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

Mague, Stephen D.; Blendy, Julie A.

doi:10.1016/j.drugalcdep.2009.12.016

Cited by 124 publications

(112 citation statements)

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“…MORs has been reported to be crucial to several biological functions, for instance, reward, analgesia and stress responses, 19,20 as well as the development of addiction, 21 including nicotine dependence. [22][23][24][25] MOR mRNA and protein in brain regions have been reported to be upregulated by nicotine.…”

Section: Introductionmentioning

confidence: 99%

OPRM1 genetic polymorphisms are associated with the plasma nicotine metabolite cotinine concentration in methadone maintenance patients: a cross sectional study

et al. 2012

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Majority of the heroin-dependent patients smoke cigarettes. Although it has been reported that the OPRM1 genetic polymorphism is associated with the brain mu-opioid receptor binding potential in cigarette smokers, there is no direct evidence showing the impact of plasma cotinine, a nicotine metabolite, on treatment responses to methadone maintenance treatment (MMT). In this study, we aimed to test the hypothesis that the genetic polymorphisms in the OPRM1 are associated with the methadone treatment responses and the severity of cigarette smoking directly measured by the plasma concentration of cotinine in a Taiwanese MMT cohort. Fifteen OPRM1 single-nucleotide polymorphisms (SNPs) were selected and genotyped on DNA samples of 366 MMT patients. Plasma concentrations of cotinine were measured by cotinine enzyme-linked immunosorbent assay. The plasma cotinine concentration had positive correlation with concentrations of methadone (P ¼ 0.042) and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenyl-pyrrolidine (P ¼ 0.037). Methadone treatment non-responders, defined by a positive urine morphine test, had a higher plasma concentration of cotinine (P ¼ 0.005), but a lower plasma concentration-todose ratio of both R-and S-methadone (P ¼ 0.001 and 0.012, respectively) than the responders. OPRM1 genetic variants, rs1074287, rs6912029, rs1799971, rs12209447, rs510769, rs3798676, rs553202, rs7748401, rs495491, rs10457090, rs589046, rs3778152 and rs563649, were significantly associated with the plasma concentration of cotinine when using recessive model for genotypes (general linear model (GLM), Po0.038; false discovery rate (FDR)o0.035) and additive model for allele types (GLM, Po0.03; FDRo0.049) in association analyses. The G allele carriers of SNP rs1799971 (A118G) on exon 1 of OPRM1 gene had a lower plasma cotinine concentration than the A allele carriers (GLM, P ¼ 0.029). OPRM1 genetic polymorphisms are associated with the plasma concentration of cotinine in a Taiwanese MMT cohort. Carriers with the major allele of SNP rs1799971 had a higher plasma cotinine concentration.

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Section: Introductionmentioning

confidence: 99%

OPRM1 genetic polymorphisms are associated with the plasma nicotine metabolite cotinine concentration in methadone maintenance patients: a cross sectional study

et al. 2012

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“…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).…”

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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.

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129

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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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“…However, although the A allele is associated with increased risk of nicotine addiction, the G allele is more frequently a risk factor for alcohol dependence (Ray et al, 2012). Thus, associations between OPRM1 variation and molecular phenotype may depend on the specific drug of abuse (Mague and Blendy, 2010).…”

Section: Structural Abnormalities Assessed With Mrimentioning

confidence: 99%

“…Finally, studies of the mu-opioid receptor variant OPRM1 A118G, which modulates receptor expression and binding affinity (Mague and Blendy, 2010), offer promising support for use of [ 11 C]carfentanil PET imaging in this context. Homozygosity for the common A allele is associated with greater receptor availability in smokers, alcohol-dependent patients and healthy controls (Ray et al, 2011;Weerts et al, 2012).…”

Section: Structural Abnormalities Assessed With Mrimentioning

confidence: 99%

Neuroimaging in Psychiatric Pharmacogenetics Research: The Promise and Pitfalls

Falcone

Smith

Chenoweth

et al. 2013

Neuropsychopharmacol

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The integration of research on neuroimaging and pharmacogenetics holds promise for improving treatment for neuropsychiatric conditions. Neuroimaging may provide a more sensitive early measure of treatment response in genetically defined patient groups, and could facilitate development of novel therapies based on an improved understanding of pathogenic mechanisms underlying pharmacogenetic associations. This review summarizes progress in efforts to incorporate neuroimaging into genetics and treatment research on major psychiatric disorders, such as schizophrenia, major depressive disorder, bipolar disorder, attention-deficit/hyperactivity disorder, and addiction. Methodological challenges include: performing genetic analyses in small study populations used in imaging studies; inclusion of patients with psychiatric comorbidities; and the extensive variability across studies in neuroimaging protocols, neurobehavioral task probes, and analytic strategies. Moreover, few studies use pharmacogenetic designs that permit testing of genotype Â drug effects. As a result of these limitations, few findings have been fully replicated. Future studies that pre-screen participants for genetic variants selected a priori based on drug metabolism and targets have the greatest potential to advance the science and practice of psychiatric treatment.

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

Cited by 124 publications

References 129 publications

OPRM1 genetic polymorphisms are associated with the plasma nicotine metabolite cotinine concentration in methadone maintenance patients: a cross sectional study

OPRM1 genetic polymorphisms are associated with the plasma nicotine metabolite cotinine concentration in methadone maintenance patients: a cross sectional study

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

Neuroimaging in Psychiatric Pharmacogenetics Research: The Promise and Pitfalls

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