leukocyte adhesion molecule [ELAM]), and platelet-activating factor (PAF). After injury, there is an increased concentration of opioid receptors on the peripheral nerve terminals, where endogenous opioids may reduce the sensitivity of nociceptive receptors. (Reproduced with permission from Kehlet. [  8 ]) 
Figure 1. Local tissue factors and peripheral pain receptors. The physical stimuli of trauma, the chemical environment (e.g., H+), algesic substances (e.g., serotonin [5-HT], bradykinin [BK]), and microcirculatory changes may all modify peripheral receptor activity. Substance P (SP) released by the axon reflex is an important peripheral pain transmitter. Efferent sympathetic activity may increase the sensitivity of receptors by means of norepinephrine (NA) release. Histamine, complement, and arachidonic cascade metabolites (e.g., prostaglandin E2[PgE], leukotriene B4[LTB4]) all may contribute to inflammation and increase the sensitivity of peripheral nociceptors, together with cytokines (e.g., tumor necrosis factor [TNF] and interleukin 1 [IL-1]), adhesion molecules (e.g., intercellular adhesion molecule [ICAM], endothelial leukocyte adhesion molecule [ELAM]), and platelet-activating factor (PAF). After injury, there is an increased concentration of opioid receptors on the peripheral nerve terminals, where endogenous opioids may reduce the sensitivity of nociceptive receptors. (Reproduced with permission from Kehlet. [  8]) 
Figure 1. Local tissue factors and peripheral pain receptors. The physical stimuli of trauma, the chemical environment (e.g., H+), algesic substances (e.g., serotonin [5-HT], bradykinin [BK]), and microcirculatory changes may all modify peripheral receptor activity. Substance P (SP) released by the axon reflex is an important peripheral pain transmitter. Efferent sympathetic activity may increase the sensitivity of receptors by means of norepinephrine (NA) release. Histamine, complement, and arachidonic cascade metabolites (e.g., prostaglandin E2[PgE], leukotriene B4[LTB4]) all may contribute to inflammation and increase the sensitivity of peripheral nociceptors, together with cytokines (e.g., tumor necrosis factor [TNF] and interleukin 1 [IL-1]), adhesion molecules (e.g., intercellular adhesion molecule [ICAM], endothelial leukocyte adhesion molecule [ELAM]), and platelet-activating factor (PAF). After injury, there is an increased concentration of opioid receptors on the peripheral nerve terminals, where endogenous opioids may reduce the sensitivity of nociceptive receptors. (Reproduced with permission from Kehlet. [  8 ]) 
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Now, let us return to the nociceptors at the periphery, the A [Greek small letter delta] and C-polymodal nociceptors, which increase their firing in association with injury because of the inflammatory soup that forms around them. I should also note that there are "silent nociceptors" that normally do not fire, but will begin to fire in the presence of this inflammatory soup. We now know that there are many sympathetic fibers that arborize around the nociceptor neurons. [9 ] This occurs not only at the periphery but, in association with nerve injury, little baskets of sympathetic neurons form around the cells of the dorsal root ganglion. This was shown recently by a colleague of ours in Syndney, Dr. Elspeth McLaughlin. [9 ] She also showed that there are [Greek small letter alpha] receptors that proliferate around the dorsal root ganglion. Initially, it was thought that norepinephrine was released and acted on [Greek small letter beta] receptors on the nociceptor. More recently, a colleague, Dr. Deborah White, working with Dr. Jon Levine in San Francisco, showed that, in fact, the norepinephrine in turn results in a release of prostaglandins. [10 ] The norepinephrine acts on [Greek small letter alpha] 2 receptors on the sympathetic terminals, which, in turn, produce the release of prostaglandins. [11 ]
Dr. White has recently investigated in our laboratories the mechanism of [Greek small letter alpha] 2-receptor activation and the subsequent release of prostaglandins. She has proposed that calcium might be involved, because there are special calcium channels on the sympathetic terminals called N-calcium channels, which might be the mechanism of the release of prostaglandins. In that study, Dr. White administered subcutaneously different calcium channel blockers in a rat model of nerve injury-induced hyperalgesia: Sciatic nerve injury produces very marked hyperalgesia in the rat paw. The method used by Dr. White was the same in all of her studies of calcium channel blockers. First, the threshold pressure for withdrawal of the rat's paw is measured in the normal situation and then after nerve ligation. If the L-type calcium channel blocker nifedipine is given, it has no effect on hyperalgesia. The new calcium channel blockers derive from a little cone fish from the Southern Pacific region, which produces conotoxins. One of them is SNX-230, and this drug had no effect on nerve injury-induced hyperalgesia; SNX-230 is a drug that works on the P and Q calcium channels. Next, however, Dr. White used the drug SNX-111, which is a rather specific blocker of the N-calcium channels in nerves: After nerve ligation but with daily injections of SNX-111 at increasing doses, at the highest dose level, hyperalgesia was abolished (Figure 2A). [12 ]
Figure 2. (A) Subcutaneous administration of SNX-111 significantly attenuates nerve injury-induced hyperalgesia. Nerve injury-induced hyperalgesia was significantly attenuated by 100 [micro sign]M SNX-111 (P < 0.05 by analysis of variance; n = 9). (B) Subcutaneous injection of the calcium-chelating agent, quin 2, attenuates nerve injury-induced hyperalgesia. Partial ligation of the sciatic nerve induces a significant decrease in mechanical threshold compared with values determined in the week before nerve ligation. Subcutaneous injection of quin 2 (20 [micro sign]g/2.5 [micro sign]l) significantly attenuates the nerve injury-induced hyperalgesia compared with vehicle-treated controls (P < 0.05). Subcutaneous injection of the vehicle, dimethyl sulfoxide (DMSO), had no effect on the nerve injury-induced hyperalgesia compared with untreated controls. (Reproduced with permission from White and Cousins. [  12 ]) 
Figure 2. (A) Subcutaneous administration of SNX-111 significantly attenuates nerve injury-induced hyperalgesia. Nerve injury-induced hyperalgesia was significantly attenuated by 100 [micro sign]M SNX-111 (P < 0.05 by analysis of variance; n = 9). (B) Subcutaneous injection of the calcium-chelating agent, quin 2, attenuates nerve injury-induced hyperalgesia. Partial ligation of the sciatic nerve induces a significant decrease in mechanical threshold compared with values determined in the week before nerve ligation. Subcutaneous injection of quin 2 (20 [micro sign]g/2.5 [micro sign]l) significantly attenuates the nerve injury-induced hyperalgesia compared with vehicle-treated controls (P < 0.05). Subcutaneous injection of the vehicle, dimethyl sulfoxide (DMSO), had no effect on the nerve injury-induced hyperalgesia compared with untreated controls. (Reproduced with permission from White and Cousins. [  12]) 
Figure 2. (A) Subcutaneous administration of SNX-111 significantly attenuates nerve injury-induced hyperalgesia. Nerve injury-induced hyperalgesia was significantly attenuated by 100 [micro sign]M SNX-111 (P < 0.05 by analysis of variance; n = 9). (B) Subcutaneous injection of the calcium-chelating agent, quin 2, attenuates nerve injury-induced hyperalgesia. Partial ligation of the sciatic nerve induces a significant decrease in mechanical threshold compared with values determined in the week before nerve ligation. Subcutaneous injection of quin 2 (20 [micro sign]g/2.5 [micro sign]l) significantly attenuates the nerve injury-induced hyperalgesia compared with vehicle-treated controls (P < 0.05). Subcutaneous injection of the vehicle, dimethyl sulfoxide (DMSO), had no effect on the nerve injury-induced hyperalgesia compared with untreated controls. (Reproduced with permission from White and Cousins. [  12 ]) 
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Does the abolition of nerve injury-induced hyperalgesia involve calcium? Dr. White used a drug called quin 2, which chelates calcium. In other words, it binds calcium so much less of it is present. Once again, after the nerve ligation, marked hyperalgesia occurs, but after daily injections of quin 2 binding the calcium, hyperalgesia is abolished (Figure 2B). [12 ] So this is a calcium mechanism, and this opens up an important new peripheral option for the treatment of hyperalgesia, such as in patients with neuropathic pains such as neuralgias, which inevitably begin at the periphery but then move centrally. We would like to treat them before they do that. This study by Dr. White is the first report of the use of SNX-111 at the peripheral level.
One of the options for pain relief at the periphery that we have not mentioned yet is using opioid receptors that are expressed peripherally in the presence of trauma. Messenger RNA in the dorsal root ganglion is transported to the periphery, and this is the specific messenger RNA for opioid receptors. So now opioid receptors become expressed on the primary afferent neurons. At the same time, in association with trauma, the inflammatory cells begin to secrete opioid peptides. [13 ] Of course, there are also opioid receptors in the spinal cord and in the brain. The problem with opioids, however, when they are used systemically, is that we really have found that they are not very good for movement-associated pain. They are also not very good for mobilizing patients. When patients have some nausea and vomiting, when their gut is not working very well, they are not very motivated to get up and about and resume normal life. The Astra Company is working on a peripherally acting opioid that is a small peptide. Their aim is to develop a drug that will not cross the blood-brain barrier.
Such a peptide will not act on spinal and brain receptors but will, after local injection, purely act at the periphery. This work already looks promising.
Now let us summarize where we have come so far. We have discussed the fact that clinical pain certainly is elicited by the A [Greek small letter delta] and C nociceptor, but it becomes really a pathologic state because there are inflammatory factors that sensitize nociceptors, and very often there will be nerve damage so that there may be neuropathic pain. We have discussed the fact that inevitably in any clinical situation, there is sensitization at the periphery. We have not yet discussed the fact that it is also inevitable that in clinical pain there will be central sensitization. In this situation, the touch fibers, the A [Greek small letter beta] fibers, will play a part in clinical pain. [7 ] In addition, importantly, pain will outlast the stimulus. For example, with nerve damage, one could come back 14 days after damaging a nerve and still find an increase in dorsal horn neuronal activity. The pain also may spread to undamaged areas (secondary hyperalgesia). [7 ] We know that this neuronal disturbance can extend for as much as four segments above and four segments below the damaged area. This is a far cry from the old idea of a strictly segmental pattern.
How does this central sensitization occur? A subtle process involving N-methyl-D-aspartate (NMDA), [Greek small letter alpha]-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and substance P receptors in the dorsal horn plays a key role. [7 ] With a very transient stimulus, such as pricking your skin with a pain, glutamate is released and acts quickly on the AMPA receptor; this response occurs rapidly and dissipates rapidly. However, in the clinical situation, the concomitant release of glutamate and substance P will cause simultaneous action on the AMPA and the various neurokinin receptors (e.g., substance P receptor), and that action will prime the central receptor, NMDA receptor. It is primed by displacement of a plug of magnesium that sits in the N-calcium channel and otherwise prevents activation. [7 ] In the ASA Scientific Program of 1997, several papers described the use of magnesium to increase magnesium concentrations and presumably to prevent this unplugging of the NMDA receptor. This is an interesting and simple approach. Importantly, we know now that the activation of this NMDA receptor is associated with at least some of these nasty dorsal horn changes associated with hyperalgesia. [7 ]
A severe stimulus at the periphery or cutting nerves or indeed damaging, crushing, or making muscles ischemic will cause a profound enhancement of neuronal activity in the spinal cord, at the dorsal horn, at the interneuronal level, and at the anterior horn cell level. [7 ] We have learned an enormous amount about why this disturbance occurs postsynaptically and also intraneurally. Inside the dorsal horn neuron, calcium appears to play a crucial role in activating a chain of events that finally results in the production of nitric oxide; this is necessary for normal nerve function, but too much glutamate release will result in excessive calcium release and, in turn, excessive nitric oxide production, which could produce neurotoxic effects. [7 ] Animal models are showing that this type of situation will result in dark bodies in the dorsal horn that are dead cells. Rather intriguingly, the cells that are the most likely to die may be the inhibitory cells, particularly the cells of the [Greek small letter gamma]-aminobutyric acidAtype, [14 ] which immediately raises the possibility that drugs of this type may be useful in this situation. There are some case reports of patients with postherpetic neuralgia, who died with pain and in whom the post mortem examination showed dead cells in the dorsal horn in addition to what we would normally expect in the dorsal root ganglion. On the other hand, patients who died having had zoster but without postherpetic neuralgia do not appear to have these dead cells in the dorsal horn. [15 ] Of course, interest again focuses on the potential for preventing such changes by blocking N-calcium channels, and this is where drugs such as SNX-111 again become of interest. Our own early studies in patients with cancer pain, and studies of other researchers, have indeed shown that the use of SNX-111 intrathecally will reverse the secondary hyperalgesia associated with some forms of severe neuropathic cancer pain. [16 ]
I will now focus my remaining remarks on nerve injury pain, because it represents the greatest challenge to most clinicians. The characteristics of neuropathic pain are summarized in Table 1. Thus, this is a condition that can be diagnosed clinically using very simple symptoms and signs. Yet, sadly, many patients with post-traumatic pain, including spinal cord injury pain [17 ] and postsurgical pain do not have neuropathic pain diagnosed early. In a prospective study of 100 patients with spinal cord injury, 55% had neuropathic pain 6 months after injury, and in 21% of these patients the pain was severe. [17 ] This study by Dr. Philip Siddall from our group confirms that neuropathic pain is an important problem in patients with spinal cord injuries and is the major factor limiting return to work and recreational activities. Another example of the lack of early diagnosis is the foot of a young girl who did not have an early diagnosis of neuropathic pain and developed a severe form of reflex sympathetic dystrophy (Figure 3). It is hard to recognize this photograph as a foot. The tissues have developed gross distortion and have become fungating and "woody." This is a tragic outcome of failure to treat such a problem early; at this stage, the patient's pain was severe and unresponsive to opioids. Why is pain associated with nerve damage poorly responsive to opioid drugs?Figure 4is taken from the work of Mao, Price, and Mayer at the University of Virginia. [18 ] In the presence of nerve injury, there is an increased release of glutamate acting on the NMDA receptor, which in turn causes a massive increase in calcium release and then nitric oxide release; this activates cyclic guanosine monophosphate and protein kinases, resulting in feedback to the NMDA receptor and thus increasing its activity. Calcium itself causes a big increase in NMDA activity. [18 ] Thus, a few vicious circles are operating here. In addition, if one administers morphine in the presence of nerve injury, these two effects will decrease the effect of morphine at the nociceptor. Both the protein kinase effect and the calcium effect have a negative feedback effect on the [micro sign] receptor. The administration of morphine also triggers this calcium mechanism, which has a negative feedback effect on the [micro sign] receptor. [18 ] Patients with neuropathic pain will not demonstrate a very efficacious effect from the administration of morphine; and if one continues to give morphine, morphine itself will contribute to the mechanisms just described, so that the neuropathic pain may worsen rather than lessen. Clearly, we are looking for other drugs that are more effective on NMDA, calcium, nitric oxide, and protein kinase mechanisms in the presence of neuropathic pain. Even in the patient with cancer, the diagnosis of neuropathic pain tends to be at a lower level than it should be. A patient with a spinal metastasis initially may experience pain caused by a noxious stimuli as the periosteum is stretched. As the cancer invades nerve roots, progressively the patient will experience pain, which is a mixed nociceptive and neuropathic type. If pain persists in the long term and opioids are given as the sole treatment, all of the mechanisms already described will come into play.
Table 1. Diagnosing Neuropathic Pain 
Image not available
Table 1. Diagnosing Neuropathic Pain 
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Figure 3. The foot of a 16-yr-old girl with a severe reflex sympathetic dystrophy (complex regional pain syndrome type 1). 
Figure 3. The foot of a 16-yr-old girl with a severe reflex sympathetic dystrophy (complex regional pain syndrome type 1). 
Figure 3. The foot of a 16-yr-old girl with a severe reflex sympathetic dystrophy (complex regional pain syndrome type 1). 
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Figure 4. Nerve injury leads to the release of glutamate (Glu) from the central terminals of primary nociceptive afferents. Glutamate activates the N-methyl D-aspartate receptor (NMDA-R), which leads to calcium influx and increased production of nitric oxide. An increase in nitric oxide leads to activation of cyclic guanosine monophosphate and various protein kinases (PKs). These substances then act as a feedback mechanism at the NMDA-R (positive feedback) and [micro sign]-opioid receptor (negative feedback). This means that subsequent administration of morphine results in a vicious cycle, with further positive feedback at the NMDA-R. (Reproduced with permission from Siddall and Cousins. [  7 ]) 
Figure 4. Nerve injury leads to the release of glutamate (Glu) from the central terminals of primary nociceptive afferents. Glutamate activates the N-methyl D-aspartate receptor (NMDA-R), which leads to calcium influx and increased production of nitric oxide. An increase in nitric oxide leads to activation of cyclic guanosine monophosphate and various protein kinases (PKs). These substances then act as a feedback mechanism at the NMDA-R (positive feedback) and [micro sign]-opioid receptor (negative feedback). This means that subsequent administration of morphine results in a vicious cycle, with further positive feedback at the NMDA-R. (Reproduced with permission from Siddall and Cousins. [  7]) 
Figure 4. Nerve injury leads to the release of glutamate (Glu) from the central terminals of primary nociceptive afferents. Glutamate activates the N-methyl D-aspartate receptor (NMDA-R), which leads to calcium influx and increased production of nitric oxide. An increase in nitric oxide leads to activation of cyclic guanosine monophosphate and various protein kinases (PKs). These substances then act as a feedback mechanism at the NMDA-R (positive feedback) and [micro sign]-opioid receptor (negative feedback). This means that subsequent administration of morphine results in a vicious cycle, with further positive feedback at the NMDA-R. (Reproduced with permission from Siddall and Cousins. [  7 ]) 
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What is the basis of neuroanatomic reorganization in response to nerve injury? As the nerve fibers come into the dorsal horn area of the spinal cord, there are various laminae, the so-called Rexed laminae. The touch fibers, A[Greek small letter beta] fibers, normally dive down deep into the third and fourth laminae of the dorsal horn. The A[Greek small letter delta] and C fibers, the nociceptors, synapse very superficially in laminae 1 and 2. Thus, the spinal cord is not "a bunch of computer cables"; in fact, there is already a rather delicate separation of touch and pain fibers. Incidentally, the original proposal of the "Gate Control" theory has been expanded enormously in the form of many facilitory and inhibitory transmitters permitting exquisitely balanced modulation. Approximately 6 years ago, Dr. Clifford Woolf, working at the University College in London, showed that about 1 week after peripheral nerve damage the A [Greek small letter beta] fibers begin to sprout from laminae 111 into the superficial laminae 11. These are touch fibers now sprouting to form synapses with pain fibers in the superficial dorsal horn. [19 ] Not surprising, then, if one now touches the skin this person will experience pain because of a touch stimulus coming in and activating the nociceptor in the superficial laminae. This work was greeted with some incredulity when it was published, but it has now been replicated in many laboratories, including our own. [20 ] In Figure 5, the dorsal horn of the spinal cord is shown with a special retrograde staining technique to stain the A [Greek small letter beta] fibers, the touch fibers. In the normal situation, the touch fibers entering into the spinal cord are located in the deeper laminae 3 and 4 areas of the spinal cord. In the superficial laminae 1 and 2 there are no A [Greek small letter beta] fibers. Dr. White has used several different methods to produce nerve damage, but perhaps the most interesting of all has been with the chemotherapy agent vinblastine, which produces a severe form of peripheral neuropathic pain. In Figure 6, treatment with vinblastine is shown, producing hyperalgesia and neuronal sprouting. [20 ]
Figure 5. Darkfield micrographs of a transverse section of the L4 level of rat spinal cord after injection of collagenoid-horseradish peroxidase into the sciatic nerve. (A) C-HRP label injected into the right sciatic nerve 2 weeks after being treated with a topical application of saline is found in laminae I, III, and IV. There is no label in lamina II (n = 2). The medial aspect is located on the left side of the micrograph. (B) Topical application of vinblastine to the left sciatic nerve of a different animal causes the labeled region to expand into laminae II (n = 4). The medial aspect is located on the right side of the micrograph. Calibration bar = 50 [micro sign]m. (Reproduced with permission from White et al. [  20 ]) 
Figure 5. Darkfield micrographs of a transverse section of the L4 level of rat spinal cord after injection of collagenoid-horseradish peroxidase into the sciatic nerve. (A) C-HRP label injected into the right sciatic nerve 2 weeks after being treated with a topical application of saline is found in laminae I, III, and IV. There is no label in lamina II (n = 2). The medial aspect is located on the left side of the micrograph. (B) Topical application of vinblastine to the left sciatic nerve of a different animal causes the labeled region to expand into laminae II (n = 4). The medial aspect is located on the right side of the micrograph. Calibration bar = 50 [micro sign]m. (Reproduced with permission from White et al. [  20]) 
Figure 5. Darkfield micrographs of a transverse section of the L4 level of rat spinal cord after injection of collagenoid-horseradish peroxidase into the sciatic nerve. (A) C-HRP label injected into the right sciatic nerve 2 weeks after being treated with a topical application of saline is found in laminae I, III, and IV. There is no label in lamina II (n = 2). The medial aspect is located on the left side of the micrograph. (B) Topical application of vinblastine to the left sciatic nerve of a different animal causes the labeled region to expand into laminae II (n = 4). The medial aspect is located on the right side of the micrograph. Calibration bar = 50 [micro sign]m. (Reproduced with permission from White et al. [  20 ]) 
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Figure 6. (A) Dissociated dorsal root ganglion cells removed 2 weeks after transection of the sciatic nerve have a significant increase in neurite outgrowth compared with dorsal root ganglion cells taken from healthy animals (*P < 0.005 by the Student t test; n = 4). Inhibition of axonal transport in the sciatic nerve by topical application of vinblastine also induced a significant increase in neurite outgrowth of the dissociated dorsal root ganglion cells compared with untreated controls (50 [micro sign]M; P < 0.005, n = 4). Topical application of the vehicle, saline (n = 4), had no effect on neurite outgrowth. (B) Behavioral experiments show that topical application of vinblastine (n = 4) induces a significant decrease in the mechanical threshold compared with saline-treated control rats (n = 4)(P < 0.0005 by two-way analysis of variance). The results are calculated as:(threshold of treated paw)-(threshold of untreated paw)/(threshold of untreated paw) x 100. (Reproduced with permission from White et al. [  20 ]) 
Figure 6. (A) Dissociated dorsal root ganglion cells removed 2 weeks after transection of the sciatic nerve have a significant increase in neurite outgrowth compared with dorsal root ganglion cells taken from healthy animals (*P < 0.005 by the Student t test; n = 4). Inhibition of axonal transport in the sciatic nerve by topical application of vinblastine also induced a significant increase in neurite outgrowth of the dissociated dorsal root ganglion cells compared with untreated controls (50 [micro sign]M; P < 0.005, n = 4). Topical application of the vehicle, saline (n = 4), had no effect on neurite outgrowth. (B) Behavioral experiments show that topical application of vinblastine (n = 4) induces a significant decrease in the mechanical threshold compared with saline-treated control rats (n = 4)(P < 0.0005 by two-way analysis of variance). The results are calculated as:(threshold of treated paw)-(threshold of untreated paw)/(threshold of untreated paw) x 100. (Reproduced with permission from White et al. [  20]) 
Figure 6. (A) Dissociated dorsal root ganglion cells removed 2 weeks after transection of the sciatic nerve have a significant increase in neurite outgrowth compared with dorsal root ganglion cells taken from healthy animals (*P < 0.005 by the Student t test; n = 4). Inhibition of axonal transport in the sciatic nerve by topical application of vinblastine also induced a significant increase in neurite outgrowth of the dissociated dorsal root ganglion cells compared with untreated controls (50 [micro sign]M; P < 0.005, n = 4). Topical application of the vehicle, saline (n = 4), had no effect on neurite outgrowth. (B) Behavioral experiments show that topical application of vinblastine (n = 4) induces a significant decrease in the mechanical threshold compared with saline-treated control rats (n = 4)(P < 0.0005 by two-way analysis of variance). The results are calculated as:(threshold of treated paw)-(threshold of untreated paw)/(threshold of untreated paw) x 100. (Reproduced with permission from White et al. [  20 ]) 
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What is the mechanism of this sprouting and how can we prevent it? This is important, because, if it occurs, it will be chronic and perhaps even permanent. Dr. White has investigated the possibility that peptides in the spinal cord, vasoactive intestinal polypeptide and neuropeptide Y, have some sort of indirect action, [21 ] which in turn increases the sprouting of A [Greek small letter beta] fibers in the dorsal horn (Figure 7). The sprouting in the dorsal horn occurs in way that is nearly identical to sprouting in the dorsal root ganglion. To examine factors that contribute to sprouting, it is convenient to study dorsal root ganglion cells, because they can be cultured and survive.
Figure 7. Possible mechanisms of involvement of vasoactive intestinal polypeptide and neuropeptide Y (NPY) in the sprouting of dorsal horn A [Greek small letter beta] fibers. (Courtesy of Dr. D. White.) 
Figure 7. Possible mechanisms of involvement of vasoactive intestinal polypeptide and neuropeptide Y (NPY) in the sprouting of dorsal horn A [Greek small letter beta] fibers. (Courtesy of Dr. D. White.) 
Figure 7. Possible mechanisms of involvement of vasoactive intestinal polypeptide and neuropeptide Y (NPY) in the sprouting of dorsal horn A [Greek small letter beta] fibers. (Courtesy of Dr. D. White.) 
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(Figure 8A) shows that neuropeptide Y increases the sprouting of dorsal root ganglion cells. However, there is a proviso that the dorsal root ganglion cells are cultured together with slices of spinal cord. If the spinal cord slice is eliminated, there is no effect of neuropeptide Y [21 ](Figure 8B). In other words, something is being produced in the spinal cord itself that is acting as a secondary factor in producing the sprouting. What could that be?Figure 7indicates that neuropeptide Y acts on a receptor in a spinal cord cell and probably produces neurotrophin 3, which in turn probably acts on a tyrosine kinase receptor. We know that if we block tyrosine kinase receptors with a drug called K252A we prevent the sprouting of these neurons. We also know that vasoactive intestinal polypeptide will produce a similar effect, again indirectly through a trophic factor, which acts via cyclic AMP. If we block cyclic AMP with an AMP isomer, the sprouting does not occur (see White [22 ]).
Figure 8. (A) Effect of vasoactive intestinal polypeptide (VIP) and neuropeptide Y (NPY) on neurite outgrowth of dissociated dorsal root ganglion cells coplated with spinal cord explants. (B) Effects of vasoactive intestinal polypeptide and neuropeptide Y on neurite outgrowth of dissociated dorsal root ganglion cells plated alone. (Reproduced with permission from White and Mansfield. [  21 ]) 
Figure 8. (A) Effect of vasoactive intestinal polypeptide (VIP) and neuropeptide Y (NPY) on neurite outgrowth of dissociated dorsal root ganglion cells coplated with spinal cord explants. (B) Effects of vasoactive intestinal polypeptide and neuropeptide Y on neurite outgrowth of dissociated dorsal root ganglion cells plated alone. (Reproduced with permission from White and Mansfield. [  21]) 
Figure 8. (A) Effect of vasoactive intestinal polypeptide (VIP) and neuropeptide Y (NPY) on neurite outgrowth of dissociated dorsal root ganglion cells coplated with spinal cord explants. (B) Effects of vasoactive intestinal polypeptide and neuropeptide Y on neurite outgrowth of dissociated dorsal root ganglion cells plated alone. (Reproduced with permission from White and Mansfield. [  21 ]) 
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How good is the evidence that the final common pathway for neuropeptide Y is neurotrophin 3? The proposal is that in the deeper layers of the dorsal horn of the spinal cord, in the third and fourth layer, the release of neuropeptide Y then results in the release of neurotrophin 3, which is the factor that causes the sprouting of touch fibers back into the superficial layers of the spinal cord (Figure 9). This time, Dr. White is working with a preparation that does not have any nerve injury and neurotrophin 3 is administered through a mini pump, which is a rat version of the spinal drug delivery pumps that we use in humans. After the mini pumps are implanted, either saline or neurotrophin 3 is administered. When neurotrophin 3 is administered (as shown in Figure 10A), the mechanical threshold decreases. In other words, the animals can tolerate much less paw pressure, so they have hyperalgesia. In addition, neurotrophin 3 by itself will cause a marked increase in sprouting of dorsal root ganglion cells. [22 ] On the other hand, if we use an antiserum to neurotrophin 3, to eliminate neurotrophin 3, the NPY-induced sprouting is prevented (Figure 10B). [22 ] So, clearly, neurotrophin 3 does play an important part. I find it extraordinary that just 6 years after Clifford Woolf demonstrated this rather malignant "rewiring effect" in the dorsal horn, we already have some important leads to develop a specific treatment. With molecular engineering, I do not think it will be long before we have specific agents to prevent this problem.
Figure 9. Possible mechanism of involvement of neurotrophin 3 (NT-3) in spinal dorsal horn sprouting. (Courtesy of Dr. D. White.) 
Figure 9. Possible mechanism of involvement of neurotrophin 3 (NT-3) in spinal dorsal horn sprouting. (Courtesy of Dr. D. White.) 
Figure 9. Possible mechanism of involvement of neurotrophin 3 (NT-3) in spinal dorsal horn sprouting. (Courtesy of Dr. D. White.) 
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Figure 10. (A) Intrathecal neurotrophin 3 (NT-3) induced hyperalgesia to mechanical stimulation. Behavioral experiments show that intrathecal administration of NT-3 (n = 5) induces a significant decrease in the mechanical threshold after 4 days compared with saline-treated control rats (n = 4;*P < 0.01 by one-way analysis of variance followed by Scheffe F test post hoc comparison). (B) The percentage of dorsal root ganglion cells with neurite outgrowth increased significantly when plated in the supernatant of spinal cord incubated with 10 nM neuropeptide Y for 2 h at 37 [degree sign]C compared with control (n = 4;*P < 0.05 by the Student t test). Control cells were plated in the supernatant of spinal cord incubated in culture medium alone. The addition of antiserum to nerve growth factor (aNGF; 0.5% solution) had no effect on the neuropeptide Y-induced increase in neurite outgrowth (n = 4). Antiserum to NT-3 (aNT-3; 1% solution) significantly inhibited the trophic effect of the neuropeptide Y-conditioned supernatant (n = 4; control vs. supernatant, ***P < 0.0005; supernatant vs. supernatant + aNT-3, **P < 0.005). (Reproduced with permission from White. [  22 ]) 
Figure 10. (A) Intrathecal neurotrophin 3 (NT-3) induced hyperalgesia to mechanical stimulation. Behavioral experiments show that intrathecal administration of NT-3 (n = 5) induces a significant decrease in the mechanical threshold after 4 days compared with saline-treated control rats (n = 4;*P < 0.01 by one-way analysis of variance followed by Scheffe F test post hoc comparison). (B) The percentage of dorsal root ganglion cells with neurite outgrowth increased significantly when plated in the supernatant of spinal cord incubated with 10 nM neuropeptide Y for 2 h at 37 [degree sign]C compared with control (n = 4;*P < 0.05 by the Student t test). Control cells were plated in the supernatant of spinal cord incubated in culture medium alone. The addition of antiserum to nerve growth factor (aNGF; 0.5% solution) had no effect on the neuropeptide Y-induced increase in neurite outgrowth (n = 4). Antiserum to NT-3 (aNT-3; 1% solution) significantly inhibited the trophic effect of the neuropeptide Y-conditioned supernatant (n = 4; control vs. supernatant, ***P < 0.0005; supernatant vs. supernatant + aNT-3, **P < 0.005). (Reproduced with permission from White. [  22]) 
Figure 10. (A) Intrathecal neurotrophin 3 (NT-3) induced hyperalgesia to mechanical stimulation. Behavioral experiments show that intrathecal administration of NT-3 (n = 5) induces a significant decrease in the mechanical threshold after 4 days compared with saline-treated control rats (n = 4;*P < 0.01 by one-way analysis of variance followed by Scheffe F test post hoc comparison). (B) The percentage of dorsal root ganglion cells with neurite outgrowth increased significantly when plated in the supernatant of spinal cord incubated with 10 nM neuropeptide Y for 2 h at 37 [degree sign]C compared with control (n = 4;*P < 0.05 by the Student t test). Control cells were plated in the supernatant of spinal cord incubated in culture medium alone. The addition of antiserum to nerve growth factor (aNGF; 0.5% solution) had no effect on the neuropeptide Y-induced increase in neurite outgrowth (n = 4). Antiserum to NT-3 (aNT-3; 1% solution) significantly inhibited the trophic effect of the neuropeptide Y-conditioned supernatant (n = 4; control vs. supernatant, ***P < 0.0005; supernatant vs. supernatant + aNT-3, **P < 0.005). (Reproduced with permission from White. [  22 ]) 
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Dr. White also studied the dorsal horn of the spinal cord in association with transganglionic labeling of the A [Greek small letter beta] fibers, using a horseradish peroxidase derivative: First, after intrathecal saline through a mini pump, the deeper layers showed significant staining for the A [Greek small letter beta] fibers, whereas in lamina 2 there was no staining for A [Greek small letter beta] fibers. However, after infusion of neurotrophin 3, the A [Greek small letter beta] fibers were stained right back into lamina 2. [22 ] So, clearly, neurotrophin 3 plays an important part in A-[Greek small letter beta] fiber sprouting. This series of studies provides strong support for the notion that chronic pain can become a disease entity. Fortunately, our insight into the neurophysiology and neuroanatomy of this disease is increasing rapidly. Such knowledge may set the scene for a direct attack on the pathophysiology and neuroanatomic reorganization via a newly proposed strategy of "combination (analgesic) spinal chemotherapy." [23 ]
Conclusions 
In the past, anesthesiology was obviously strongly influenced by an environment created by the romantic era of the first half of the 1800s, in which the relief of pain associated with surgery and with childbirth could be accepted. This occurred despite substantial opposition from some powerful figures of the era. Anesthesia for surgery and labor pain relief has been accepted worldwide as virtually a human right, although there remains some opposition in some parts of the world to the use of epidural analgesia in childbirth. In addition, the acceptance of anesthesia and analgesia for neonates surprisingly has occurred only recently. A focus on fiscal concerns in the past 20 yr has deemphasized humanitarian issues in medicine. Yet, we have the knowledge and expertise to relieve most postsurgical and cancer-related pain, and encouraging advances are being made in chronic pain management and in pain research, some of which I have tried to illustrate in this Rovenstine lecture. However, the need to overcome opposition challenges us again if we are to realize the advances possible in pain treatment, in a similar manner to what occurred in the mid-1800s for anesthesia and the relief of the pain of childbirth. In the future, anesthesiology can play the key role in the management of what will undoubtedly be the disease of the new millennium. I hope we will take up this challenge. I also hope that we will lead a societal debate that pain relief is a basic human right. We would want nothing less for ourselves and certainly for our loved ones.
[dagger] Quoted in Papper EM: Fifth Rovenstine memorial lecture. Anesthesiology 1967; 28:1074–84.
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Carr DB, Cousins MJ: The spinal route of analgesia: Opioids and future options, Neural Blockade in Clinical Anesthesia and Management of Pain, 3rd Edition. Edited by Cousins MJ, Bridenbaugh PO. Philadelphia, Lippincott-Raven, 1998, pp 915-83
Figure 1. Local tissue factors and peripheral pain receptors. The physical stimuli of trauma, the chemical environment (e.g., H+), algesic substances (e.g., serotonin [5-HT], bradykinin [BK]), and microcirculatory changes may all modify peripheral receptor activity. Substance P (SP) released by the axon reflex is an important peripheral pain transmitter. Efferent sympathetic activity may increase the sensitivity of receptors by means of norepinephrine (NA) release. Histamine, complement, and arachidonic cascade metabolites (e.g., prostaglandin E2[PgE], leukotriene B4[LTB4]) all may contribute to inflammation and increase the sensitivity of peripheral nociceptors, together with cytokines (e.g., tumor necrosis factor [TNF] and interleukin 1 [IL-1]), adhesion molecules (e.g., intercellular adhesion molecule [ICAM], endothelial leukocyte adhesion molecule [ELAM]), and platelet-activating factor (PAF). After injury, there is an increased concentration of opioid receptors on the peripheral nerve terminals, where endogenous opioids may reduce the sensitivity of nociceptive receptors. (Reproduced with permission from Kehlet. [  8 ]) 
Figure 1. Local tissue factors and peripheral pain receptors. The physical stimuli of trauma, the chemical environment (e.g., H+), algesic substances (e.g., serotonin [5-HT], bradykinin [BK]), and microcirculatory changes may all modify peripheral receptor activity. Substance P (SP) released by the axon reflex is an important peripheral pain transmitter. Efferent sympathetic activity may increase the sensitivity of receptors by means of norepinephrine (NA) release. Histamine, complement, and arachidonic cascade metabolites (e.g., prostaglandin E2[PgE], leukotriene B4[LTB4]) all may contribute to inflammation and increase the sensitivity of peripheral nociceptors, together with cytokines (e.g., tumor necrosis factor [TNF] and interleukin 1 [IL-1]), adhesion molecules (e.g., intercellular adhesion molecule [ICAM], endothelial leukocyte adhesion molecule [ELAM]), and platelet-activating factor (PAF). After injury, there is an increased concentration of opioid receptors on the peripheral nerve terminals, where endogenous opioids may reduce the sensitivity of nociceptive receptors. (Reproduced with permission from Kehlet. [  8]) 
Figure 1. Local tissue factors and peripheral pain receptors. The physical stimuli of trauma, the chemical environment (e.g., H+), algesic substances (e.g., serotonin [5-HT], bradykinin [BK]), and microcirculatory changes may all modify peripheral receptor activity. Substance P (SP) released by the axon reflex is an important peripheral pain transmitter. Efferent sympathetic activity may increase the sensitivity of receptors by means of norepinephrine (NA) release. Histamine, complement, and arachidonic cascade metabolites (e.g., prostaglandin E2[PgE], leukotriene B4[LTB4]) all may contribute to inflammation and increase the sensitivity of peripheral nociceptors, together with cytokines (e.g., tumor necrosis factor [TNF] and interleukin 1 [IL-1]), adhesion molecules (e.g., intercellular adhesion molecule [ICAM], endothelial leukocyte adhesion molecule [ELAM]), and platelet-activating factor (PAF). After injury, there is an increased concentration of opioid receptors on the peripheral nerve terminals, where endogenous opioids may reduce the sensitivity of nociceptive receptors. (Reproduced with permission from Kehlet. [  8 ]) 
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Figure 2. (A) Subcutaneous administration of SNX-111 significantly attenuates nerve injury-induced hyperalgesia. Nerve injury-induced hyperalgesia was significantly attenuated by 100 [micro sign]M SNX-111 (P < 0.05 by analysis of variance; n = 9). (B) Subcutaneous injection of the calcium-chelating agent, quin 2, attenuates nerve injury-induced hyperalgesia. Partial ligation of the sciatic nerve induces a significant decrease in mechanical threshold compared with values determined in the week before nerve ligation. Subcutaneous injection of quin 2 (20 [micro sign]g/2.5 [micro sign]l) significantly attenuates the nerve injury-induced hyperalgesia compared with vehicle-treated controls (P < 0.05). Subcutaneous injection of the vehicle, dimethyl sulfoxide (DMSO), had no effect on the nerve injury-induced hyperalgesia compared with untreated controls. (Reproduced with permission from White and Cousins. [  12 ]) 
Figure 2. (A) Subcutaneous administration of SNX-111 significantly attenuates nerve injury-induced hyperalgesia. Nerve injury-induced hyperalgesia was significantly attenuated by 100 [micro sign]M SNX-111 (P < 0.05 by analysis of variance; n = 9). (B) Subcutaneous injection of the calcium-chelating agent, quin 2, attenuates nerve injury-induced hyperalgesia. Partial ligation of the sciatic nerve induces a significant decrease in mechanical threshold compared with values determined in the week before nerve ligation. Subcutaneous injection of quin 2 (20 [micro sign]g/2.5 [micro sign]l) significantly attenuates the nerve injury-induced hyperalgesia compared with vehicle-treated controls (P < 0.05). Subcutaneous injection of the vehicle, dimethyl sulfoxide (DMSO), had no effect on the nerve injury-induced hyperalgesia compared with untreated controls. (Reproduced with permission from White and Cousins. [  12]) 
Figure 2. (A) Subcutaneous administration of SNX-111 significantly attenuates nerve injury-induced hyperalgesia. Nerve injury-induced hyperalgesia was significantly attenuated by 100 [micro sign]M SNX-111 (P < 0.05 by analysis of variance; n = 9). (B) Subcutaneous injection of the calcium-chelating agent, quin 2, attenuates nerve injury-induced hyperalgesia. Partial ligation of the sciatic nerve induces a significant decrease in mechanical threshold compared with values determined in the week before nerve ligation. Subcutaneous injection of quin 2 (20 [micro sign]g/2.5 [micro sign]l) significantly attenuates the nerve injury-induced hyperalgesia compared with vehicle-treated controls (P < 0.05). Subcutaneous injection of the vehicle, dimethyl sulfoxide (DMSO), had no effect on the nerve injury-induced hyperalgesia compared with untreated controls. (Reproduced with permission from White and Cousins. [  12 ]) 
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Figure 3. The foot of a 16-yr-old girl with a severe reflex sympathetic dystrophy (complex regional pain syndrome type 1). 
Figure 3. The foot of a 16-yr-old girl with a severe reflex sympathetic dystrophy (complex regional pain syndrome type 1). 
Figure 3. The foot of a 16-yr-old girl with a severe reflex sympathetic dystrophy (complex regional pain syndrome type 1). 
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Figure 4. Nerve injury leads to the release of glutamate (Glu) from the central terminals of primary nociceptive afferents. Glutamate activates the N-methyl D-aspartate receptor (NMDA-R), which leads to calcium influx and increased production of nitric oxide. An increase in nitric oxide leads to activation of cyclic guanosine monophosphate and various protein kinases (PKs). These substances then act as a feedback mechanism at the NMDA-R (positive feedback) and [micro sign]-opioid receptor (negative feedback). This means that subsequent administration of morphine results in a vicious cycle, with further positive feedback at the NMDA-R. (Reproduced with permission from Siddall and Cousins. [  7 ]) 
Figure 4. Nerve injury leads to the release of glutamate (Glu) from the central terminals of primary nociceptive afferents. Glutamate activates the N-methyl D-aspartate receptor (NMDA-R), which leads to calcium influx and increased production of nitric oxide. An increase in nitric oxide leads to activation of cyclic guanosine monophosphate and various protein kinases (PKs). These substances then act as a feedback mechanism at the NMDA-R (positive feedback) and [micro sign]-opioid receptor (negative feedback). This means that subsequent administration of morphine results in a vicious cycle, with further positive feedback at the NMDA-R. (Reproduced with permission from Siddall and Cousins. [  7]) 
Figure 4. Nerve injury leads to the release of glutamate (Glu) from the central terminals of primary nociceptive afferents. Glutamate activates the N-methyl D-aspartate receptor (NMDA-R), which leads to calcium influx and increased production of nitric oxide. An increase in nitric oxide leads to activation of cyclic guanosine monophosphate and various protein kinases (PKs). These substances then act as a feedback mechanism at the NMDA-R (positive feedback) and [micro sign]-opioid receptor (negative feedback). This means that subsequent administration of morphine results in a vicious cycle, with further positive feedback at the NMDA-R. (Reproduced with permission from Siddall and Cousins. [  7 ]) 
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Figure 5. Darkfield micrographs of a transverse section of the L4 level of rat spinal cord after injection of collagenoid-horseradish peroxidase into the sciatic nerve. (A) C-HRP label injected into the right sciatic nerve 2 weeks after being treated with a topical application of saline is found in laminae I, III, and IV. There is no label in lamina II (n = 2). The medial aspect is located on the left side of the micrograph. (B) Topical application of vinblastine to the left sciatic nerve of a different animal causes the labeled region to expand into laminae II (n = 4). The medial aspect is located on the right side of the micrograph. Calibration bar = 50 [micro sign]m. (Reproduced with permission from White et al. [  20 ]) 
Figure 5. Darkfield micrographs of a transverse section of the L4 level of rat spinal cord after injection of collagenoid-horseradish peroxidase into the sciatic nerve. (A) C-HRP label injected into the right sciatic nerve 2 weeks after being treated with a topical application of saline is found in laminae I, III, and IV. There is no label in lamina II (n = 2). The medial aspect is located on the left side of the micrograph. (B) Topical application of vinblastine to the left sciatic nerve of a different animal causes the labeled region to expand into laminae II (n = 4). The medial aspect is located on the right side of the micrograph. Calibration bar = 50 [micro sign]m. (Reproduced with permission from White et al. [  20]) 
Figure 5. Darkfield micrographs of a transverse section of the L4 level of rat spinal cord after injection of collagenoid-horseradish peroxidase into the sciatic nerve. (A) C-HRP label injected into the right sciatic nerve 2 weeks after being treated with a topical application of saline is found in laminae I, III, and IV. There is no label in lamina II (n = 2). The medial aspect is located on the left side of the micrograph. (B) Topical application of vinblastine to the left sciatic nerve of a different animal causes the labeled region to expand into laminae II (n = 4). The medial aspect is located on the right side of the micrograph. Calibration bar = 50 [micro sign]m. (Reproduced with permission from White et al. [  20 ]) 
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Figure 6. (A) Dissociated dorsal root ganglion cells removed 2 weeks after transection of the sciatic nerve have a significant increase in neurite outgrowth compared with dorsal root ganglion cells taken from healthy animals (*P < 0.005 by the Student t test; n = 4). Inhibition of axonal transport in the sciatic nerve by topical application of vinblastine also induced a significant increase in neurite outgrowth of the dissociated dorsal root ganglion cells compared with untreated controls (50 [micro sign]M; P < 0.005, n = 4). Topical application of the vehicle, saline (n = 4), had no effect on neurite outgrowth. (B) Behavioral experiments show that topical application of vinblastine (n = 4) induces a significant decrease in the mechanical threshold compared with saline-treated control rats (n = 4)(P < 0.0005 by two-way analysis of variance). The results are calculated as:(threshold of treated paw)-(threshold of untreated paw)/(threshold of untreated paw) x 100. (Reproduced with permission from White et al. [  20 ]) 
Figure 6. (A) Dissociated dorsal root ganglion cells removed 2 weeks after transection of the sciatic nerve have a significant increase in neurite outgrowth compared with dorsal root ganglion cells taken from healthy animals (*P < 0.005 by the Student t test; n = 4). Inhibition of axonal transport in the sciatic nerve by topical application of vinblastine also induced a significant increase in neurite outgrowth of the dissociated dorsal root ganglion cells compared with untreated controls (50 [micro sign]M; P < 0.005, n = 4). Topical application of the vehicle, saline (n = 4), had no effect on neurite outgrowth. (B) Behavioral experiments show that topical application of vinblastine (n = 4) induces a significant decrease in the mechanical threshold compared with saline-treated control rats (n = 4)(P < 0.0005 by two-way analysis of variance). The results are calculated as:(threshold of treated paw)-(threshold of untreated paw)/(threshold of untreated paw) x 100. (Reproduced with permission from White et al. [  20]) 
Figure 6. (A) Dissociated dorsal root ganglion cells removed 2 weeks after transection of the sciatic nerve have a significant increase in neurite outgrowth compared with dorsal root ganglion cells taken from healthy animals (*P < 0.005 by the Student t test; n = 4). Inhibition of axonal transport in the sciatic nerve by topical application of vinblastine also induced a significant increase in neurite outgrowth of the dissociated dorsal root ganglion cells compared with untreated controls (50 [micro sign]M; P < 0.005, n = 4). Topical application of the vehicle, saline (n = 4), had no effect on neurite outgrowth. (B) Behavioral experiments show that topical application of vinblastine (n = 4) induces a significant decrease in the mechanical threshold compared with saline-treated control rats (n = 4)(P < 0.0005 by two-way analysis of variance). The results are calculated as:(threshold of treated paw)-(threshold of untreated paw)/(threshold of untreated paw) x 100. (Reproduced with permission from White et al. [  20 ]) 
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Figure 7. Possible mechanisms of involvement of vasoactive intestinal polypeptide and neuropeptide Y (NPY) in the sprouting of dorsal horn A [Greek small letter beta] fibers. (Courtesy of Dr. D. White.) 
Figure 7. Possible mechanisms of involvement of vasoactive intestinal polypeptide and neuropeptide Y (NPY) in the sprouting of dorsal horn A [Greek small letter beta] fibers. (Courtesy of Dr. D. White.) 
Figure 7. Possible mechanisms of involvement of vasoactive intestinal polypeptide and neuropeptide Y (NPY) in the sprouting of dorsal horn A [Greek small letter beta] fibers. (Courtesy of Dr. D. White.) 
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Figure 8. (A) Effect of vasoactive intestinal polypeptide (VIP) and neuropeptide Y (NPY) on neurite outgrowth of dissociated dorsal root ganglion cells coplated with spinal cord explants. (B) Effects of vasoactive intestinal polypeptide and neuropeptide Y on neurite outgrowth of dissociated dorsal root ganglion cells plated alone. (Reproduced with permission from White and Mansfield. [  21 ]) 
Figure 8. (A) Effect of vasoactive intestinal polypeptide (VIP) and neuropeptide Y (NPY) on neurite outgrowth of dissociated dorsal root ganglion cells coplated with spinal cord explants. (B) Effects of vasoactive intestinal polypeptide and neuropeptide Y on neurite outgrowth of dissociated dorsal root ganglion cells plated alone. (Reproduced with permission from White and Mansfield. [  21]) 
Figure 8. (A) Effect of vasoactive intestinal polypeptide (VIP) and neuropeptide Y (NPY) on neurite outgrowth of dissociated dorsal root ganglion cells coplated with spinal cord explants. (B) Effects of vasoactive intestinal polypeptide and neuropeptide Y on neurite outgrowth of dissociated dorsal root ganglion cells plated alone. (Reproduced with permission from White and Mansfield. [  21 ]) 
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Figure 9. Possible mechanism of involvement of neurotrophin 3 (NT-3) in spinal dorsal horn sprouting. (Courtesy of Dr. D. White.) 
Figure 9. Possible mechanism of involvement of neurotrophin 3 (NT-3) in spinal dorsal horn sprouting. (Courtesy of Dr. D. White.) 
Figure 9. Possible mechanism of involvement of neurotrophin 3 (NT-3) in spinal dorsal horn sprouting. (Courtesy of Dr. D. White.) 
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Figure 10. (A) Intrathecal neurotrophin 3 (NT-3) induced hyperalgesia to mechanical stimulation. Behavioral experiments show that intrathecal administration of NT-3 (n = 5) induces a significant decrease in the mechanical threshold after 4 days compared with saline-treated control rats (n = 4;*P < 0.01 by one-way analysis of variance followed by Scheffe F test post hoc comparison). (B) The percentage of dorsal root ganglion cells with neurite outgrowth increased significantly when plated in the supernatant of spinal cord incubated with 10 nM neuropeptide Y for 2 h at 37 [degree sign]C compared with control (n = 4;*P < 0.05 by the Student t test). Control cells were plated in the supernatant of spinal cord incubated in culture medium alone. The addition of antiserum to nerve growth factor (aNGF; 0.5% solution) had no effect on the neuropeptide Y-induced increase in neurite outgrowth (n = 4). Antiserum to NT-3 (aNT-3; 1% solution) significantly inhibited the trophic effect of the neuropeptide Y-conditioned supernatant (n = 4; control vs. supernatant, ***P < 0.0005; supernatant vs. supernatant + aNT-3, **P < 0.005). (Reproduced with permission from White. [  22 ]) 
Figure 10. (A) Intrathecal neurotrophin 3 (NT-3) induced hyperalgesia to mechanical stimulation. Behavioral experiments show that intrathecal administration of NT-3 (n = 5) induces a significant decrease in the mechanical threshold after 4 days compared with saline-treated control rats (n = 4;*P < 0.01 by one-way analysis of variance followed by Scheffe F test post hoc comparison). (B) The percentage of dorsal root ganglion cells with neurite outgrowth increased significantly when plated in the supernatant of spinal cord incubated with 10 nM neuropeptide Y for 2 h at 37 [degree sign]C compared with control (n = 4;*P < 0.05 by the Student t test). Control cells were plated in the supernatant of spinal cord incubated in culture medium alone. The addition of antiserum to nerve growth factor (aNGF; 0.5% solution) had no effect on the neuropeptide Y-induced increase in neurite outgrowth (n = 4). Antiserum to NT-3 (aNT-3; 1% solution) significantly inhibited the trophic effect of the neuropeptide Y-conditioned supernatant (n = 4; control vs. supernatant, ***P < 0.0005; supernatant vs. supernatant + aNT-3, **P < 0.005). (Reproduced with permission from White. [  22]) 
Figure 10. (A) Intrathecal neurotrophin 3 (NT-3) induced hyperalgesia to mechanical stimulation. Behavioral experiments show that intrathecal administration of NT-3 (n = 5) induces a significant decrease in the mechanical threshold after 4 days compared with saline-treated control rats (n = 4;*P < 0.01 by one-way analysis of variance followed by Scheffe F test post hoc comparison). (B) The percentage of dorsal root ganglion cells with neurite outgrowth increased significantly when plated in the supernatant of spinal cord incubated with 10 nM neuropeptide Y for 2 h at 37 [degree sign]C compared with control (n = 4;*P < 0.05 by the Student t test). Control cells were plated in the supernatant of spinal cord incubated in culture medium alone. The addition of antiserum to nerve growth factor (aNGF; 0.5% solution) had no effect on the neuropeptide Y-induced increase in neurite outgrowth (n = 4). Antiserum to NT-3 (aNT-3; 1% solution) significantly inhibited the trophic effect of the neuropeptide Y-conditioned supernatant (n = 4; control vs. supernatant, ***P < 0.0005; supernatant vs. supernatant + aNT-3, **P < 0.005). (Reproduced with permission from White. [  22 ]) 
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Table 1. Diagnosing Neuropathic Pain 
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Table 1. Diagnosing Neuropathic Pain 
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