MU OPIOID RECEPTOR POLYMORPHISMS AND ALCOHOL DEPENDENCE

阿片受体与酒精和其他药物滥用的奖赏、耐受和戒断效应有关。我们直接对人类mu阿片受体位点OPRM1进行了测序，以检测可能影响该受体功能或与阿片功能相关的精神表型相关的自然变异。发现4个DNA序列变异：3个氨基酸取代（Ala6Val[罕见]，Asn40Asp[频率10%]，Ser147Cys[罕见]）和1个内含子变异（IVS2+691G/C[频率50%]）。使用来自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兄弟对连锁分析。在三个人群样本中，OPRM1与酒精依赖之间没有显著的关联或联系。这些结果和功率计算强烈表明，mu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Stephanie O'Malley合作，正在研究变异与阿片类药物治疗反应和阿片类功能变异的可能关联。美国国立卫生研究院牙科和颅面研究所的Ray Dionne和Michael Iadarola发起了一项关于伤害感受遗传差异的研究。一项关于阿片类药物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。

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.