Receptor Reserve Moderates Mesolimbic Responses to Opioids in a Humanized Mouse Model of the OPRM1 A118G Polymorphism.
Receptor Reserve Moderates Mesolimbic Responses to Opioids in a Humanized Mouse Model of the OPRM1 A118G Polymorphism.
复制标题
在 OPRM1 A118G 多态性人源化小鼠模型中，受体储备调节中脑边缘对阿片类药物的反应。
DOI：
10.1038/npp.2015.109
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发表时间：
2015
期刊：
影响因子：
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通讯作者：
Malanga,CJ
中科院分区：
文献类型：
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作者：
Robinson,JElliott;Vardy,Eyal;DiBerto,JeffreyF;Chefer,VladimirI;White,KateL;Fish,EricW;Chen,Meng;Gigante,Eduardo;Krouse,MichaelC;Sun,Hui;Thorsell,Annika;Roth,BryanL;Heilig,Markus;Malanga,CJ
OPRM 1 A118 G多态性是研究最广泛的μ-阿片受体（莫尔）变体。虽然其参与急性酒精效应的特点是很好的，但很少有人知道它在多大程度上改变阿片类药物的反应。先前的工作已经表明，电生理和镇痛反应吗啡，但不芬太尼是由OPRM 1 A118 G变异缓和，但这种解离背后的机制是未知的。在这里，我们发现，携带118 GG等位基因（h/mOPRM 1 - 118 GG）的人源化小鼠比h/mOPRM 1 - 118 AA同窝小鼠对吗啡和氢可酮的奖励作用不敏感，但对颅内自我刺激测量的其他阿片类药物的奖励作用不敏感。减少吗啡奖励在118 GG小鼠与减少多巴胺释放在延髓核和减少GABA释放的腹侧被盖区，这不是由于药物的效力或疗效在体外或受体结合亲和力的变化的影响。在h/mOPRM 1 - 118 GG小鼠中观察到更少的MOR结合位点，并且莫尔可用性的药理学降低揭示了芬太尼敏感性的基因型差异。这些发现表明，OPRM 1 A118 G多态性通过减少受体储备而不显著改变受体功能来降低对低效激动剂的敏感性。
The OPRM1 A118G polymorphism is the most widely studied μ-opioid receptor (MOR) variant. Although its involvement in acute alcohol effects is well characterized, less is known about the extent to which it alters responses to opioids. Prior work has shown that both electrophysiological and analgesic responses to morphine but not to fentanyl are moderated by OPRM1 A118G variation, but the mechanism behind this dissociation is not known. Here we found that humanized mice carrying the 118GG allele (h/mOPRM1-118GG) were less sensitive than h/mOPRM1-118AA littermates to the rewarding effects of morphine and hydrocodone but not those of other opioids measured with intracranial self-stimulation. Reduced morphine reward in 118GG mice was associated with decreased dopamine release in the nucleus accumbens and reduced effects on GABA release in the ventral tegmental area that were not due to changes in drug potency or efficacy in vitro or receptor-binding affinity. Fewer MOR-binding sites were observed in h/mOPRM1-118GG mice, and pharmacological reduction of MOR availability unmasked genotypic differences in fentanyl sensitivity. These findings suggest that the OPRM1 A118G polymorphism decreases sensitivity to low-potency agonists by decreasing receptor reserve without significantly altering receptor function.