Mu Opioid Receptor Polymorphisms And Alcohol Dependence

Mu阿片受体与酒精和其他滥用药物的奖赏、耐受和戒断效应有关。我们直接对人类MU阿片受体基因座OPRM1进行测序，以检测可能影响该受体功能或与阿片类药物功能相关的精神表型的自然变异。发现了4个DNA序列变异：3个氨基酸替换(Ala6Val[Rare]，Asn40Asp[频率10%]，Ser147 Cys[Rare])和1个内含子变异(IVS2+691G/C[频率50%])。采用3个精神病学特征人群样本(N=791)的OPRM1等位基因、基因型和单倍型对酒精依赖进行关联和同胞连锁分析。在三个人群样本中的任何一个样本中，OPRM1与酒精依赖都没有显著的关联或联系。这些结果和能量计算有力地表明，u阿片受体的变异与DSM-III-R酒精依赖的易感性无关。与耶鲁大学的斯蒂芬妮·奥马利合作，正在研究变异是否与阿片类药物治疗的反应和阿片类药物功能的变异有关。美国国立卫生研究院牙科和颅面研究所的Ray Dionne和Michael Iadarola共同发起了一项关于痛觉遗传差异的研究。一项关于阿片成瘾的大规模病例对照关联研究已经完成，这些结果正在准备发表。在另一种研究方法中，正在研究影响多巴胺功能的遗传变异之间的相互作用，以研究它们在调节中枢阿片功能方面的作用。在来自德国和中国的大型病例对照数据集中，10个座位的DRD2单倍型预测阿片成瘾。Comt Val158Met预测了在疼痛/压力挑战期间的亚慢性疼痛反应和杏仁核卡芬烯结合。

The mu opioid receptor is implicated in the reward, tolerance and withdrawal effects of alcohol and other drugs of abuse. We directly sequenced the human mu opioid receptor locus, OPRM1, to detect natural variation that might affect the function of this receptor or be associated with psychiatric phenotypes related to opioid function. Four DNA sequence variants were found: three amino acid substitutions(Ala6Val [rare], Asn40Asp [frequency 10%], Ser147Cys [rare]) and one intronic variant (IVS2+691G/C [frequency 50%]). OPRM1 alleles, genotypes and haplotypes from three psychiatrically characterized population samples (N = 791) were used to perform association and sib-pair linkage analyses to alcohol dependence. There was no significant association or linkage between OPRM1 and alcohol dependence in any of the three population samples. These results and power calculations strongly suggest that variation at the mu opioid receptor is not involved in vulnerability to DSM-III-R Alcohol Dependence. Variation is being investigated for possible association to response to opiate pharmacotherapy and to variation in opioid function, in collaboration with Stephanie O'Malley, Yale University. A study on inherited differences in nociception has been initiated with Ray Dionne & Michael Iadarola of the National Institute of Dental and Craniofacial Research, NIH. A large scale case-control association study on opioid addiction has been completed and these results are in preparation for publication. In another avenue of research, interactions of the genetic variants affecting dopamine function are being investigated for their role in modulating central opioid function. A ten locus DRD2 haplotype predicted opioid addiction in large case control datasets from both Germany and China. COMT Val158Met predicted subchronic pain response and amygdala carfentenyl binding during a pain/stress challenge.