F140PHARMACOEPIGENETICS OF ALCOHOL DEPENDENCE: NO SIGNIFICANT EFFECT OF MU-OPIOID RECEPTOR GENE (OPRM1) PROMOTER METHYLATION ON NALTREXONE TREATMENT RESPONSE

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.

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

Scientific Reports ◽

10.1038/s41598-020-78783-4 ◽

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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A118G Single Nucleotide Polymorphism of Human μ-Opioid Receptor Gene Influences Pain Perception and Patient-controlled Intravenous Morphine Consumption after Intrathecal Morphine for Postcesarean Analgesia

Anesthesiology ◽

10.1097/aln.0b013e318182af21 ◽

2008 ◽

Vol 109 (3) ◽

pp. 520-526 ◽

Cited By ~ 197

Author(s):

Alex T. Sia ◽

Yvonne Lim ◽

Eileen C. P. Lim ◽

Rachelle W. C. Goh ◽

Hai Yang Law ◽

...

Keyword(s):

Opioid Receptor ◽

Pain Perception ◽

Intrathecal Morphine ◽

Receptor Gene ◽

Mu Opioid Receptor ◽

Morphine Consumption ◽

Mu Opioid ◽

Pain Scores ◽

Significant Difference ◽

Intravenous Morphine

Background Previous studies have shown that genetic variability at position 118 of the human mu-opioid receptor gene altered patients' response to intravenous morphine. The purpose of this study was to investigate whether this polymorphism contributes to the variability in response to morphine for postcesarean analgesia. Methods After investigators obtained informed consent, 588 healthy women received 0.1 mg intrathecal morphine for postcesarean analgesia. Their blood samples were genotyped for the A118G polymorphism-A118 homozygous (AA), heterozygous (AG), or homozygous for the G allele (GG). Pain scores, the severity of nausea and vomiting, the incidence of pruritus, and the total self-administered intravenous morphine were recorded for the first 24 postoperative hours. Results Two hundred seventy women (46%) were AA, 234 (40%) were AG, and 82 (14%) were GG. The 24-h self-administered intravenous morphine consumption was lowest in the AA group (P = 0.001; mean, 5.9; 95% confidence interval, 5.1-6.8) versus the AG (8.0; 6.9-9.1) and GG groups (9.4; 7.3-11.5). Pain scores were lowest in the AA group and highest in the GG group, with a statistically significant difference detected between AA, AG, and GG (P = 0.049). Total morphine consumption was also influenced by patients' age and paying status. AA group was associated with the highest incidence of nausea (26 of 272 [9.6%]; P = 0.02) versus the other two groups (13 of 234 [5.6%] and 1 of 82 [1.2%] for AG and GG, respectively). Conclusion Genetic variation at position 118 of the mu-opioid receptor is associated with interindividual differences in pain scores, self-administered intravenous morphine, and the incidence of nausea postoperatively.

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