Differential Regulation of Behavioral Tolerance to WIN55,212-2 by GASP1
Differential Regulation of Behavioral Tolerance to WIN55,212-2 by GASP1
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DOI：
10.1038/npp.2010.6
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发表时间：
2010-05-01
影响因子：
7.6
通讯作者：
Whistler, Jennifer L.
中科院分区：
文献类型：
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作者：
Martini, Lene;Thompson, Dawn;Whistler, Jennifer L.
大麻素激动剂在临床上作为镇痛药已经显示出一些希望，特别是对于癌症疼痛，它们有减少恶心的额外好处。然而，就像大多数其他药物一样，大麻素的长期使用受到耐受性发展的限制。已经提出了几种分子机制来解释药物耐受性，包括受体下调。大麻素1 （CB1）受体可以在体外通过与g蛋白偶联受体相关分选蛋白1 （GASP1）的相互作用下调，GASP1在CB1受体激动剂介导的内吞作用后靶向CB1受体降解。为了研究GASP1介导的CB1受体的内吞后分选是否有助于体内对大麻素药物的耐受，我们制造了一只GASP1被破坏的小鼠。在野生型小鼠中，反复给药大麻素激动剂WIN55,212-2可促进CB1受体水平下调，并伴随对药物抗感觉、运动不协调和运动功能减退的耐受性。相比之下，GASP1基因敲除小鼠没有对这些影响产生耐受性，也没有表现出明显的受体下调。综上所述，本研究提供了GASP1在体内调节CB1受体下调的证据，并且内吞后受体的转运在WIN55,212-2耐受性的发展中起关键作用。神经精神药理学（2010）35,1363-1373；doi: 10.1038 / npp.2010.6;2010年2月17日在线发布
Cannabinoid agonists have shown some promise clinically as analgesics, in particular for cancer pain, in which they have the additional benefit of decreasing nausea. However, as for most other drugs, the long-term use of cannabinoids is limited by the development of tolerance. Several molecular mechanisms have been proposed to explain drug tolerance, including receptor downregulation. The cannabinoid 1 (CB1) receptors can be downregulated in vitro through an interaction with the G-protein-coupled receptor-associated sorting protein1, GASP1, that targets CB1 receptors for degradation after their agonist-mediated endocytosis. To investigate whether GASP1-mediated postendocytic sorting of the CB1 receptor contributes to tolerance to cannabinoid drugs in vivo, we generated a mouse with a disruption of GASP1. In wild-type mice, repeated administration of the cannabinoid agonist WIN55,212-2 promoted downregulation of CB1 receptor levels and concomitant tolerance to the effects of drug on antinociception, motor incoordination, and locomotor hypoactivity. In contrast, GASP1 knockout mice did not develop tolerance to any of these effects and showed no significant receptor downregulation. Taken together, this study provides evidence that GASP1 regulates CB1 receptor downregulation in vivo, and that postendocytic receptor trafficking has a key role in the development of tolerance to WIN55,212-2. Neuropsychopharmacology (2010) 35, 1363-1373; doi: 10.1038/npp.2010.6; published online 17 February 2010