Differences in efficacies between morphine and methadone demonstrated in the guinea pig ileum: a possible explanation for previous observations on incomplete opioid cross-tolerance.
We have compared the effectiveness of morphine and methadone as agonists in untreated guinea-pig longitudinal muscle preparations and after their treatment with the specific opioid receptor alkylating agent beta-chloronaltrexamine. In untreated ilea, the naloxone pA2 was 8.5 to both morphine and methadone, and their dose-response curves were parallel. After alkylation, the dose-response curve for morphine was shifted to the right with a decreased maximal effect. It was found that about 70% of the receptors were inactivated by the treatment, corresponding to a morphine receptor occupancy at IC50 of about 24%. The maximal effect of methadone was not decreased by the same beta-chloronaltrexamine treatment, indicating a much higher efficacy or receptor reserve for the drug. The possibility that differences in efficacies could account for previously reported heterogeneities in actions of opioids, such as assymmetries in cross-tolerance towards morphine and methadone in experimental animal and man, is discussed.
Ivarsson
M
M
Department of Pharmacology, Faculty of Pharmacy, Uppsala University, Sweden.
Neil
A
A
D000478:Alkylation; D000818:Animals; D004361:Drug Tolerance; D004558:Electric Stimulation; D005260:Female; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008691:Methadone / Q000494:pharmacology*; D009020:Morphine / Q000494:pharmacology*; D009130:Muscle, Smooth / Q000187:drug effects*; D011957:Receptors, Opioid / Q000187:drug effects
D011957:Receptors, Opioid; D009020:Morphine; D008691:Methadone