Synergy between μ Opioid Ligands: Evidence for Functional Interactions among μ Opioid Receptor Subtypes

Abstract

Pharmacological differences among μ opioid drugs have been observed in in vitro and in vivo preclinical models, as well as clinically, implying that all μ opioids may not be working through the same mechanism of action. Here we demonstrate analgesic synergy betweenl-methadone and several μ opioid ligands. Of the compounds examined, l-methadone selectively synergizes with morphine, morphine-6β-glucuronide, codeine, and the active metabolite of heroin, 6-acetylmorphine. Morphine synergizes only withl-methadone. In analgesic assays, d-methadone was inactive alone and did not enhance morphine analgesia when the two were given together, confirming that l-methadone was not acting through N-methyl-d-aspartate mechanisms. Both l-methadone and morphine displayed only additive effects when paired with oxymorphone, oxycodone, fentanyl, alfentanyl, or meperidine. Although it displays synergy in analgesic assays, the l-methadone/morphine combination does not exhibit synergy in the gastrointestinal transit assay. This analgesic synergy of l-methadone with selective μ opioid drugs and the differences in opioid-mediated actions suggest that these drugs may be acting via different mechanisms. These findings provide further evidence for the complexity of the pharmacology of μ opioids.