Pain Medicine  |   June 2018
Peripherally Acting μ-Opioid Receptor Agonists Attenuate Ongoing Pain-associated Behavior and Spontaneous Neuronal Activity after Nerve Injury in Rats
Author Notes
  • From the Department of Anesthesiology and Critical Care Medicine (Vinod T., M.A., F.Y., Vineeta T., S.-Q.H., T.Z., B.S., S.A.G., Z.C., S.N.R., Y.G.), the Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology (M.A., Q.Z., X.D.), Department of Pharmacology and Molecular Sciences and the Center for Epigenetics (K.E.S.), and the Howard Hughes Medical Institute (X.D.), Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat, India (Vinod T.); Department of Neurology, Tiantan Hospital, Capital Medical University, Beijing, China (T.Z.); Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Wuhan, China (B.S.); and the Department of Orthopedics, Luhe Hospital, Capital Medical University, Beijing, China (X.C.).
  • Vinod T., M.A., and F.Y. contributed equally to this article.
    Vinod T., M.A., and F.Y. contributed equally to this article.×
  • Submitted for publication June 22, 2017. Accepted for publication February 21, 2018.
    Submitted for publication June 22, 2017. Accepted for publication February 21, 2018.×
  • Address correspondence to Dr. Guan: Division of Pain Medicine, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, 720 Rutland Avenue, Ross 350, Baltimore, Maryland 21205. yguan1@jhmi.edu. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Pain Medicine / Basic Science / Central and Peripheral Nervous Systems / Pain Medicine / Pharmacology / Opioid
Pain Medicine   |   June 2018
Peripherally Acting μ-Opioid Receptor Agonists Attenuate Ongoing Pain-associated Behavior and Spontaneous Neuronal Activity after Nerve Injury in Rats
Anesthesiology 6 2018, Vol.128, 1220-1236. doi:10.1097/ALN.0000000000002191
Anesthesiology 6 2018, Vol.128, 1220-1236. doi:10.1097/ALN.0000000000002191
Abstract

Background: Ongoing neuropathic pain is difficult to treat. The authors examined whether dermorphin [D-Arg2, Lys4] (1–4) amide, a peripherally acting µ-opioid receptor agonist, attenuates ongoing pain-associated manifestations after nerve injury in rats and mice.

Methods: Using conditioned place preference assay, the authors tested whether animals show a preference to the environment associated with drug treatment. Wide-dynamic range and dorsal root ganglion neuronal activities were measured by electrophysiology recording and calcium imaging.

Results: Nerve-injured animals stayed longer in dermorphin [D-Arg2, Lys4] (1–4) amide–paired chamber after conditioning than during preconditioning (rats: 402.4 ± 61.3 vs. 322.1 ± 45.0 s, 10 mg/kg, n = 9, P = 0.009; mice: 437.8 ± 59.4 vs. 351.3 ± 95.9 s, 2 mg/kg, n = 8, P = 0.047). Topical ganglionic application of dermorphin [D-Arg2, Lys4] (1–4) amide (5 μM, 1 μl, n = 5) reduced the numbers of small-diameter dorsal root ganglion neurons that showed spontaneous activity (1.1 ± 0.4 vs. 1.5 ± 0.3, P = 0.044) and that were activated by test stimulation (15.5 ± 5.5 vs. 28.2 ± 8.2, P = 0.009) after injury. In neuropathic rats, dermorphin [D-Arg2, Lys4] (1–4) amide (10 mg/kg, n = 8) decreased spontaneous firing rates in wide-dynamic range neurons to 53.2 ± 46.6% of predrug level, and methylnaltrexone (5 mg/kg, n = 9) blocked dermorphin [D-Arg2, Lys4] (1–4) amide–induced place preference and inhibition of wide-dynamic range neurons. Dermorphin [D-Arg2, Lys4] (1–4) amide increased paw withdrawal threshold (17.5 ± 2.2 g) from baseline (3.5 ± 0.7 g, 10 mg/kg, n = 8, P = 0.002) in nerve-injured rats, but the effect diminished after repeated administrations.

Conclusions: Peripherally acting μ-opioids may attenuate ongoing pain-related behavior and its neurophysiologic correlates. Yet, repeated administrations cause antiallodynic tolerance.