Tolerance to methadone lethality and microsomal enzyme induction in mice tolerant to and dependent on morphine.

In an attempt to explain a loss of cross-tolerance between morphine and methadone and an increased tolerance to methadone lethality in morphine-dependent mice administered methadone orally for six days, the possibility that methadone was stimulating its own metabolism was investigated. It was found that methadone did enhance its own metabolism two-fold. This increase in activity correlated with the development of tolerance to the lethal effects of methadone as measured by an elevation of the oral methadone LD50. Furthermore, SKF-525A, a potent microsomal inhibitor, abolished this tolerance. The intracerbroventricular methadone LD50 was not altered by six days administration of oral methadone, suggesting that the tolerance observed was dispositional in nature.