scholarly journals An analysis of the effect of mu-opioid receptor gene (OPRM1) promoter region DNA methylation on the response of naltrexone treatment of alcohol dependence

2020 ◽  
Vol 20 (5) ◽  
pp. 672-680
Author(s):  
Yufei Lin ◽  
Henry R. Kranzler ◽  
Lindsay A. Farrer ◽  
Hongqin Xu ◽  
David C. Henderson ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Alcohol Dependence ◽  
Opioid Receptor ◽  
Promoter Region ◽  
Receptor Gene ◽  
Mu Opioid Receptor ◽  
Mu Opioid ◽  
Naltrexone Treatment

scholarly journals Evidence of Endogenous Mu Opioid Receptor Regulation by Epigenetic Control of the Promoters

2007 ◽  
Vol 27 (13) ◽  
pp. 4720-4736 ◽  
Author(s):  
Cheol Kyu Hwang ◽  
Kyu Young Song ◽  
Chun Sung Kim ◽  
Hack Sun Choi ◽  
Xiao-Hong Guo ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Opioid Receptor ◽  
Promoter Region ◽  
Histone Deacetylase Inhibitors ◽  
Mu Opioid Receptor ◽  
Histone Deacetylation ◽  
Epigenetic Mechanism ◽  
Proximal Promoter ◽  
Mu Opioid

ABSTRACT The pharmacological effect of morphine as a painkiller is mediated mainly via the mu opioid receptor (MOR) and is dependent on the number of MORs in the cell surface membrane. While several studies have reported that the MOR gene is regulated by various cis- and trans-acting factors, many questions remain unanswered regarding in vivo regulation. The present study shows that epigenetic silencing and activation of the MOR gene are achieved through coordinated regulation at both the histone and DNA levels. In P19 mouse embryonal carcinoma cells, expression of the MOR was greatly increased after neuronal differentiation. MOR expression could also be induced by a demethylating agent (5′-aza-2′-deoxycytidine) or histone deacetylase inhibitors in the P19 cells, suggesting involvement of DNA methylation and histone deacetylation for MOR gene silencing. Analysis of CpG DNA methylation revealed that the proximal promoter region was unmethylated in differentiated cells compared to its hypermethylation in undifferentiated cells. In contrast, the methylation of other regions was not changed in either cell type. Similar methylation patterns were observed in the mouse brain. In vitro methylation of the MOR promoters suppressed promoter activity in the reporter assay. Upon differentiation, the in vivo interaction of MeCP2 was reduced in the MOR promoter region, coincident with histone modifications that are relevant to active transcription. When MeCP2 was disrupted using MeCP2 small interfering RNA, the endogenous MOR gene was increased. These data suggest that DNA methylation is closely linked to the MeCP2-mediated chromatin structure of the MOR gene. Here, we propose that an epigenetic mechanism consisting of DNA methylation and chromatin modification underlies the cell stage-specific mechanism of MOR gene expression.

scholarly journals OPRM1 A118G and serum β-endorphin interact with sex and digit ratio (2D:4D) to influence risk and course of alcohol dependence

2017 ◽  
Author(s):  
Jordan Bruno Gegenhuber ◽  
Christian Weinland ◽  
Johannes Kornhuber ◽  
Christiane Mühle ◽  
Bernd Lenz
Keyword(s):  
Alcohol Dependence ◽  
Opioid Receptor ◽  
Sex Hormones ◽  
Receptor Gene ◽  
Drinking Behavior ◽  
Mu Opioid Receptor ◽  
Sex Hormone ◽  
Opioid System ◽  
Endogenous Opioid ◽  
Mu Opioid

AbstractActivation of mesolimbic mu-opioid receptor by its endogenous ligand, β-endorphin, mediates part of the rewarding effects of alcohol, yet there is controversial evidence surrounding the relationship between the functional mu-opioid receptor gene (OPRM1) A118G single nucleotide polymorphism and alcohol dependence risk. Some 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 A118G variant and measured serum β-endorphin level at recruitment and during acute withdrawal. We then evaluated the association between these factors and alcohol dependence risk and outcome in the context of both sex and second-to-fourth digit length ratio (2D:4D) – a biomarker of prenatal sex hormone load. For the first time, the AA genotype was found to be associated with elevated alcohol-related hospital readmission risk, more readmissions, and fewer days until first readmission in male but not female patients. Upon accounting for 2D:4D, the G-allele predicted alcohol dependence and more readmissions (1 vs ≥2) in males, suggesting prenatal sex hormones interact with OPRM1 to influence addiction pathology. Withdrawal β-endorphin level also correlated negatively with withdrawal severity in females but not in males, indicating β-endorphin might protect against withdrawal-induced stress in a sex-specific manner. Organizational effects of sex hormones may prime individuals for alcohol dependence by inducing permanent changes to the endogenous opioid system.

scholarly journals Variation of the human mu-opioid receptor (OPRM1) gene predicts vulnerability to frustration

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Alan M. Daniel ◽  
Brenda G. Rushing ◽  
Karla Y. Tapia Menchaca
Keyword(s):  
Individual Differences ◽  
Animal Models ◽  
Opioid Receptor ◽  
Receptor Gene ◽  
Emotional Reaction ◽  
Mu Opioid Receptor ◽  
Reward Processing ◽  
Physical Pain ◽  
Mu Opioid ◽  
Allelic Differences

AbstractUnderstanding the emotional reaction to loss, or frustration, is a critical problem for the field of mental health. Animal models of loss have pointed to the opioid system as a nexus of frustration, physical pain, and substance abuse. However, few attempts have been made to connect the results of animal models of loss to human behavior. Allelic differences in the human mu opioid receptor gene, notably the A118G single nucleotide polymorphism, have been linked to individual differences in pain sensitivity, depressive symptoms, and reward processing. The present study explored the relationship between A118G and behavior in two frustrating tasks in humans. Results showed that carriers of the mutant G-allele were slower to recover behavior following a reward downshift and abandoned a frustrating task earlier than those without the mutation. Additionally, G-carriers were more sensitive to physical pain. These results highlight the overlap between frustration and pain, and suggest that genetic variation in opioid tone may contribute to individual differences in vulnerability and resilience following emotional disturbances.

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