An analysis of the effect of mu-opioid receptor gene (OPRM1) promoter region DNA methylation on the response of naltrexone treatment of alcohol dependence. Lin Yufei,Kranzler Henry R,Farrer Lindsay A,Xu Hongqin,Henderson David C,Zhang Huiping The pharmacogenomics journal This study explored the effect of OPRM1 promoter region DNA methylation on the outcome of treatment with the opioid antagonist naltrexone (NTX) for alcohol dependence (AD). Ninety-three patients with DSM-IV AD [41 African Americans (AAs) and 52 European Americans (EAs)] received double-blind treatment with NTX or placebo for at least three months. Relapse to heavy drinking was assessed during the first 13 weeks of the trial. Peripheral blood methylation levels of 33 CpG units in the OPRM1 promoter region were quantified using Sequenom EpiTYPER technology. Bayesian logistic regression was used to analyze the effects of NTX treatment, CpG methylation, CpG methylation × NTX treatment, and age on AD relapse. The Random Forest machine learning algorithm was applied to select AD relapse predictors. No significant effect of individual OPRM1 promoter CpG units on AD relapse was observed in either AAs or EAs. Age was significantly associated with AD relapse in EAs, among whom older subjects had a lower relapse rate. Random forest analyses revealed that the prediction rate for AD relapse reached 66.0% with five top variables (age and four CpG units; ranked by their importance to AD relapse) in the prediction model. These findings suggest that methylation levels of individual OPRM1 promoter CpG units do not contribute significantly to inter-individual variation in NTX response. However, the age of subjects in combination with a cluster of specific OPRM1 promoter CpG units may affect NTX treatment outcome. Additional studies of OPRM1 DNA methylation changes during and after NTX treatment of AD are needed. 10.1038/s41397-020-0158-1

Selective alterations in endogenous opioid system genes expression in rats selected for high ethanol intake during adolescence. Drug and alcohol dependence Historically, the roots of alcoholism have been linked to either environment or heredity. However, the interaction between these factors is still largely unexplored. The evidence supports a link between alcohol consumption and the endogenous opioid system. We here studied the opioid genes expression in male and female Wistar rats derived from a short-term breeding program which selected -- at adolescence -- for high (ADHI line) or low (ADLO line) ethanol drinking. Specifically, in this work we analyzed central opioid gene expression in the rats of the second filial generation (S-ADLO and S-ADHI). Selective downregulation of pronociceptin (Pnoc) and its receptor (Oprl1) mRNA levels were observed in the prefrontal cortex of male S-ADHI rats when compared to S-ADLO, and for Oprl1 also in the nucleus accumbens. An increase in gene expression was instead observed for pro-opiomelanocortin (Pomc) in the nucleus accumbens of S-ADHI males when compared to S-ADLO, as well as for mu opioid receptor (Oprm1) but in females. The differences in mRNA levels may be due to the different alcohol consumption between the two groups of rats or may represent pre-existing differences between them. Moreover, we show a sex-specific modulation of the expression of these genes, thus pointing out the importance of sex on ethanol responses. The results might lead to more specific and effective pharmacological treatments for alcoholism. 10.1016/j.drugalcdep.2020.108025

Association between the nociceptin receptor gene (OPRL1) single nucleotide polymorphisms and alcohol dependence. Huang Jia,Young Brandon,Pletcher Mathew T,Heilig Markus,Wahlestedt Claes Addiction biology OPRL1 encodes the nociceptin receptor, which has been shown to be involved in alcohol dependence in previous studies. In the present study, we investigated the association between genetic polymorphisms of OPRL1 and alcohol dependence in a Scandinavian population. We genotyped 15 single nucleotide polymorphisms (SNPs) spanning the OPRL1 locus and found that SNP rs6010718 was significantly associated with both Type I and Type II alcoholics (P < 0.05). Linkage disequilibrium and haplotype analysis identified two haplotype blocks in this region. Furthermore, two haplotypes composed of five tag SNPs showed significant association with alcohol dependence. These findings suggest that genetic variants of the OPRL1 gene play a role in alcohol dependence in the Scandinavian population, warranting further investigation at the OPRL1 locus. 10.1111/j.1369-1600.2007.00089.x