Abstract

The mu opioid receptor is implicated in the reward, tolerance and withdrawal effects of alcohol and other drugs of abuse. We directly sequenced the human mu opioid receptor locus, OPRM1, to detect natural variation that might affect the function of this receptor or be associated with psychiatric phenotypes related to opioid function. Four DNA sequence variants were found: three amino acid substitutions(Ala6Val [rare], Asn40Asp [frequency 10%], Ser147Cys [rare]) and one intronic variant (IVS2+691G/C [frequency 50%]). OPRM1 alleles, genotypes and haplotypes from three psychiatrically characterized population samples (N = 791) were used to perform association and sib-pair linkage analyses to alcohol dependence. There was no significant association or linkage between OPRM1 and alcohol dependence in any of the three population samples. These results and power calculations strongly suggest that variation at the mu opioid receptor is not involved in vulnerability to DSM-III-R Alcohol Dependence. Variation is being investigated for possible association to response to opiate pharmacotherapy and to variation in opioid function, in collaboration with Stephanie O'Malley, Yale University. A study on inherited differences in nociception has been initiated with Ray Dionne & Michael Iadarola of the National Institute of Dental and Craniofacial Research, NIH. A large scale case-control association study on opioid addiction has been completed and these results are in preparation for publication.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Intramural Research (Z01)
Project #
1Z01AA000298-05
Application #
6521830
Study Section
(LNG)
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2001
Total Cost
Indirect Cost

  Institution

Name
Alcohol Abuse and Alcoholism
Department
Type
DUNS #
City
State
Country
United States
Zip Code

  Publications

Belfer, Inna; Buzas, Beata; Hipp, Heather et al. (2005) Haplotype-based analysis of alpha 2A, 2B, and 2C adrenergic receptor genes captures information on common functional loci at each gene. J Hum Genet 50:12-20
Diatchenko, Luda; Slade, Gary D; Nackley, Andrea G et al. (2005) Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Hum Mol Genet 14:135-43
Belfer, Inna; Buzas, Beata; Evans, Catherine et al. (2005) Haplotype structure of the beta adrenergic receptor genes in US Caucasians and African Americans. Eur J Hum Genet 13:341-51
Belfer, Inna; Wu, Tianxia; Kingman, Albert et al. (2004) Candidate gene studies of human pain mechanisms: methods for optimizing choice of polymorphisms and sample size. Anesthesiology 100:1562-72
Buzas, B; Belfer, I; Hipp, H et al. (2004) Haplotype block and superblock structures of the alpha1-adrenergic receptor genes reveal echoes from the chromosomal past. Mol Genet Genomics 272:519-29
Xu, Ke; Lichtermann, Dirk; Lipsky, Robert H et al. (2004) Association of specific haplotypes of D2 dopamine receptor gene with vulnerability to heroin dependence in 2 distinct populations. Arch Gen Psychiatry 61:597-606
Kim, Hyungsuk; Neubert, John K; San Miguel, Anitza et al. (2004) Genetic influence on variability in human acute experimental pain sensitivity associated with gender, ethnicity and psychological temperament. Pain 109:488-96
Zubieta, Jon-Kar; Heitzeg, Mary M; Smith, Yolanda R et al. (2003) COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor. Science 299:1240-3
Xu, Ke; Liu, Xie-he; Nagarajan, Saumya et al. (2002) Relationship of the delta-opioid receptor gene to heroin abuse in a large Chinese case/control sample. Am J Med Genet 110:45-50
Malhotra, A K; Goldman, D (1999) Benefits and pitfalls encountered in psychiatric genetic association studies. Biol Psychiatry 45:544-50