Combination of a δ-opioid Receptor Agonist and Loperamide Produces Peripherally-mediated Analgesic Synergy in Mice

WHAT WE ALREADY KNOW ABOUT THIS TOPICThe adverse effects of opioids are largely mediated by central μ-opioid receptorsCentral μ- and δ-opioid receptors synergistically provide analgesia WHAT THIS ARTICLE TELLS US THAT IS NEWThe administration of a selective δ-opioid agonist, oxymorphindole, and a peripherally-restricted μ-agonist, loperamide, provided synergistic analgesia in a mouse inflammatory pain modelThe 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 theoretic