Article

OPRM1 SNP (A118G): involvement in disease development, treatment response, and animal models.

Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, TRL, PA 19104, USA.
Drug and alcohol dependence (Impact Factor: 3.28). 05/2010; 108(3):172-82. DOI: 10.1016/j.drugalcdep.2009.12.016
Source: PubMed

ABSTRACT 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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    ABSTRACT: Neonatal abstinence syndrome (NAS) caused by in utero opioid exposure is a growing problem; genetic factors influencing the incidence and severity have not been previously examined. Single-nucleotide polymorphisms (SNPs) in the μ-opioid receptor (OPRM1), multidrug resistance (ABCB1), and catechol-o-methyltransferase (COMT) genes are associated with risk for opioid addiction in adults. To determine whether SNPs in the OPRM1, ABCB1, and COMT genes are associated with length of hospital stay and the need for treatment of NAS. Prospective multicenter cohort study conducted at 5 tertiary care centers and community hospitals in Massachusetts and Maine between July 2011 and July 2012. DNA samples were genotyped for SNPs, and then NAS outcomes were correlated with genotype. Eighty-six of 140 eligible mother-infant dyads were enrolled. Infants were eligible if they were 36 weeks' gestational age or older and exposed to methadone or buprenorphine in utero . MAIN OUTCOMES AND MEASURES: Primary outcome measure was length of hospital stay, with between-group differences expressed as β and calculated with linear regression models. Secondary outcome measures included need for any medical treatment for NAS and treatment with 2 or more medications. Infants with the OPRM1 118A>G AG/GG genotype had shortened length of stay (β = -8.5 days; 95% CI, -14.9 to -2.1 days; P = .009) and were less likely to receive any treatment than AA infants (48% vs 72%; adjusted odds ratio, 0.76; 95% CI, 0.63-0.96; P = .006). The COMT 158A>G AG/GG genotype was associated with shortened length of stay (β = -10.8 days; 95% CI, -18.2 to -3.4 days; P = .005) and less treatment with 2 or more medications (18% vs 56%; adjusted odds ratio, 0.68; 95% CI, 0.55-0.86; P = .001) than the AA genotype. Associations with the ABCB1 SNPs were not significant. Among infants with NAS, variants in the OPRM1 and COMT genes were associated with a shorter length of hospital stay and less need for treatment. These preliminary findings may provide insight into the mechanisms underlying NAS.
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    ABSTRACT: Background and purposeNaturally occurring single-nucleotide polymorphisms (SNPs) within G protein-coupled receptors (GPCRs) can result in alterations in various pharmacological parameters. Understanding the regulation and function of endocytic trafficking of the μ-opioid receptor (MOPr) is of great importance given its implication in the development of opioid tolerance. This study has compared the agonist-dependent trafficking and signalling of L83I, the rat orthologue of a naturally occurring variant of the MOPr.Experimental approachCell surface ELISA, confocal microscopy and immunoprecipitation assays were used to characterize the trafficking properties of the MOPr-L83I variant in comparison to the wild-type receptor in HEK 293 cells. Functional assays were used to compare the ability of the L83I variant to signal to several downstream pathways.Key resultsMorphine-induced internalization of L83I was markedly increased in comparison to the wild-type receptor. The altered trafficking of this variant was found to be specific to morphine and was both GRK- and dynamin-dependent. The enhanced internalization of L83I in response to morphine was not due to increased phosphorylation of Serine 375, arrestin association or an increased ability to signal.Conclusions and implicationsThese results suggest that morphine promotes a specific conformation of the L83I variant that makes it more liable to internalize to morphine unlike the wild-type receptor which undergoes significantly less morphine-stimulated internalization, providing an example of a ligand-selective biased receptor. The presence of this SNP within an individual may consequently affect the development of tolerance and analgesic responses.
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    ABSTRACT: Rationale: Mu opioid receptors (MOPRs) are the target of heroin and other prescription opioids, which are currently responsible for massive addiction morbidity in the U.S. The gene coding for the human MOPR (OPRM1) has an important functional single nucleotide polymorphism (SNP), A118G. The OPRM1 A118G genotype results in substantially increased risk of heroin addiction in humans; however the neurobiological mechanism for this increased risk is not fully understood. Objectives: This study examined heroin self-administration (SA) behavior in A112G (G/G) mice, harboring a functionally equivalent SNP in Oprm1 with a similar amino acid substitution, in extended (4 hours) SA sessions. Methods: Adult male and female G/G mice and "wild type" litter mates (A/A) were allowed to self administer heroin (0.25 mg/kg/unit dose, FR1 with a nose poke response) for 4 hours/day, for 10 consecutive days. Half of the mice then continued in a heroin dose-response study, while extinction from heroin SA was studied in the other half. In vivo microdialysis was used to measure acute heroin-induced increases of striatal dopamine in the GG versus AA genotypes. Results: Male and female G/G mice responded for heroin significantly more (and thus had greater intake) than A/A mice, in the initial 10 days of heroin SA, and in the subsequent dose-response study. There were no significant differences in extinction of self administration between the A/A and G/G mice. Heroin-induced increases in striatal dopamine levels are higher in the GG mice than in the AA mice. Conclusion: Both male and female G/G mice self-administered more heroin than did A/A mice over a 10-day period, possibly due to the greater increases of heroin-induced striatal dopamine in the GG mice. Furthermore, G/G male mice escalated the amount of heroin self administration across 10 extended-access sessions more than A/A male mice did. These are the first studies to examine the acquisition of heroin SA in this mouse model. These studies may lead to a better understanding of the neurobiological and behavioral mechanisms that underlie greater risk of heroin addiction in carriers of the A118G SNP.Neuropsychopharmacology accepted article preview online, 22 October 2014. doi:10.1038/npp.2014.286.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 10/2014; 40(5). DOI:10.1038/npp.2014.286 · 7.83 Impact Factor

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