Papers of the Week

The 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 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 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.