Masten L W, Hine C H, Way E L
Drug Alcohol Depend. 1978 Nov;3(6):405-18. doi: 10.1016/0376-8716(78)90013-3.
Mice were rendered tolerant to and dependent on morphine via a morphine pellet implantation. Three days later methadone hydrochloride was administered at a dose of 100mg/kg per os 3 hours after pellet removal and then daily for a total of 5--6 days. This dose of methadone was shown to exhibit a high efficacy for the blockade of morphine abrupt withdrawal jumping and only minimal toxicity. Under these conditions, the level of analgetic tolerance with respect to morphine and methadone and the level of dependence as measured by the naloxone ED50 were initially elevated by the morphine treatment. However, upon substitution with oral methadone these levels declined with time at a rate which did not differ from that of a group of mice receiving only water after morphine pellet removal. Despite these findings, the methadone treatment was associated with an increasing tolerance to methadone lethality during the administration of this narcotic which was nearly double that of a similarly treated water control group by the sixth day. This observation could not be explained by an elevation in the level of cellular tolerance rendered by the methadone treatment since the morphine LD50 was not elevated following identical treatment with morphine and then methadone. The significance of these results is discussed with respect to the role of methadone administration and its metabolism in the modification of tolerance and dependence.
通过植入吗啡缓释片使小鼠对吗啡产生耐受性并形成依赖。三天后，在取出缓释片3小时后，以100mg/kg的剂量口服给予盐酸美沙酮，然后每天给药，共给药5 - 6天。已证明该剂量的美沙酮对阻断吗啡戒断跳跃具有高效性且毒性极小。在这些条件下，吗啡和美沙酮的镇痛耐受性水平以及用纳洛酮ED50测定的依赖水平最初因吗啡处理而升高。然而，在用口服美沙酮替代后，这些水平随时间下降，其下降速率与一组在取出吗啡缓释片后仅接受水的小鼠没有差异。尽管有这些发现，但在给予这种麻醉剂期间，美沙酮治疗与对美沙酮致死性的耐受性增加有关，到第六天，这种耐受性几乎是接受类似处理的水对照组的两倍。由于用吗啡然后美沙酮进行相同处理后吗啡的LD50没有升高，因此美沙酮处理导致的细胞耐受性水平升高无法解释这一观察结果。就美沙酮给药及其代谢在耐受性和依赖性改变中的作用对这些结果的意义进行了讨论。
