Association of the mu-opioid receptor gene with smoking cessation

Munafò, Marcus R.; Elliot, Katherine M.; Murphy, Michael; Walton, Robert; Johnstone, Elaine

doi:10.1038/sj.tpj.6500432

Cited by 71 publications

(46 citation statements)

References 64 publications

(73 reference statements)

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“…Further, the current study was designed to eliminate carryover effects of smoking by scanning smokers on two separate occasions. It will be important in future studies to include sufficient numbers of males and females, as the behavioral effects of this polymorphism may be sex specific (14,18,35), and female sex and estradiol alter MOR binding availability (36,37).…”

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.

133

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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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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.

133

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“…Most research on the role of genetic variation on smoking cessation pharmacotherapy has been directed to the two most widely accepted and licensed forms of smoking cessation therapy: nicotine replacement therapy (NRT) [111,[124][125][126][127][128][129][130][131][132][133][134][135][136][137][138][139][140] and the antidepressant bupropion (Zyban1) [129,137,[141][142][143][144][145][146][147][148][149].…”

Section: Influence Of Genetic Variations On Smoking Cessation Treatmentmentioning

confidence: 99%

“…Secondly, smokers who carry genetic polymorphisms associated with reduced nicotinic receptor (and possibly also dopaminergic) activity may experience greater benefit from nicotine spray (NS) compared with transdermal nicotine patches (TN), because of the greater rewarding effects of NS [133]. Thirdly, smokers who have increased activity variants in the m-opioid receptor (MOR) may have better success with the higher levels of nicotine delivered by TN compared with the lower levels of nicotine from NS [125,136,138], possibly only in combination with variants in MOR-interacting proteins [138]. Fourthly, an increased nicotine metabolism (determined primarily by CYP2A6 genotype but probably not by CYP2B6 genotype) lowers quit rates with TN [128,130,135].…”

Section: Influence Of Genetic Variations On Smoking Cessation Treatmentmentioning

confidence: 99%

Genetic variation as a predictor of smoking cessation success. A promising preventive and intervention tool for chronic respiratory diseases?

Quaak¹,

Schayck²,

Knaapen³

et al. 2009

Eur Respir J

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Tobacco smoking continues to be the largest preventable cause of premature morbidity and mortality throughout the world, including chronic respiratory diseases such as asthma and chronic obstructive pulmonary disease. Although most smokers are highly motivated to quit and many smoking cessation therapies are available, cessation rates remain very low.Recent research strongly suggests that variation in genetic background is an important determinant of smoking behaviour and addiction. Since these genetic variants might also influence the response to smoking cessation pharmacotherapies, it is likely that assessment of genetic background could be a promising tool to guide selection of the most effective cessation treatment for an individual smoker. Recently, it has been shown that genetic variants in the dopaminergic system, opioid receptors, the bupropion-metabolising enzyme CYP2B6 and the nicotine-metabolising enzyme CYP2A6 may play an important role in predicting smoking cessation responses to nicotine replacement therapy and bupropion treatment. Despite the progress that has been made, several challenges will still have to be overcome before genetically tailored smoking cessation therapy can be implemented in standard clinical practice.

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“…34 In our previous study, we found that patients with the G allele required higher a methadone dose than those with the A allele. 35 Furthermore, rs1799971 has also been reported to be significantly associated with long-term smoking cessation in both males and females, 36 with nicotine reinforcement in women, and with the brain m-opioid receptor binding potential in smokers. 11,15 However, the results are not consistent.…”

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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Association of the mu-opioid receptor gene with smoking cessation

Cited by 71 publications

References 64 publications

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

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

Genetic variation as a predictor of smoking cessation success. A promising preventive and intervention tool for chronic respiratory diseases?

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

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