Acute and chronic opiate-regulation of adenylate cyclase in brain: specific effects in locus coeruleus.
Acute and chronic opiate-regulation of adenylate cyclase in brain: specific effects in locus coeruleus.
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发表时间：
1988-09
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通讯作者：
R. Duman;J. Tallman;Eric J. Nestler
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作者：
R. Duman;J. Tallman;Eric J. Nestler
吗啡和D-Ala 2-D-leu-enkephalin（DADLE）在体外对蓝斑（LC）、中缝背核（dorsal raphe）、额叶皮质和新纹状体的腺苷酸环化酶（adenylate cyclase，ACC）有急性抑制作用，其抑制作用可被阿片受体拮抗剂纳洛酮阻断。尽管吗啡在所检查的四个脑区域中同样有效（10-15%抑制），但DADLE在皮质和纹状体中更大程度地抑制环AMP（cAMP）产生（20-25%抑制）。体外百日咳毒素处理显著降低了所有脑区域中腺苷酸环化酶的DADLE抑制，表明这种阿片样物质反应是由百日咳毒素敏感性G蛋白（即，Gi和/或Go）。慢性（体内）管理的吗啡丸5天，治疗已知诱导阿片类药物的耐受性和依赖性，增加基础，GTP和毛喉素刺激的腺苷酸环化酶的LC，但不是在其他三个大脑区域的研究。发现DADLE在体外抑制LC中cAMP的产生，在对照和吗啡处理的大鼠中达到相同的程度，表明缺乏阿片受体耐受性。吗啡诱导的腺苷酸环化酶的增加需要长期暴露于阿片类药物，因为较短的治疗时间，即2小时和1天，未能产生这种效果。事实上，在2小时时，观察到LC中腺苷酸环化酶的小幅降低，这似乎不是由于吗啡保留在膜部分中。两者合计，本研究的结果提供了支持的观点，即在LC中的cAMP系统的变化发挥了作用，在介导急性阿片类药物的作用，以及在阿片类药物的耐受性，依赖性和/或戒断的发展的基础。
Acutely, morphine and D-ala2-D-leu-enkephalin (DADLE) inhibited adenylate cyclase in vitro in locus coeruleus (LC), dorsal raphe, frontal cortex and neostriatum and the inhibition by each agonist was blocked by the opiate-receptor antagonist naloxone. Although morphine was equally efficacious in the four brain regions examined (10-15% inhibition), DADLE inhibited cyclic AMP (cAMP) production to a greater extent in cortex and striatum (20-25% inhibition). Pertussis toxin treatment in vitro significantly reduced DADLE-inhibition of adenylate cyclase in all brain areas, indicating that this opiate response is mediated by a pertussis toxin-sensitive G-protein (i.e., Gi and/or Go). Chronic (in vivo) administration of morphine pellets for 5 days, treatment known to induce opiate tolerance and dependence, increased basal, GTP- and forskolin-stimulated adenylate cyclase in the LC, but not in the other three brain regions studied. DADLE was found to inhibit cAMP production in LC in vitro to the same extent in control and morphine-treated rats, suggesting a lack of opiate receptor tolerance. The morphine-induced increase in adenylate cyclase required chronic exposure to the opiate, as shorter treatment times, namely 2 hr and 1 day, failed to produce this effect. In fact, at 2 hr a small decrease in adenylate cyclase in the LC was observed that did not appear to be due to morphine being retained in the membrane fraction. Taken together, the findings of this study provide support for the view that changes in the cAMP system in the LC play a role in mediating acute opiate action as well as in underlying the development of opiate tolerance, dependence and/or withdrawal.