Opioid and nonopioid behavioral effects of methadone isomers.

The effect of l-, d- and dl-methadone were determined on keypecking by pigeons under three different conditions: alone, in the presence of 1 mg/kg of naloxone and during daily administration of 60 mg/kg of dl-methadone. l-Methadone decreased responding at much lower doses than either dl- or d-methadone. Both naloxone and daily dl-methadone administration shifted l-methadone's dose-effect curves to the right until they could be superimposed over d-methadone's dose-effect curves. Doses of naloxone as low as 0.01 and 0.1 mg/kg shifted the dose-effect curves of l-methadone. Chronic daily administration of dl-methadone shifted the dose-effect curve for fentanyl to the right by 10-fold, whereas the effects of pentobarbital were slightly potentiated. These data indicate that l-methadone produces its effects by an interaction with an opioid receptor, whereas d-methadone's behavioral effects are produced by a nonopioid action. When the l-methadone-sensitive, opioid receptor is blocked by naloxone or tolerance has developed, than l-methadone can produce behavioral effects by a nonopioid mechanism. The tolerance produced by daily administration of dl-methadone in the pigeon is a result of cellular adaptation and not due to a drug dispositional mechanism.