μ-Opioid receptor desensitization by β-arrestin-2 determines morphine tolerance but not dependence
μ-Opioid receptor desensitization by β-arrestin-2 determines morphine tolerance but not dependence
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DOI：
10.1038/35047086
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发表时间：
2000-12-07
期刊：
影响因子：
64.8
通讯作者：
Caron, MG
中科院分区：
文献类型：
--
作者：
Bohn, LM;Gainetdinov, RR;Caron, MG
吗啡是一种有效的止痛药，但也是耐受性和依赖性的有效诱因。阿片类药物耐受性的形成是在持续使用药物时发生的，因此必须增加引起疼痛缓解所需的药量，以弥补反应减弱的影响(1-3)。在许多系统中，对激动剂的反应性降低与G蛋白偶联受体的脱敏有关。体外证据表明，这一过程涉及G蛋白偶联受体的磷酸化和随后被称为β-arrestins(4，5)的调节蛋白的结合。使用缺乏β-arrestin-2的基因敲除小鼠(beta arr2(-/-))，我们评估了u-阿片受体脱敏在吗啡抗伤害耐受性的形成和随后的身体依赖的发生中的作用。在这里，我们表明，在缺乏β-arrestin-2的小鼠中，在慢性吗啡治疗后，u-阿片受体不会发生脱敏，并且这些动物无法产生抗伤害耐受性。然而，β-arrestin-2的缺失并不能阻止慢性吗啡诱导的腺苷环化酶活性的上调，腺苷环化酶是一种依赖的细胞标志，突变的小鼠仍然成为对药物的物理依赖。
Morphine is a powerful pain reliever, but also a potent inducer of tolerance and dependence. The development of opiate tolerance occurs on continued use of the drug such that the amount of drug required to elicit pain relief must be increased to compensate for diminished responsiveness(1-3). In many systems, decreased responsiveness to agonists has been correlated with the desensitization of G-protein-coupled receptors. In vitro evidence indicates that this process involves phosphorylation of G-protein-coupled receptors and subsequent binding of regulatory proteins called beta -arrestins(4,5). Using a knockout mouse lacking beta -arrestin-2 (beta arr2(-/-)), we have assessed the contribution of desensitization of the mu -opioid receptor to the development of morphine antinociceptive tolerance and the subsequent onset of physical dependence. Here we show that in mice lacking beta -arrestin-2, desensitization of the mu -opioid receptor does not occur after chronic morphine treatment, and that these animals fail to develop antinociceptive tolerance. However, the deletion of beta -arrestin-2 does not prevent the chronic morphine-induced upregulation of adenylyl cyclase activity, a cellular marker of dependence, and the mutant mice still become physically dependent on the drug.