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糖尿病对μ-阿片类激动剂诱导的运动活性的影响及吗啡依赖性的发展

Modification of mu-opioid agonist-induced locomotor activity and development of morphine dependence by diabetes.

作者信息

Kamei J, Ohsawa M, Saitoh A, Iwamoto Y, Suzuki T, Misawa M, Nagase H, Kasuya Y

机构信息

Department of Pathophysiology & Therapeutics, Faculty of Pharmaceutical Sciences, Hoshi University, Tokyo, Japan.

出版信息

J Pharmacol Exp Ther. 1995 Aug;274(2):700-6.

PMID:7636731
Abstract

We examined the locomotor-enhancing action of mu-opioid receptor agonists, such as morphine and [D-Ala2, N-MePhe4, Gly-ol5]enkephalin (DAMGO), and physical dependence on morphine in diabetic and nondiabetic mice. Morphine (5-20 mg/kg, s.c.) and DAMGO (1-4 nmol, i.c.v.) had a dose-dependent locomotor-enhancing effect in both nondiabetic and diabetic mice. The locomotor-enhancing effects of morphine and DAMGO were significantly less in diabetic mice than in nondiabetic mice, and were significantly reduced after pretreatment with either beta-funaltrexamine (20 mg/kg, s.c.), a selective mu-opioid receptor antagonist, or naloxonazine (35 mg/kg, s.c.), a selective mu1-opioid receptor antagonist. Both diabetic and nondiabetic mice were chronically treated with morphine (8-45 mg/kg, s.c.) for 5 days. During this treatment, neither diabetic nor nondiabetic mice showed any signs of toxicity. After morphine treatment, withdrawal was precipitated by injection of naloxone (0.3-10 mg/kg, s.c.). Several withdrawal signs, such as weight loss, diarrhea, ptosis, jumping and body shakes, were observed after naloxone challenge in morphine-dependent nondiabetic mice. Although morphine-dependent diabetic mice showed greater weight loss than nondiabetic mice, the incidence of jumping and body shakes after naloxone challenge in diabetic mice were lower than that in nondiabetic mice. These results suggest that diabetic mice are selectively hyporesponsive to mu1-opioid receptor-mediated locomotor enhancement. Furthermore, diabetes may affect mu1-opioid receptor-mediated naloxone-precipitated signs of withdrawal from physical dependence on morphine.

摘要

我们研究了μ-阿片受体激动剂(如吗啡和[D-丙氨酸2,N-甲基苯丙氨酸4,甘氨酸醇5]脑啡肽(DAMGO))对糖尿病和非糖尿病小鼠的运动增强作用以及对吗啡的身体依赖性。吗啡(5-20mg/kg,皮下注射)和DAMGO(1-4nmol,脑室内注射)在非糖尿病和糖尿病小鼠中均具有剂量依赖性的运动增强作用。糖尿病小鼠中吗啡和DAMGO的运动增强作用明显低于非糖尿病小鼠,并且在用选择性μ-阿片受体拮抗剂β-氟纳曲胺(20mg/kg,皮下注射)或选择性μ1-阿片受体拮抗剂纳洛嗪(35mg/kg,皮下注射)预处理后显著降低。将糖尿病和非糖尿病小鼠均用吗啡(8-45mg/kg,皮下注射)慢性治疗5天。在此治疗期间,糖尿病和非糖尿病小鼠均未表现出任何毒性迹象。吗啡治疗后,通过注射纳洛酮(0.3-10mg/kg,皮下注射)引发戒断反应。在吗啡依赖的非糖尿病小鼠中,纳洛酮激发后观察到几种戒断症状,如体重减轻、腹泻、眼睑下垂、跳跃和身体颤抖。虽然吗啡依赖的糖尿病小鼠比非糖尿病小鼠体重减轻更多,但糖尿病小鼠在纳洛酮激发后跳跃和身体颤抖的发生率低于非糖尿病小鼠。这些结果表明,糖尿病小鼠对μ1-阿片受体介导的运动增强选择性低反应。此外,糖尿病可能影响μ1-阿片受体介导的纳洛酮引发的对吗啡身体依赖性戒断症状。

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