Yamaguchi T, Hagiwara Y, Tanaka H, Sugiura T, Waku K, Shoyama Y, Watanabe S, Yamamoto T
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, 812-8582, Fukuoka, Japan.
Brain Res. 2001 Aug 3;909(1-2):121-6. doi: 10.1016/s0006-8993(01)02655-5.
In the present study, we examined the effects of endogenous ligand 2-arachidonoylglycerol (2-AG) on naloxone-precipitated withdrawal in morphine-dependent mice, in comparison with that of two cannabinoid agonists, an ingredient of Cannabis sativa Delta(8)-tetrahydrocannabinol (Delta(8)-THC) and the synthetic cannabinoid CB1 receptor agonist HU-210. 2-AG at a dose of 10 microg per mouse (i.c.v.) significantly inhibited both jumping and forepaw tremor as signs of withdrawal following naloxone challenge in morphine-dependent mice. Furthermore, both Delta(8)-THC and HU-210 significantly attenuated these symptoms of withdrawal in morphine-dependent mice. Therefore, it is suggested that inactivation of the endogenous cannabinoid system is related to the induction of withdrawal syndrome in morphine-dependent mice. Moreover, hyperlocomotor activity in morphine-dependent mice was markedly increased by Delta(8)-THC 10 mg/kg, which had no effect in naive mice. This finding suggested that in morphine dependence, upregulation of cannabinoid CB1 receptors occurred. Non-psychoactive CB1 receptor agonists or accelerators of endocannabinoid synthesis may be potential as therapeutic drugs for opiate withdrawal symptoms.
在本研究中，我们检测了内源性配体2-花生四烯酸甘油酯（2-AG）对吗啡依赖小鼠中纳洛酮诱发的戒断反应的影响，并与两种大麻素激动剂、大麻（Cannabis sativa）成分Δ⁸-四氢大麻酚（Δ⁸-THC）和合成大麻素CB1受体激动剂HU-210进行了比较。以每只小鼠10微克（脑室内注射）的剂量给予2-AG，可显著抑制吗啡依赖小鼠在纳洛酮激发后出现的跳跃和前爪震颤等戒断体征。此外，Δ⁸-THC和HU-210均能显著减轻吗啡依赖小鼠的这些戒断症状。因此，提示内源性大麻素系统失活与吗啡依赖小鼠戒断综合征的诱发有关。此外，10毫克/千克的Δ⁸-THC可显著增加吗啡依赖小鼠的运动活性，而对正常小鼠无此作用。这一发现提示在吗啡依赖状态下，大麻素CB1受体发生了上调。非精神活性CB1受体激动剂或内源性大麻素合成促进剂可能有望成为治疗阿片类戒断症状的药物。
