Pain Medicine  |   September 2019
Combination of a δ-opioid Receptor Agonist and Loperamide Produces Peripherally-mediated Analgesic Synergy in Mice
Author Notes
  • From the Departments of Pharmacology (D.J.B., C.A.F., G.L.W.), Neuroscience (C.D.P., K.F.K., S.L., C.A.F., G.L.W.), Pharmaceutics (C.A.F.), Dermatology (G.L.W.), and Medicinal Chemistry (E.A., P.S.P.), University of Minnesota, Minneapolis, Minnesota.
  • Part of the work has been presented at the University of Minnesota PharmacoNeuroImmunology Seminar in Minneapolis, Minnesota, on November 23, 2015; the International Narcotics Research Conference (INRC) in Bath, United Kingdom on July 11-14, 2016; Graduate Program in Neuroscience Colloquium, Minneapolis, September 14, 2016; the International Association for the Study of Pain (IASP) Symposium in Yokohama, Japan on September 29, 2016; the Society for Neuroscience Annual Meeting in San Diego, California on November 12, 2016; the Society for Neuroscience Annual Meeting in Washington, DC on November 11, 2017; the Montagna Symposium on the Biology of Skin in Gleneden Beach, Oregon on October 22, 2016; the Winter Conference on Brain Research in Big Sky, Montana on January 31, 2017; the Virginia Commonwealth University, Department of Pharmacology and Toxicology Seminar, in Richmond, Virginia on April 4, 2017; the American Pain Society Annual Scientific Meeting in Pittsburgh, Pennsylvania on May 18, 2017; the IASP Special Meeting Symposium in Santa Cruz, Bolivia on October 27, 2017; and the Pain Mechanisms and Therapeutics Conference in Taormina, Sicily, Italy on June 5, 2016 and June 2, 2018.
    Part of the work has been presented at the University of Minnesota PharmacoNeuroImmunology Seminar in Minneapolis, Minnesota, on November 23, 2015; the International Narcotics Research Conference (INRC) in Bath, United Kingdom on July 11-14, 2016; Graduate Program in Neuroscience Colloquium, Minneapolis, September 14, 2016; the International Association for the Study of Pain (IASP) Symposium in Yokohama, Japan on September 29, 2016; the Society for Neuroscience Annual Meeting in San Diego, California on November 12, 2016; the Society for Neuroscience Annual Meeting in Washington, DC on November 11, 2017; the Montagna Symposium on the Biology of Skin in Gleneden Beach, Oregon on October 22, 2016; the Winter Conference on Brain Research in Big Sky, Montana on January 31, 2017; the Virginia Commonwealth University, Department of Pharmacology and Toxicology Seminar, in Richmond, Virginia on April 4, 2017; the American Pain Society Annual Scientific Meeting in Pittsburgh, Pennsylvania on May 18, 2017; the IASP Special Meeting Symposium in Santa Cruz, Bolivia on October 27, 2017; and the Pain Mechanisms and Therapeutics Conference in Taormina, Sicily, Italy on June 5, 2016 and June 2, 2018.×
  • For a downloadable PPT slide containing this article’s citation information, please visit https://anesthesiology.pubs.asahq.org/ss/downloadable_slide.aspx.
    For a downloadable PPT slide containing this article’s citation information, please visit https://anesthesiology.pubs.asahq.org/ss/downloadable_slide.aspx.×
  • Submitted for publication July 31, 2018. Accepted for publication May 9, 2019.
    Submitted for publication July 31, 2018. Accepted for publication May 9, 2019.×
  • Address correspondence to Dr. Wilcox: 6–145 Jackson Hall, 321 Church Street, Southeast, Minneapolis, Minnesota 55455. george@umn.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 / Pain Medicine / Pharmacology / Opioid
Pain Medicine   |   September 2019
Combination of a δ-opioid Receptor Agonist and Loperamide Produces Peripherally-mediated Analgesic Synergy in Mice
Anesthesiology 9 2019, Vol.131, 649-663. doi:10.1097/ALN.0000000000002840
Anesthesiology 9 2019, Vol.131, 649-663. doi:10.1097/ALN.0000000000002840
Abstract

Editor’s Perspective:

What We Already Know about This Topic:

  • The adverse effects of opioids are largely mediated by central μ-opioid receptors

  • Central μ- and δ-opioid receptors synergistically provide analgesia

What This Article Tells Us That Is New:

  • The administration of a selective δ-opioid agonist, oxymorphindole, and a peripherally-restricted μ-agonist, loperamide, provided synergistic analgesia in a mouse inflammatory pain model

  • The use of combinations of peripherally-restricted opioid ligands may provide analgesia with reduced side effects when compared with centrally acting opioids

Background: The long-term use of opioids for analgesia carries significant risk for tolerance, addiction, and diversion. These adverse effects are largely mediated by μ-opioid receptors in the central nervous system. Based on the authors’ previous observation that morphine and δ-opioid receptor agonists synergize in spinal cord in a protein kinase Cε–dependent manner, they predicted that this μ-opioid receptor–δ-opioid receptor synergy would take place in the central terminals of nociceptive afferent fibers and generalize to their peripheral terminals. Therefore, the authors hypothesized that loperamide, a highly efficacious μ-opioid receptor agonist that is excluded from the central nervous system, and oxymorphindole, a δ-opioid receptor agonist that was shown to synergize with morphine spinally, would synergistically reverse complete Freund’s adjuvant–induced hyperalgesia.

Methods: Using the Hargreaves assay for thermal nociception, the von Frey assay for mechanical nociception and the complete Freund’s adjuvant–induced model of inflammatory pain, we tested the antinociceptive and antihyperalgesic effect of loperamide, oxymorphindole, or the loperamide–oxymorphindole combination. Animals (Institute for Cancer Research [ICR] CD1 strain mice; n = 511) received drug by systemic injection, intraplantar injection to the injured paw, or a transdermal solution on the injured paw. Dose–response curves for each route of administration and each nociceptive test were generated, and analgesic synergy was assessed by isobolographic analysis.

Results: In naïve animals, the loperamide–oxymorphindole combination ED50 value was 10 times lower than the theoretical additive ED50 value whether given systemically or locally. In inflamed animals, the combination was 150 times more potent systemically, and 84 times more potent locally. All combinations showed statistically significant synergy when compared to the theoretical additive values, as verified by isobolographic analysis. The antihyperalgesia was ablated by a peripherally-restricted opioid antagonist.

Conclusions: From these data we conclude that the loperamide–oxymorphindole combination synergistically reverses complete Freund’s adjuvant–induced inflammatory hyperalgesia. The authors also conclude that this interaction is mediated by opioid receptors located in the peripheral nervous system.