选择性毒蕈碱受体拮抗剂减轻吗啡耐受和依赖的实验研究

Experimental study of selective muscarinic receptor antagonists on attenuation of morphine tolerance and dependence in rats

探讨毒蕈碱受体亚型在吗啡耐受和依赖中的作用。方法热板反应测定ＳＤ大鼠（ｎ＝６３）吗啡镇痛，纳洛酮激发作为ＳＤ大鼠（ｎ＝７７）吗啡依赖模型，腹腔或脊髓鞘内注射选择性Ｍ１受体拮抗剂哌拉唑嗪和Ｍ２受体拮抗剂美索四氨，观察对吗啡耐受和依赖的影响。结果吗啡耐受大鼠腹腔注射美索四氨（０．２５ｍｇ／ｋｇ）６天后，对吗啡的敏感性恢复，对照组和哌拉唑嗪组动物仍处于耐受状态。鞘内注射６天后，哌拉唑嗪呈剂量依赖方式减轻吗啡耐受，美索四氨可轻度减轻吗啡耐受。美索四氨或哌拉唑嗪以剂量依赖方式抑制吗啡依赖大鼠纳洛酮激发的戒断症状。仅大剂量美索四氨可抑制戒断症状。结论毒蕈碱受体在外周以Ｍ２受体，在脊髓水平以Ｍ１受体为主参与吗啡耐受和依赖过程。

Objective To characterize the role of muscarinic receptor subtype in the process of the morphine tolerance and dependence. Methods The morphine (antinociception) tolerance was assessed by using hot plate latency, and morphine dependence was characterized by naloxone precipitated withdrawal. Intraperitoneal (ip) or intrathecal (it) injection of muscarinic M1 selective antagonist pirenzepine or M2 selective antagonist methoctramine was carried out. Results Methoctramine (ip) for 6 days restored the sensitivity to morphine in male Sprague Dawley rats that are tolerant as a result of 6 days of b.i.d.morphine injection, in contrast, saline and pirenzepine (ip) did not increase the mean HP latency of morphine tolerant rats. Both methoctramine and pirenzepine in doses did not alter the baseline HP latency. Concurrent treatment with pirenzepine (it) significantly attenuated the development of morphine tolerance produced by twice daily injection of morphine in a dose dependent manner, however, methoctramine(it) also decreased without dose relation. In addition, the withdrawal symptoms precipitated by naloxone in morphine dependent rats were blocked by methoctramine(ip) or pirenzepine (it) at single dose injection in a dose dependent manner. Methoctramine(it) at 200μg/kg could partially inhibit the withdrawal symptoms. Conclusions The data suggested that the muscarinic receptor subtype predominating M2 receptor at the peripheral and M1 in the spinal cord mediate the process of morphine tolerance and dependence in rat.