Activation of mesolimbic mu-opioid receptors by their endogenous ligand, β-endorphin, can mediate the rewarding effects of alcohol. However, there is conflicting evidence on the relationship between the mu-opioid receptor (OPRM1) A118G single nucleotide polymorphism (SNP) and alcohol dependence risk. Preclinical evidence suggests that sex and sex hormone-dependent prenatal brain organization may interact with the opioid system to influence alcohol drinking behavior. We genotyped 200 alcohol-dependent patients and 240 healthy individuals for the OPRM1 A118G SNP and measured serum β-endorphin level at recruitment and after acute withdrawal. We then determined the association between these factors and alcohol dependence risk and 24-month outcome in the context of both sex and second-to-fourth digit lengths ratio (2D:4D) - a biomarker of prenatal sex hormone levels. The OPRM1 A118G AA genotype associated with elevated risk of alcohol-related hospital readmission, more readmissions, and fewer days until first readmission in male patients only. After normalizing patient 2D:4D against control 2D:4D, we found that normalized 2D:4D ratios were lower in male 118G patients than male AA patients, suggesting prenatal androgens interact with OPRM1 to influence alcohol dependence risk. In addition, β-endorphin levels after acute withdrawal correlated negatively with withdrawal severity in females but not in males, which may indicate β-endorphin protects against withdrawal-induced stress in a sex-specific manner.

译文

:中枢边缘类阿片受体通过其内源性配体β-内啡肽的激活可以介导酒精的有益作用。但是,关于μ阿片受体(OPRM1)A118G单核苷酸多态性(SNP)与酒精依赖风险之间的关系有相互矛盾的证据。临床前证据表明,性和依赖性激素的产前大脑组织可能与阿片样物质系统相互作用,从而影响饮酒行为。我们对200名酒精依赖患者和240名健康个体的OPRM1 A118G SNP进行了基因分型,并在募集时和急性停药后测量了血清β-内啡肽水平。然后,我们在性别和第二至第四位数长度比(2D:4D)的背景下确定了这些因素与酒精依赖风险和24个月结局之间的关联-产前性激素水平的生物标记。仅男性患者中,OPRM1 A118G AA基因型与酒精相关的医院再次入院,更多的再次入院和更少的天数相关。在将患者2D:4D与对照2D:4D标准化后,我们发现男性118G患者的标准化2D:4D比率低于男性AA患者,这表明产前雄激素与OPRM1相互作用会影响酒精依赖风险。另外,急性戒断后的β-内啡肽水平与女性的戒断严重程度呈负相关,而与男性无关,这可能表明β-内啡肽以性别特异性的方式保护免受戒断诱发的压力。

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