μ Opioid receptor-mediated G-protein activation by heroin metabolites:: evidence for greater efficacy of 6-monoacetylmorphine compared with morphine
μ Opioid receptor-mediated G-protein activation by heroin metabolites:: evidence for greater efficacy of 6-monoacetylmorphine compared with morphine
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DOI：
10.1016/s0006-2952(01)00689-x
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发表时间：
2001-08-15
影响因子：
5.8
通讯作者：
Childers, SR
中科院分区：
文献类型：
--
作者：
Selley, DE;Cao, CC;Childers, SR
使用激动剂刺激的[S-35]鸟苷-5 ' -O-（γ-硫代）-三磷酸结合研究了海洛因代谢物刺激CL阿片受体介导的G蛋白活化的功效。在大鼠丘脑膜中，海洛因及其主要代谢产物6-单乙酰吗啡（6-MAM）比吗啡或吗啡-6-β-D-葡萄糖醛酸苷更有效。通过纳洛酮的竞争性拮抗作用、纳曲吲哚缺乏拮抗作用以及与吗啡的竞争性部分拮抗作用确定，这种增加的疗效不是由于海洛因和6-MAM对δ受体的作用增加。与这种解释一致。在C6神经胶质瘤细胞中表达的克隆的人μ阿片样物质受体上观察到海洛因及其代谢物的相同的相对功效曲线。此外，这些疗效差异具有GDP依赖性，与公认的受体介导的G蛋白活化机制一致。通过HPLC分析证实，海洛因的活性归因于体外脱乙酰化为6-MAM。这些结果表明，海洛因代谢物6-MAM具有更高的效力比其他海洛因代谢物在CL阿片受体，这可能有助于海洛因的疗效比吗啡在某些行为范例在体内。(C)2001 Elsevier Science Inc. All rights reserved.
The efficacy of heroin metabolites for the stimulation of CL opioid receptor-mediated G-protein activation was investigated using agonist-stimulated [S-35]guanosine-5 ' -O-(gamma -thio)-triphosphate binding. In rat thalamic membranes, heroin and its primary metabolite, 6-monoacetylmorphine (6-MAM), were more efficacious than morphine or morphine-6-betaD-glucuronide. This increased efficacy was not due to increased action of heroin and 6-MAM at delta receptors, as determined by competitive antagonism by naloxone, lack of antagonism by naltrindole, and competitive partial antagonism with morphine. In agreement with this interpretation. the same relative efficacy profile of heroin and its metabolites was observed at the cloned human mu opioid receptor expressed in C6 glioma cells. Moreover, these efficacy differences were GDP-dependent in a manner consistent with accepted mechanisms of receptor-mediated G-protein activation. The activity of heroin was attributed to in vitro deacetylation to 6-MAM, as confirmed by HPLC analysis. These results indicate that the heroin metabolite 6-MAM possesses higher efficacy than other heroin metabolites at CL opioid receptors, which may contribute to the higher efficacy of heroin compared with morphine in certain behavioral paradigms in vivo. (C) 2001 Elsevier Science Inc. All rights reserved.