μ Opioid receptor A118G polymorphism in association with striatal opioid neuropeptide gene expression in heroin abusers

Drakenberg, Katarina; Nikoshkov, Andrej; Horváth, Márton; Fagergren, Pernilla; Gharibyan, Anna L.; Saarelainen, Kati; Rahman, Sadia; Nylander, Ingrid; Bakalkin, Georgy; Rajs, Jovan; Keller, Éva; Hurd, Yasmin L.

doi:10.1073/pnas.0600871103

Cited by 104 publications

(106 citation statements)

References 43 publications

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“…Consistent with the results of our study, multiple investigations have reported an association of the 118G allele with opioid abuse [4][5][6]. However, the mu opioid receptor is involved in multiple physiological functions, thus the 118G allele could be beneficial for some processes, but adverse for others.…”

supporting

confidence: 91%

On the Role of Genetic Testing for Personalized Drug Overdose Management

et al. 2013

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Author Reply: We thank our colleagues for their interest in our study entitled "Opioid Receptor Polymorphism A118G Associated with Clinical Severity in a Drug Overdose Population." Our results add to the growing literature over the past decade that implicate a handful of promising single nucleotide polymorphisms (SNPs) of the mu opioid receptor gene (OPRM1) as candidates for clinically relevant variability in baseline mesolimbic reward neurobiology (dopamine-opioid interaction), opioid sensitivity, and addiction [1]. Our findings warrant further research to understand the mechanisms underlying specific at-risk overdose populations. We completely concur that results of our pilot study, as with all such investigations, will require validation in larger populations, an effort which is currently being addressed at our institution. Confirming our results would have significant impact in the field of addiction to pave the way for personalized prescription practices not only for opioids, but for those at risk for drug overdose.Our data which demonstrated higher overdose severity in G allele subjects, not limited to opioid drugs, is likely due to dopamine-opioid interactions in the mesolimbic/striatal pathways relevant to reward and habit formation. Indeed, several lines of evidence have established significant disturbances of the opioid system in association with various drugs of abuse [2,3]. We therefore chose not to limit the analysis to only opioids given the biologic plausibility of enhanced abuse and addiction behaviors which apply for all drugs, not limited to opioids. To address our colleagues' suggestion to eliminate sympathomimetics, such as cocaine, from the analysis, we would argue that it is equally plausible that OPRM1 variants affect the same reward pathways for sympathomimetics, and thus arbitrary removal of these exposures would actually introduce, not eliminate, bias.A question was also raised as to whether the 118G allele confers resistance rather than increased susceptibility as suggested by the findings of our study. Consistent with the results of our study, multiple investigations have reported an

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supporting

confidence: 91%

On the Role of Genetic Testing for Personalized Drug Overdose Management

et al. 2013

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“…An alternate hypothesis is that long-term chronic exposure to nicotine produces greater up-regulation in the A/A group or downregulation in the */G group, a hypothesis that could be tested in the A112 knock-in mice. It is also plausible that the MOR BP ND differences are secondary to variation in endogenous opioid tone (26). Also supporting this mechanism, G allele carriers exhibit elevated cortisol responses to MOR blockade (27).…”

Section: Discussionmentioning

confidence: 75%

“…Indeed, evidence cited above (26,27) suggests that compensatory alterations in endogenous opioid tone are present in this group. Altered levels of G protein-coupled signaling molecules have also been observed in Neuro 2A cells transfected with the 118G hOPRM1 (31).…”

Section: Discussionmentioning

confidence: 99%

Human Mu Opioid Receptor ( OPRM1 A118G) polymorphism is associated with brain mu-opioid receptor binding potential in smokers

Ray

Ruparel²,

Newberg³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

131

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Evidence points to the endogenous opioid system, and the muopioid receptor (MOR) in particular, in mediating the rewarding effects of drugs of abuse, including nicotine. A single nucleotide polymorphism (SNP) in the human MOR gene (OPRM1 A118G) has been shown to alter receptor protein level in preclinical models and smoking behavior in humans. To clarify the underlying mechanisms for these associations, we conducted an in vivo investigation of the effects of OPRM1 A118G genotype on MOR binding potential (BP ND or receptor availability). Twenty-two smokers prescreened for genotype (12 A/A, 10 */G) completed two [ 11 C]carfentanil positron emission tomography (PET) imaging sessions following overnight abstinence and exposure to a nicotine-containing cigarette and a denicotinized cigarette. Independent of session, smokers homozygous for the wild-type OPRM1 A allele exhibited significantly higher levels of MOR BP ND than smokers carrying the G allele in bilateral amygdala, left thalamus, and left anterior cingulate cortex. Among G allele carriers, the extent of subjective reward difference (denicotinized versus nicotine cigarette) was associated significantly with MOR BP ND difference in right amygdala, caudate, anterior cingulate cortex, and thalamus. Future translational investigations can elucidate the role of MORs in nicotine addiction, which may lead to development of novel therapeutics.genetics | neuroimaging | tobacco W ith 1 billion tobacco users worldwide, nicotine dependence has a major impact on global health. Advances in medication development for nicotine dependence require an improved understanding of the neurobiology of this complex, relapsing brain disorder (1). Although multiple neurobiological mechanisms have been implicated, a growing body of evidence points to the endogenous opioid system, and the mu-opioid receptor (MOR) in particular, in mediating the reinforcing effects of drugs of abuse, including nicotine (2-5). Nicotine upregulates MOR mRNA and protein expression in brain regions important in drug reward in rodents (4, 6) and stimulates endogenous opioid release (7,8), resulting in MOR activation and dopamine release (9).Genetic variation in MORs can modulate the endogenous opioid system, thereby altering behavior. A common single nucleotide polymorphism (SNP) in the mu-opioid receptor gene (OPRM1 A118G) results in an amino acid exchange at a putative glycosylation site in the extracellular terminus of the MOR (10). This OPRM1 SNP has been associated with a variety of drug dependence phenotypes in rodent and human studies (11), including nicotine reward, nicotine withdrawal severity, and smoking relapse (12)(13)(14).Despite substantial attention to the OPRM1 A118G in drug addiction research, the precise function of this SNP has yet to be clarified. Although the minor (G) allele was originally thought to be a "gain-of-function" variant, on the basis of increased affinity of MOR agonists (15), other data suggest that the G allele is associated with reduced mRNA and protein expression (16,17)....

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“…For example, A118G increases the affinity of MOR-1 for ␤-endorphin (Bond et al, 1998;Kroslak et al, 2007), and lowers expression of MOR-1 mRNA and protein likely via altering an mRNA secondary structure , or reducing the N-glycosylation and protein stability of MOR-1 (Huang et al, 2012). The roles of OPRM1 SNPs have also been implicated in modulating agonist-induced receptor signaling and promoter activities (Befort et al, 2001;Kraus et al, 2001;Wang et al, 2001;Bayerer et al, 2007;Ravindranathan et al, 2009;Fortin et al, 2010). However, little is known about the effect of SNPs on OPRM1 alternative splicing.…”

Section: Introductionmentioning

confidence: 99%

A Heroin Addiction Severity-Associated Intronic Single Nucleotide Polymorphism Modulates Alternative Pre-mRNA Splicing of the Opioid Receptor Gene OPRM1 via hnRNPH Interactions

et al. 2014

Journal of Neuroscience

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Single nucleotide polymorphisms (SNPs) in the OPRM1 gene have been associated with vulnerability to opioid dependence. The current study identifies an association of an intronic SNP (rs9479757) with the severity of heroin addiction among Han-Chinese male heroin addicts. Individual SNP analysis and haplotype-based analysis with additional SNPs in the OPRM1 locus showed that mild heroin addiction was associated with the AG genotype, whereas severe heroin addiction was associated with the GG genotype. In vitro studies such as electrophoretic mobility shift assay, minigene, siRNA, and antisense morpholino oligonucleotide studies have identified heterogeneous nuclear ribonucleoprotein H (hnRNPH) as the major binding partner for the G-containing SNP site. The G-to-A transition weakens hnRNPH binding and facilitates exon 2 skipping, leading to altered expressions of OPRM1 splice-variant mRNAs and hMOR-1 proteins. Similar changes in splicing and hMOR-1 proteins were observed in human postmortem prefrontal cortex with the AG genotype of this SNP when compared with the GG genotype. Interestingly, the altered splicing led to an increase in hMOR-1 protein levels despite decreased hMOR-1 mRNA levels, which is likely contributed by a concurrent increase in single transmembrane domain variants that have a chaperone-like function on MOR-1 protein stability. Our studies delineate the role of this SNP as a modifier of OPRM1 alternative splicing via hnRNPH interactions, and suggest a functional link between an SNP-containing splicing modifier and the severity of heroin addiction.

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μ Opioid receptor A118G polymorphism in association with striatal opioid neuropeptide gene expression in heroin abusers

Cited by 104 publications

References 43 publications

On the Role of Genetic Testing for Personalized Drug Overdose Management

On the Role of Genetic Testing for Personalized Drug Overdose Management

Human Mu Opioid Receptor ( OPRM1 A118G) polymorphism is associated with brain mu-opioid receptor binding potential in smokers

A Heroin Addiction Severity-Associated Intronic Single Nucleotide Polymorphism Modulates Alternative Pre-mRNA Splicing of the Opioid Receptor Gene OPRM1 via hnRNPH Interactions

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