Tejwani G A, Sheu M J, Sribanditmongkol P, Satyapriya A
Department of Pharmacology, The Ohio State University, College of Medicine and Public Health, 5197 Graves Hall, 333 W. 10th Avenue, Columbus, OH 43210-1239, USA.
Brain Res. 1998 Jun 29;797(2):305-12. doi: 10.1016/s0006-8993(98)00416-8.
We have recently observed that concomitant administration of diazepam to morphine pellet implanted rats results in the inhibition of the development of morphine tolerance and dependence. We have now analyzed mu-opioid receptors in rats treated with morphine and diazepam for 5 days by using [3H]-DAMGO for binding studies. Male Sprague-Dawley rats were made tolerant and dependent by subcutaneous (s.c.) implantation of six morphine pellets (two pellets on the first day, and four on the second day). Diazepam (0.25 mg/kg b.wt) was injected once daily intraperitoneally (i.p.) for 5 days. Control rats were implanted with placebo pellets and injected once daily with saline or diazepam (i.p.). Animals were administered s.c. naloxone (10 mg/kg) to induce naloxone-precipitated withdrawal syndrome on the final day of the experiment (day 5). There was an up-regulation of mu-receptor (Bmax increased) in the spinal cord of morphine tolerant (+139%) and dependent (+155%) rats compared to saline treated animals. Diazepam treatment abolished the up-regulation of mu-receptors in spinal cord of morphine treated rats. In the cortex, Bmax was not affected in morphine tolerant or dependent rats but it decreased by 38% in morphine tolerant and 65% in morphine dependent rats treated with diazepam. The Kd of mu-receptors increased in the cortex, striatum and hypothalamus of morphine dependent rats. Diazepam treatment decreased the Kd of mu-receptors in the cortex of morphine tolerant and hypothalamus of morphine-dependent rats. These results suggest that diazepam treatment antagonizes the up-regulation of CNS mu-receptors observed in morphine tolerant rats. In addition, morphine tolerance and dependence may be associated with conversion of mu-opioid receptors to mu-constitutive opioid receptors that are less active, and this conversion is prevented in the brain of animals treated with diazepam.
我们最近观察到，给植入吗啡丸的大鼠同时给予地西泮会抑制吗啡耐受性和依赖性的发展。我们现在通过使用[3H]-DAMGO进行结合研究，分析了用吗啡和地西泮处理5天的大鼠体内的μ-阿片受体。雄性Sprague-Dawley大鼠通过皮下（s.c.）植入六枚吗啡丸（第一天植入两枚，第二天植入四枚）产生耐受性和依赖性。地西泮（0.25mg/kg体重）每天腹腔内（i.p.）注射一次，共注射5天。对照大鼠植入安慰剂丸，并每天腹腔内注射一次生理盐水或地西泮（i.p.）。在实验的最后一天（第5天），给动物皮下注射纳洛酮（10mg/kg）以诱发纳洛酮诱发的戒断综合征。与生理盐水处理的动物相比，吗啡耐受（+139%）和依赖（+155%）大鼠脊髓中的μ-受体上调（Bmax增加）。地西泮处理消除了吗啡处理大鼠脊髓中μ-受体的上调。在皮质中，Bmax在吗啡耐受或依赖的大鼠中不受影响，但在用吗啡耐受的大鼠中降低了38%，在用吗啡依赖的大鼠中降低了65%。吗啡依赖大鼠的皮质、纹状体和下丘脑中μ-受体的Kd增加。地西泮处理降低了吗啡耐受大鼠皮质和吗啡依赖大鼠下丘脑中μ-受体的Kd。这些结果表明，地西泮处理可拮抗吗啡耐受大鼠中观察到的中枢神经系统μ-受体上调。此外，吗啡耐受性和依赖性可能与μ-阿片受体转化为活性较低的μ-组成型阿片受体有关，而在用地西泮处理的动物大脑中这种转化被阻止。
