Increased Attributable Risk Related to a Functional μ-Opioid Receptor Gene Polymorphism in Association with Alcohol Dependence in Central Sweden

Bart, Gavin; Kreek, Mary Jeanne; Ott, Jürg; LaForge, K. Steven; Proudnikov, Dmitri; Pollak, Lotta; Heilig, Markus

doi:10.1038/sj.npp.1300598

Cited by 197 publications

(149 citation statements)

References 42 publications

(64 reference statements)

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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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confidence: 91%

On the Role of Genetic Testing for Personalized Drug Overdose Management

et al. 2013

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“…Relative m-receptor to k-receptor blockade effects would be expected to differ in subjects with low circulating levels of endogenous m-receptor ligands, as is the case with alcoholics and their offspring (Govoni et al, 1983;Vescovi et al, 1992;del Arbol et al, 1995;Dai et al, 2005), or in subjects with low levels of m-receptor expression, as is found in subjects with low frontal DA levels (Berthele et al, 2005) owing to their catechol-O-methyltransferase genotype (Meyer-Lindenberg et al, 2005), and in subjects with the A118G polymorphism of the m-receptor (Zhang et al, 2005). This latter polymorphism has also shown a functional differentiation in the therapeutic response to NTX (Oslin et al, 2003), and has distinguished alcoholics from non-alcoholics in some populations (Bart et al, 2005). Based on this line of reasoning, we would expect to find a group difference in NTX on decision-making, however given the small sample size and large variance within groups, this study lacked sufficient statistical power to draw such a conclusion.…”

Section: Discussion Ntx Effects On Impulsive Choicementioning

confidence: 99%

Endogenous Opioid Blockade and Impulsive Responding in Alcoholics and Healthy Controls

Mitchell

Fields

et al. 2006

Neuropsychopharmacol

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The opioid receptor antagonist naltrexone (NTX) is one of few approved treatments for alcoholism, yet the mechanism by which it reduces drinking remains unclear. In rats, NTX reduces morphine-induced impulsive choice bias; however, nothing is known about the drug's effect on discrete aspects of impulsive behavior in humans, such as decision-making and inhibitory control. Here, we used a modified delay discounting procedure to investigate whether NTX improves decision-making or inhibitory control in humans. We measured the effect of acute NTX (50 mg) on choice between smaller sooner (SS) and larger later monetary rewards and on response errors (motor mismatch) in a high conflict condition in a group of abstinent alcoholics (AA) and healthy control subjects (CS). We previously reported that AA selected the SS option significantly more often than did CS in this paradigm. If the choice bias of AA is due to enhanced endogenous opioid signaling in response to potential reward, NTX should reduce such bias in the AA group. We found that NTX did not reliably reduce impulsive choice in the AA group; however, NTX's effect on choice bias across individuals was robustly predictable. NTX's effect on choice bias was significantly correlated with scores on Rotter's Locus of Control (LOC) scale; increasingly internal LOC scores predicted increasing likelihood of impulsive choices on NTX. In addition, we found that NTX significantly enhanced control of motor responses, particularly within the CS group. These results suggest that endogenous opioids may impair response selection during decision-making under conflict, and that NTX's effects on explicit decision-making are personality-dependent. Determining the biological basis of this dependence could have important implications for effective alcoholism treatment.

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“…A number of studies have reported positive association between OPRM1 functional variant A118G and OD, [27][28][29][30] cocaine dependence (CD) 31 or AD. [31][32][33][34] Moreover, three studies adopting haplotype-based approaches also demonstrated the association between OPRM1 variants and DD or AD. [35][36][37] However, a meta-analysis showed no consistent evidence of an association of the A118G polymorphism with SD.…”

Section: Introductionmentioning

confidence: 93%

The OPRD1 and OPRK1 loci in alcohol or drug dependence: OPRD1 variation modulates substance dependence risk

et al. 2007

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Eleven single-nucleotide polymorphisms (SNPs) spanning OPRD1 were examined in 1063 European Americans (EAs) (620 cases with substance dependence (SD), including 557 with alcohol dependence (AD), 225 with cocaine dependence (CD) and 111 with opioid dependence (OD), and 443 controls). Nominally significant associations (P < 0.05) of five SNPs with SD were observed; only the association of the non-synonymous variant G80T with OD remained significant after correction for multiple testing using SNPSpD. Haplotype analyses with six tag SNPs indicated that a specific haplotype GCAACT, which harbors G80T G-allele and C921T C-allele, was significantly associated with AD (v 2 = 14.82, degrees of freedom (d.f.) = 1, P < 0.001), CD (v 2 = 9.19, d.f. = 1, P = 0.002) and OD (v 2 = 20.68, d.f. = 1, P < 0.001). Logistic regression analyses, with sex and age being considered, demonstrated that this haplotype had a risk effect on AD (P = 0.03, b = 1.86, odds ratio (OR) = 6.43) and especially on OD (P < 0.001, b = 3.92, OR = 50.57). Moreover, seven SNPs covering OPRK1 were examined in the majority of the above subjects (390 cases, including 327 AD, 177 CD and 97 OD subjects, and 358 controls). Although no significant differences in allele, genotype or haplotype frequency distributions were seen between cases and controls, a specific OPRK1 haplotype, GGCTTCT, was significantly associated with AD (v 2 = 8.12, d.f. = 1, P = 0.004). Logistic regression analyses also revealed its risk effect on AD (P = 0.009, b = 1.06, OR = 2.90). Population stratification artifact was not observed in the sample. Taken together, our findings supported a positive association between OPRD1 variants and SD, and a positive haplotypic association between OPRK1 and AD in EAs.

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Increased Attributable Risk Related to a Functional μ-Opioid Receptor Gene Polymorphism in Association with Alcohol Dependence in Central Sweden

Cited by 197 publications

References 42 publications

On the Role of Genetic Testing for Personalized Drug Overdose Management

On the Role of Genetic Testing for Personalized Drug Overdose Management

Endogenous Opioid Blockade and Impulsive Responding in Alcoholics and Healthy Controls

The OPRD1 and OPRK1 loci in alcohol or drug dependence: OPRD1 variation modulates substance dependence risk

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