Mague SD, Blendy JA. OPRM1 SNP (A118G): involvement in disease development, treatment response, and animal models. Drug Alcohol Depend 108: 172-182

Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, TRL, PA 19104, USA.
Drug and alcohol dependence (Impact Factor: 3.42). 05/2010; 108(3):172-82. DOI: 10.1016/j.drugalcdep.2009.12.016
Source: PubMed


Endogenous opioids acting at mu-opioid receptors mediate many biological functions. Pharmacological intervention at these receptors has greatly aided in the treatment of acute and chronic pain, in addition to other uses. However, the development of tolerance and dependence has made it difficult to adequately prescribe these therapeutics. A common single nucleotide polymorphism (SNP), A118G, in the mu-opioid receptor gene can affect opioid function and, consequently, has been suggested to contribute to individual variability in pain management and drug addiction. Investigation into the role of A118G in human disease and treatment response has generated a large number of association studies across various disease states as well as physiological responses. However, characterizing the functional consequences of this SNP and establishing if it causes or contributes to disease phenotypes have been significant challenges. In this manuscript, we will review a number of association studies as well as investigations of the functional impact of this gene variant. In addition, we will describe a novel mouse model that was generated to recapitulate this SNP in mice. Evaluation of models that incorporate known human genetic variants into a tractable system, like the mouse, will facilitate the understanding of discrete contributions of SNPs to human disease.

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    • "Using an additive genetic model, an association of the OPRM1 A118G (rs1799971) G alelle with improved NAS outcomes was found in the present study, as was identified by our group using a dominant genetic model (Wachman et al., 2013). This OPRM1 SNP has been associated with differences in -endorphin levels and -opioid receptor binding, and with differences in pain and withdrawal tolerance (Klepstad et al., 2005; Mague and Blendy, 2010). As demonstrated in another study in our series, epigenetic mechanisms such as DNA methylation within OPRM1 after chronic in utero opioid exposure also are likely important in modulating the response to post-natal opioid therapy (Wachman et al., 2014). "
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    ABSTRACT: There is significant variability in the severity of neonatal abstinence syndrome (NAS) due to in-utero opioid exposure. We wanted to determine if single nucleotide polymorphisms (SNPs) in key candidate genes contribute to this variability. Full-term opioid-exposed newborns and their mothers (n=86 pairs) were studied. DNA was genotyped for 80 SNPs from 14 genes utilizing a custom designed microarray. The association of each SNP with NAS outcomes was evaluated. SNPs in two opioid receptor genes in the infants were associated with worse NAS severity: (1) The PNOC rs732636 A allele (OR=3.8, p=0.004) for treatment with 2 medications and a longer hospital stay (LOS) of 5.8 days (p=0.01), and (2) The OPRK1 rs702764 C allele (OR=4.1, p=0.003) for treatment with 2 medications. The OPRM1 rs1799971 G allele (β=-6.9 days, p=0.02) and COMT rs740603 A allele (β=-5.3 days, p=0.01) were associated with shorter LOS. The OPRD1 rs204076 A allele in the mothers was associated with a longer LOS by 6.6 days (p=0.008). Results were significant point-wise but did not meet the experiment-wide significance level. These findings suggest that SNPs in opioid receptor and the PNOC genes are associated with NAS severity. However, further testing in a large sample is warranted. This has important implications for prenatal prediction and personalized treatment regimens for infants at highest risk for severe NAS. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Drug and alcohol dependence 07/2015; 155. DOI:10.1016/j.drugalcdep.2015.07.001 · 3.42 Impact Factor
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    • "MOPR stimulation in the hippocampus increases net excitatory activity by decreasing GABAergic inhibition from local interneurons, resulting in the disruption of pyramidal cell firing synchrony and an alteration in hippocampal function (Faulkner et al., 1998). A common SNP in the gene encoding the MOPR has been shown to alter a variety of behaviors and drug responses in clinical populations [for review, (Mague and Blendy, 2010)] and in animal models (Barr and Goldman, 2006; Mague et al., 2009; Ramchandani et al., 2011; Zhang et al., 2014). Neither the extent of these changes nor the mechanisms mediating the effects are completely understood. "
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    ABSTRACT: A single nucleotide polymorphism (SNP) in the human μ-opioid receptor gene (OPRM1 A118G) has been widely studied for its association in a variety of drug addiction and pain sensitivity phenotypes; however, the extent of these adaptations and the mechanisms underlying these associations remain elusive. To clarify the functional mechanisms linking the OPRM1 A118G SNP to altered phenotypes, we used a mouse model possessing the equivalent nucleotide/amino acid substitution in the Oprm1 gene. In order to investigate the impact of this SNP on circuit function, we used voltage-sensitive dye imaging in hippocampal slices and in vivo electroencephalogram recordings of the hippocampus following MOPR activation. As the hippocampus contains excitatory pyramidal cells whose activity is highly regulated by a dense network of inhibitory neurons, it serves as an ideal structure to evaluate how putative receptor function abnormalities may influence circuit activity. We found that MOPR activation increased excitatory responses in wild-type animals, an effect that was significantly reduced in animals possessing the Oprm1 SNP. Furthermore, in order to assess the in vivo effects of this SNP during MOPR activation, EEG recordings of hippocampal activity following morphine administration corroborated a loss-of-function phenotype. In conclusion, as these mice have been shown to have similar MOPR expression in the hippocampus between genotypes, these data suggest that the MOPR A118G SNP results in a loss of receptor function. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Neuropharmacology 05/2015; 97. DOI:10.1016/j.neuropharm.2015.04.032 · 5.11 Impact Factor
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    • "occurring in exon 1 of the MOR gene is relatively common in individuals of European ancestry (15e30%) and Asian ancestry (40e50%) (Kwok et al., 2014). Individuals with the G118 allele exhibit less sensitivity to morphine analgesia and in vitro studies suggest that this SNP confers a loss of function although this is not a uniform finding of all studies (Mague and Blendy, 2010). For example, HPA inhibition is greater in animals with this SNP, suggesting increased opioid inhibitory tone. "
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    ABSTRACT: The stress response is characterized by the coordinated engagement of central and peripheral neural systems in response to life-threatening challenges. It has been conserved through evolution and is essential for survival. However, the frequent or continual elicitation of the stress response by repeated or chronic stress, respectively, results in the dysfunction of stress response circuits, ultimately leading to stress-related pathology. In an effort to best respond to stressors, yet at the same time maintain homeostasis and avoid dysfunction, stress response systems are finely balanced and co-regulated by neuromodulators that exert opposing effects. These opposing systems serve to restrain certain stress response systems and promote recovery. However, the engagement of opposing systems comes with the cost of alternate dysfunctions. This review describes, as an example of this dynamic, how endogenous opioids function to oppose the effects of the major stress neuromediator, corticotropin-releasing hormone, and promote recovery from a stress response and how these actions can both protect and be hazardous to health.
    F1000 Prime Reports 05/2015; 7. DOI:10.12703/P7-58
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