A genetic association study of the mu opioid receptor and severe opioid dependence

Crowley, James J.; Oslin, David W.; Patkar, Ashwin A.; Gottheil, Edward; DeMaria, Peter A.; O’Brien, Charles P.; Berrettini, Wade H.; Grice, Dorothy E.

doi:10.1097/00041444-200309000-00006

Cited by 127 publications

(109 citation statements)

References 23 publications

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“…In particular, two polymorphisms in exon 1 of the gene alter amino acid sequence, A +118 G (Asn40Asp) and C +17 T (Ala6Val), and these have received the most research attention. However, case-control studies have failed to demonstrate a consistent association between OPRM1 sequence variation and the presence of alcohol and/or drug dependence (Bergen et al, 1997;Berrettini et al, 1997;Bond et al, 1998;Kranzler et al, 1998;Sander et al, 1998;Gelernter et al, 1999;Town et al, 1999;Hoehe et al, 2000;Franke et al, 2001;Rommelspacher et al, 2001;Szeto et al, 2001;Schinka et al, 2002;Crowley et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…Consistent with evidence of greater effects of naloxone among subjects with the Asp40 variant, we hypothesized that this allele would predict greater clinical response among patients who underwent naltrexone treatment for a minimum of 5 weeks. At least one copy of the Asp40 variant is expected to be present in 24.3-36% of the general population of adults of European descent (Bergen et al, 1997;Bond et al, 1998;Gelernter et al, 1999;Crowley et al, 2003). Consequently, this polymorphism is also of potential importance on an epidemiological level, since the allele is sufficiently common to be clinically relevant if associated with treatment response.…”

Section: Introductionmentioning

confidence: 99%

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A Functional Polymorphism of the μ-Opioid Receptor Gene is Associated with Naltrexone Response in Alcohol-Dependent Patients

Oslin

Berrettini

Kranzler

et al. 2003

Neuropsychopharmacol

546

399

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This study examined the association between two specific polymorphisms of the gene encoding the m-opioid receptor and treatment outcomes in alcohol-dependent patients who were prescribed naltrexone or placebo. A total of 82 patients (71 of European descent) who were randomized to naltrexone and 59 who were randomized to placebo (all of European descent) in one of three randomized, placebo-controlled clinical trials of naltrexone were genotyped at the A +118 G (Asn40Asp) and C +17 T (Ala6Val) SNPs in the gene encoding the m-opioid receptor (OPRM1). The association between genotype and drinking outcomes was measured over 12 weeks of treatment. In subjects of European descent, individuals with one or two copies of the Asp40 allele treated with naltrexone had significantly lower rates of relapse (p ¼ 0.044) and a longer time to return to heavy drinking (p ¼ 0.040) than those homozygous for the Asn40 allele. There were no differences in overall abstinence rates (p ¼ 0.611), nor were there differences in relapse rates or abstinence rates between the two genotype groups among those assigned to placebo. These preliminary results are consistent with prior literature demonstrating that the opioid system is involved in the reinforcing properties of alcohol and that allelic variation at OPRM1 is associated with differential response to a m-receptor antagonist. If replicated, these results would help to identify alcohol-dependent individuals who may be most likely to respond to treatment with naltrexone.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Functional Polymorphism of the μ-Opioid Receptor Gene is Associated with Naltrexone Response in Alcohol-Dependent Patients

Oslin

Berrettini

Kranzler

et al. 2003

Neuropsychopharmacol

546

399

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“…The Asp40 variant increases the binding affinity of beta-endorphin for this receptor by three-fold, relative to the wild-type Asn40 OPRM1. 7 The Asp40 variant in OPRM1 is found in about 25-30% of individuals of European ancestry, 8,9 and is therefore sufficiently common to explain the clinically significant differences in response to different forms of NRT.…”

Section: Introductionmentioning

confidence: 99%

The functional mu opioid receptor (OPRM1) Asn40Asp variant predicts short-term response to nicotine replacement therapy in a clinical trial

et al. 2004

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To determine whether the functional mu-opioid receptor (OPRM1) Asn40Asp variant predicts the comparative efficacy of different forms of NRT, we conducted a clinical trial of transdermal nicotine (TN) vs nicotine nasal spray (NS) in 320 smokers of European ancestry. Smokers carrying the OPRM1 Asp40 variant (n ¼ 82) were significantly more likely than those homozygous for the Asn40 variant (n ¼ 238) to be abstinent at the end of treatment, and reported less mood disturbance and weight gain. The genotype effect on treatment outcome was most pronounced among smokers receiving TN, particularly during the 21 mg dose phase. Smokers who carry the OPRM1 Asp40 variant are likely to have a favorable response to TN and may benefit from extended therapy with the 21 mg dose.

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“…Because of the central role of MOR in analgesia and alcohol and substance use disorders (ASUD), numerous studies have addressed the potential contribution of alternative splicing, oligomerization, and naturally-occurring sequence variation in the OPRM1 gene to substance abuse susceptibility and variable analgesic response (11)(12)(13)(14)(15). Also, splice variants of MOR have been reported for rodents and humans (16), and can result in isoforms with varying trafficking and signaling properties (17).…”

mentioning

confidence: 99%

Functional characterization of human variants of the mu-opioid receptor gene

Ravindranathan

Joslyn

Robertson

et al. 2009

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

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Opioids and their receptors have an important role in analgesia and alcohol and substance use disorders (ASUD). We have identified several naturally occurring amino acid changing variants of the human mu-opioid receptor (MOR), and assessed the functional consequences of these previously undescribed variants in stably expressing cell lines. Several of these variants had altered trafficking and signaling properties. We found that an L85I variant showed significant internalization in response to morphine, in contrast to the WT MOR, which did not internalize in response to morphine. Also, when L85I and WT receptor were coexpressed, WT MOR internalized with the L85I MOR, suggesting that, in the heterozygous condition, the L85I phenotype would be dominant. This finding is potentially important, because receptor internalization has been associated with development of tolerance to opiate analgesics. In contrast, an R181C variant abolished both signaling and internalization in response to saturating doses of the hydrolysis-resistant enkephalin [D-Ala2,N-MePhe4,Gly5-ol]enkephalin (DAMGO). Coexpression of the R181C and WT receptor led to independent trafficking of the 2 receptors. S42T and C192F variants showed a rightward shift in potency of both morphine and DAMGO, whereas the S147C variant displayed a subtle leftward shift in morphine potency. These data suggest that these and other such variants may have clinical relevance to opioid responsiveness to both endogenous ligands and exogenous drugs, and could influence a broad range of phenotypes, including ASUD, pain responses, and the development of tolerance to morphine.OPRM1 ͉ SNP ͉ tolerance ͉ morphine ͉ opiate

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A genetic association study of the mu opioid receptor and severe opioid dependence

Cited by 127 publications

References 23 publications

A Functional Polymorphism of the μ-Opioid Receptor Gene is Associated with Naltrexone Response in Alcohol-Dependent Patients

A Functional Polymorphism of the μ-Opioid Receptor Gene is Associated with Naltrexone Response in Alcohol-Dependent Patients

The functional mu opioid receptor (OPRM1) Asn40Asp variant predicts short-term response to nicotine replacement therapy in a clinical trial

Functional characterization of human variants of the mu-opioid receptor gene

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