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Vol. 303, Issue 2, 557-562, November 2002

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

Elizabeth A. Bolan, Ronald J. Tallarida and Gavril W. Pasternak

Laboratory of Molecular Neuropharmacology, Memorial Sloan-Kettering Cancer Center and the Program in Neuroscience, the Weill Graduate School of Medical Sciences of Cornell University, New York, New York (E.A.B., G.W.P.), and Department of Pharmacology, Temple University Medical School, Philadelphia, Pennsylvania (R.J.T.)

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 between L-methadone and several µ opioid ligands. Of the compounds examined, L-methadone selectively synergizes with morphine, morphine-6beta -glucuronide, codeine, and the active metabolite of heroin, 6-acetylmorphine. Morphine synergizes only with L-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.

0022-3565/02/3032-0557$07.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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