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.