Masten L W, Peterson G R, Burkhalter A, Way E L
Drug Alcohol Depend. 1980 Jan;5(1):27-37. doi: 10.1016/0376-8716(80)90168-4.
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.
为了解释吗啡依赖小鼠口服美沙酮六天后吗啡与美沙酮之间交叉耐受性的丧失以及对美沙酮致死性耐受性的增加，研究了美沙酮刺激自身代谢的可能性。结果发现，美沙酮确实使其自身代谢增强了两倍。这种活性增加与口服美沙酮LD50升高所衡量的对美沙酮致死效应耐受性的发展相关。此外，强效微粒体抑制剂SKF-525A消除了这种耐受性。口服美沙酮六天并未改变脑室内美沙酮的LD50，这表明所观察到的耐受性本质上是处置性的。
