预先应用咪哒唑仑抑制小鼠和大鼠吗啡戒断反应

摘要

目的:研究咪哒唑仑对小鼠和大鼠吗啡戒断反应的影响.方法:实验中采用急性和慢性吗啡依赖和纳洛酮催促戒断模型.使用放免法测定cAMP含量,免疫组织化学方法观察Fos蛋白表达变化.结果:合用咪哒唑仑和吗啡可抑制小鼠急性和慢性吗啡依赖的发展.在急性吗啡依赖小鼠,咪哒唑仑-吗啡组纳络酮催促跳跃的ED50(10.4,8.5-12.3 mg/kg)明显大于生理盐水-吗啡组(3.0,1. 9-4.3 mg/kg)(P＜0.01).在慢性吗啡依赖小鼠,咪哒唑仑-吗啡组纳络酮催促跳跃的发生率和跳跃次数明显低于生理盐水-吗啡组(P＜0.01).预先使用咪哒唑仑抑制吗啡戒断大鼠脊髓Fos蛋白表达,但不能抑制脊髓cAMP含量的增加.结论:咪哒唑仑通过抑制脊髓神经元敏感化减轻吗啡戒断反应,cAMP信号转导通路不参与介导这一效应.%AIM: To investigate the roles of pretreatment with midazolam on morphine withdrawal in mice and rats.METHODS: Acute and chronic morphine dependence and naloxone-precipitated withdrawal models were em ployed in the present study. Cyclic adenosine monophosphate (AMP) content and Fos protein expression were measured by radioimmunoassay and immunocytochemistry, respectively. RESULTS: Coadministration of midazolam (2 mg/kg, ip) and morphine prevented the development of both acute and chronic morphine dependence in mice. Compared to saline-morphine group (3.0, 95 % confidence limits: 1.9-4.3 rmg/kg), ED50 of naloxone precipiated withdrawal jumping increased significantly in midazolam-morphine group (10.4, 95 % confidence limits:8.5-12.3 mg/kg) in acute morphine-dependent mice (P＜0.01). Pretreatment with midazolam lowered the number and incidence of naloxone-precepiated withdrawal jumping and prevented loss in body weight in chronic mot phine-dependent mice (P＜0.01). Midazolam-pretreatment inhibited the increase of Fos protein expression, not cyclic AMP content, in rat spinal cord during morphine withdrawal. CONCLUSION: Midazolam suppresses morphine withdrawal response by inhibiting hypersensitization of the spinal cord neurons, and this effect may not be mediated by cAMP pathway.