Matsuoka I, Maldonado R, Defer N, Noël F, Hanoune J, Roques B P
Unité de Pharmacologie et Physiologie Hépatique U99 INSERM Hôpital Henri Mondor, Créteil, France.
Eur J Pharmacol. 1994 Jul 15;268(2):215-21. doi: 10.1016/0922-4106(94)90191-0.
The up-regulation of the cyclic AMP system and enhanced phosphorylation of protein substrates after either sudden interruption of chronic opioid treatment or antagonist administration has been proposed to account for the various behavioral responses observed during withdrawal. Using in situ hybridization histochemistry, we show here for the first time that type VIII adenylyl cyclase mRNA is selectively increased, as early as 12 h after morphine treatment in the locus coeruleus and the amygdala, two brain regions suggested to be important in morphine dependence expression. Moreover, the time course of morphine-induced changes in type VIII adenylyl cyclase mRNA in locus coeruleus is related to the incidence of jumping, the most important sign of morphine withdrawal in mice. In addition, the overexpression of type VIII adenylyl cyclase mRNA in thalamic nuclei could add to morphine tolerance. These findings offer a strong support, at the molecular level, for an altered regulation of the cyclic AMP system in opiate tolerance and dependence. The present measure relates only to type VIII adenylyl cyclase mRNA and similar tests with other cyclases are needed to explore fully this relationship.
慢性阿片类药物治疗突然中断或给予拮抗剂后，环磷酸腺苷（cAMP）系统上调以及蛋白质底物磷酸化增强，这被认为是戒断期间观察到的各种行为反应的原因。通过原位杂交组织化学，我们首次表明，早在吗啡治疗后12小时，蓝斑和杏仁核（这两个脑区被认为在吗啡依赖性表达中很重要）中的VIII型腺苷酸环化酶mRNA就选择性增加。此外，吗啡诱导的蓝斑中VIII型腺苷酸环化酶mRNA变化的时间进程与跳跃发生率相关，跳跃是小鼠吗啡戒断的最重要标志。另外，丘脑核中VIII型腺苷酸环化酶mRNA的过表达可能会增加吗啡耐受性。这些发现从分子水平为阿片类药物耐受性和依赖性中环磷酸腺苷系统调节改变提供了有力支持。目前的测量仅涉及VIII型腺苷酸环化酶mRNA，需要用其他环化酶进行类似测试以充分探索这种关系。
