Sheu M J, Sribanditmongkol P, Santosa D N, Tejwani G A
Department of Pharmacology, Ohio State University, College of Medicine, Columbus 43210-1239, USA.
Brain Res. 1995 Mar 27;675(1-2):31-7. doi: 10.1016/0006-8993(95)00036-p.
Diazepam inhibits morphine tolerance and dependence and reverses a decrease in the met-enkephalin level in brain induced by morphine. In this study, we investigated whether inhibition of morphine-induced tolerance and dependence by diazepam involved a change in cyclic AMP levels in discrete rat brain regions and spinal cord. 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.). Tail-flick antinociception was measured 1 h after injections everyday. Animals were administered s.c. naloxone (10 mg/kg) to induce naloxone-precipitated withdrawal syndrome on the final day of the experiment (day 5), and the jumping behavior was observed for 30 min. Concomitant treatment with diazepam (0.25 mg/kg) significantly decreased the development of morphine tolerance and dependence. Diazepam (0.25 mg/kg) treated rats also showed a significant decrease in the jumping behavior compared to animals treated with morphine alone. Rats were sacrificed 2 h after the injection of saline or diazepam (0.25 mg/kg) on the fifth day. Cyclic AMP was estimated by RIA. In the control rats, the concentration of cyclic AMP in cortex was > hippocampus > cerebellum > hypothalamus > striatum > midbrain > pituitary > pons/medulla > spinal cord. There was no change in the concentration of cyclic AMP in any of the brain regions examined from morphine tolerant animals.(ABSTRACT TRUNCATED AT 250 WORDS)
地西泮可抑制吗啡耐受性和依赖性,并逆转吗啡引起的脑内甲硫氨酸脑啡肽水平降低。在本研究中,我们调查了地西泮对吗啡诱导的耐受性和依赖性的抑制作用是否涉及大鼠离散脑区和脊髓中环磷酸腺苷(cAMP)水平的变化。雄性Sprague-Dawley大鼠通过皮下植入六枚吗啡丸剂(第一天两枚,第二天四枚)产生耐受性和依赖性。地西泮(0.25mg/kg体重)每天腹腔注射一次,共5天。对照大鼠植入安慰剂丸剂,每天腹腔注射一次生理盐水或地西泮。每天注射后1小时测量甩尾镇痛效应。在实验的最后一天(第5天),给动物皮下注射纳洛酮(10mg/kg)以诱发纳洛酮催促戒断综合征,并观察跳跃行为30分钟。地西泮(0.25mg/kg)联合治疗显著降低了吗啡耐受性和依赖性的发展。与仅用吗啡治疗的动物相比,地西泮(0.25mg/kg)治疗的大鼠跳跃行为也显著减少。在第5天注射生理盐水或地西泮(0.25mg/kg)2小时后处死大鼠。通过放射免疫分析法测定cAMP。在对照大鼠中,皮质中cAMP的浓度>海马>小脑>下丘脑>纹状体>中脑>垂体>脑桥/延髓>脊髓。吗啡耐受动物的任何检测脑区中cAMP浓度均无变化。(摘要截断于250字)