The Role of the Asn40Asp Polymorphism of the Mu Opioid Receptor Gene (OPRM1) on Alcoholism Etiology and Treatment: A Critical Review

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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Deciphering the Novel Role of Gαz in Mu Opioid Receptor Signaling

The FASEB Journal ◽

10.1096/fasebj.2021.35.s1.02393 ◽

2021 ◽

Vol 35 (S1) ◽

Author(s):

Miriam Barnett ◽

Brian Knapp ◽

Jean Bidlack

Keyword(s):

Opioid Receptor ◽

Mu Opioid Receptor ◽

The Novel ◽

Receptor Signaling ◽

Mu Opioid

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Mu Opioid Receptor Gene (OPRM1) in Patients With Opiate Use Disorder

Addictive Disorders & Their Treatment ◽

10.1097/adt.0000000000000174 ◽

2020 ◽

Vol 19 (1) ◽

pp. 16-21

Author(s):

Nehal Mostafa ◽

Maha W. Mobasher ◽

Heba N. El Baz ◽

Mohamed A. Khalil

Keyword(s):

Opioid Receptor ◽

Receptor Gene ◽

Mu Opioid Receptor ◽

Mu Opioid ◽

Opiate Use ◽

Opiate Use Disorder

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The role of peripherally acting mu-opioid receptor antagonists (PAMORA) in the treatment of constipation in palliative care

Palliative Medicine ◽

10.5114/pm.2019.86528 ◽

2019 ◽

Vol 11 (2) ◽

pp. 51-57

Author(s):

Tomasz Dzierżanowski

Keyword(s):

Palliative Care ◽

Opioid Receptor ◽

Mu Opioid Receptor ◽

Receptor Antagonists ◽

Mu Opioid ◽

Opioid Receptor Antagonists

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Deletion of the mu opioid receptor gene in mice reshapes the reward–aversion connectome

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1601640113 ◽

2016 ◽

Vol 113 (41) ◽

pp. 11603-11608 ◽

Cited By ~ 35

Author(s):

Anna E. Mechling ◽

Tanzil Arefin ◽

Hsu-Lei Lee ◽

Thomas Bienert ◽

Marco Reisert ◽

...

Keyword(s):

Functional Connectivity ◽

Opioid Receptor ◽

Resting State ◽

Receptor Gene ◽

Resting State Fmri ◽

Mu Opioid Receptor ◽

Major Influence ◽

Mu Opioid ◽

Brain Connectome ◽

Intergroup Comparison

Connectome genetics seeks to uncover how genetic factors shape brain functional connectivity; however, the causal impact of a single gene’s activity on whole-brain networks remains unknown. We tested whether the sole targeted deletion of the mu opioid receptor gene (Oprm1) alters the brain connectome in living mice. Hypothesis-free analysis of combined resting-state fMRI diffusion tractography showed pronounced modifications of functional connectivity with only minor changes in structural pathways. Fine-grained resting-state fMRI mapping, graph theory, and intergroup comparison revealed Oprm1-specific hubs and captured a unique Oprm1 gene-to-network signature. Strongest perturbations occurred in connectional patterns of pain/aversion-related nodes, including the mu receptor-enriched habenula node. Our data demonstrate that the main receptor for morphine predominantly shapes the so-called reward/aversion circuitry, with major influence on negative affect centers.

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Novel function of the poly(C)‐binding protein αCP3 as a transcriptional repressor of the mu opioid receptor gene

The FASEB Journal ◽

10.1096/fj.07-8561com ◽

2007 ◽

Vol 21 (14) ◽

pp. 3963-3973 ◽

Cited By ~ 20

Author(s):

Hack Sun Choi ◽

Chun Sung Kim ◽

Cheol Kyu Hwang ◽

Kyu Young Song ◽

Ping‐Yee Law ◽

...

Keyword(s):

Opioid Receptor ◽

Binding Protein ◽

Receptor Gene ◽

Transcriptional Repressor ◽

Mu Opioid Receptor ◽

Mu Opioid

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Single-nucleotide polymorphism in the human mu opioid receptor gene alters β-endorphin binding and activity: Possible implications for opiate addiction

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.95.16.9608 ◽

1998 ◽

Vol 95 (16) ◽

pp. 9608-9613 ◽

Cited By ~ 746

Author(s):

Cherie Bond ◽

K. Steven LaForge ◽

Mingting Tian ◽

Dorothy Melia ◽

Shengwen Zhang ◽

...

Keyword(s):

Opioid Receptor ◽

Methadone Maintenance ◽

Receptor Gene ◽

Mu Opioid Receptor ◽

Coding Region ◽

Allelic Form ◽

Endogenous Opioid ◽

Single Nucleotide ◽

Allele Distribution ◽

Mu Opioid

Opioid drugs play important roles in the clinical management of pain, as well as in the development and treatment of drug abuse. The mu opioid receptor is the primary site of action for the most commonly used opioids, including morphine, heroin, fentanyl, and methadone. By sequencing DNA from 113 former heroin addicts in methadone maintenance and 39 individuals with no history of drug or alcohol abuse or dependence, we have identified five different single-nucleotide polymorphisms (SNPs) in the coding region of the mu opioid receptor gene. The most prevalent SNP is a nucleotide substitution at position 118 (A118G), predicting an amino acid change at a putative N-glycosylation site. This SNP displays an allelic frequency of approximately 10% in our study population. Significant differences in allele distribution were observed among ethnic groups studied. The variant receptor resulting from the A118G SNP did not show altered binding affinities for most opioid peptides and alkaloids tested. However, the A118G variant receptor binds β-endorphin, an endogenous opioid that activates the mu opioid receptor, approximately three times more tightly than the most common allelic form of the receptor. Furthermore, β-endorphin is approximately three times more potent at the A118G variant receptor than at the most common allelic form in agonist-induced activation of G protein-coupled potassium channels. These results show that SNPs in the mu opioid receptor gene can alter binding and signal transduction in the resulting receptor and may have implications for normal physiology, therapeutics, and vulnerability to develop or protection from diverse diseases including the addictive diseases.

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