Influence of OPRM1 Asn40Asp variant (A118G) on [ 11C]carfentanil binding potential: Preliminary findings in human subjects

Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
The International Journal of Neuropsychopharmacology (Impact Factor: 4.01). 03/2012; 16(1):1-7. DOI: 10.1017/S146114571200017X
Source: PubMed


The Asn40Asp variant (A118G) of the μ opioid receptor (OPRM1) gene is thought to contribute to the development and treatment of alcohol dependence. Employing positron emission tomography (PET), we first examined whether the single nucleotide polymorphism (SNP) modifies binding potential (BPND) of the μ-selective ligand [11C]carfentanil in healthy control (Con) and 5-d abstinent alcohol-dependent (AD) subjects (unblocked basal scan). Second, we examined whether the allelic variants were associated with differences in OPRM1 occupancy by naltrexone (50 mg) in AD subjects. Con and AD carriers of the G allele (AG) had lower global BPND at the basal scan than subjects homozygous for the A allele (AA). In AD subjects, naltrexone occupancy was slightly higher in AG subjects (98.9%) compared to AA subjects (93.1%), but this was not significant. We are the first to demonstrate using PET in healthy normal and AD subjects that the A118G SNP alters OPRM1 availability.

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Available from: Elise M Weerts, Feb 13, 2015
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    • "Several studies have indicated that NTX efficacy may be moderated by variation at a non-synonymous single nucleotide polymorphism (SNP) in the first exon of the m-opioid receptor gene (OPRM1), A118G (also known as Asn40Asp; rs1799971; although this SNP is referred to in the literature, as well as in this manuscript, as A118G, this designation has been changed on the NCBI Human Genome Assembly to A355G (Asn102Asp), as recent evidence suggests that OPRM1 may contain 62 additional amino acids), such that NTX blunts alcohol-induced craving, stimulation, and subjective intoxication (Ray and Hutchison, 2007; Ray et al, 2012b) and reduces relapse rates (Anton et al, 2008; Chamorro et al, 2012; Oslin et al, 2003) to a greater extent among individuals who carry at least one copy of the G allele. This allele, which encodes an asparagine (Asn) to aspartate (Asp) amino-acid substitution, has been reported to engender a threefold increase in b-endorphin-binding affinity for m-opioid receptors (Bond et al, 1998) and has been associated with reduced binding of [11(C)] -carfentanil, a selective m-opioid agonist (Weerts et al, 2012). However, it has also been associated with reduced OPRM1 mRNA and protein expression (Zhang et al, 2005), and some studies have reported no (Coller et al, 2011; Gelernter et al, 2007) or opposing (McGeary et al, 2006) interactions with NTX; "
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    ABSTRACT: Variation at a single nucleotide polymorphism in the μ-opioid receptor gene (OPRM1), A118G (Asn40Asp), may moderate naltrexone (NTX) effects in alcohol dependence. Both NTX and A118G variation have also been reported to affect alcohol cue-elicited brain activation. This study investigated whether sub-acute NTX treatment and A118G genotype interacted in their effects on cue-elicited activation of the ventral striatum (VS), medial prefrontal cortex (mPFC), and orbitofrontal cortex (OFC). Secondarily, variation at a variable number tandem repeat polymorphism in the dopamine transporter gene (DAT1/SLC6A3), which has been associated with increased reward-related activation in VS, was analyzed as a moderator of medication and A118G effects. Seventy-four non-treatment-seeking alcohol-dependent individuals, half preselected to carry at least one copy of the A118G G (Asp) allele, were randomized to NTX (50 mg) or placebo for 7 days, and performed an fMRI alcohol cue reactivity task on day 6. Region-of-interest analyses indicated no main effects of medication or A118G genotype. However, these factors interacted in their effects on OFC activation, such that, among NTX-treated individuals, G-allele carriers had less activation than A-allele homozygotes. DAT1 variation also moderated medication/A118G effects. There was a three-way interaction between medication and A118G and DAT1 genotypes on VS activation, such that, among G-allele carriers who received NTX, DAT1 10-repeat-allele (10R) homozygotes had less activation than 9-repeat-allele (9R) carriers. Further, 10R homozygotes who received NTX had less mPFC activation than 9R carriers. Polymorphic variation in OPRM1 and DAT1 should be considered in future studies of NTX, particularly regarding its effects on reward processing.Neuropsychopharmacology advance online publication, 3 October 2012; doi:10.1038/npp.2012.195.
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    ABSTRACT: Alcohol-use disorders are thought to be heterogeneous in etiology, pathophysiology and response to treatment. One hypothesized contributor to this variability is the common A118G polymorphism of the µ-opioid receptor gene, OPRM1. This article critically evaluates the evidence that the A118G substitution affects subjective, behavioral and neurobiological responses to alcohol and the opioid receptor antagonist, naltrexone. Although screening of patients in a clinical setting remains premature, results suggest the A118G substitution may influence one etiological pathway to alcoholism, for which naltrexone pharmacotherapy is more effective.
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