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Human Expression Variation in the Mu-Opioid Receptor is Paralleled in Rhesus Macaque

Behavior Genetics volume 38, pages 390–395 (2008)Cite this article

Abstract

The mu-opioid receptor is a key component in many neurobiological systems including those affecting perceptions of pain and pleasure. In humans and non-human primate model systems, genetic variation in the receptor has been associated with numerous behavioral and physiological traits. In humans, polymorphisms have been identified which affect not only the biochemical function of the receptor, but also expression level. Existing rhesus macaque variation parallels the functional protein changes seen in human, but it remains unknown if expression level differences or concomitant protein changes may also exist. Here we perform a comprehensive survey of naturally occurring polymorphisms in Indian-origin rhesus macaques and identify three 5′ UTR haplotypes with effects on expression level. These expression level effects are in linkage disequilibrium with the previously identified rhesus coding polymorphism C77G. The C77G polymorphism in rhesus parallels the functional effects of the A118G polymorphism in humans and expression level differences occur within both species. Together, the functional variations reported here have implications for future studies seeking to model the opioid system and its associated phenotypes in rhesus macaques.

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References

  • Barr CS, Schwandt M, Lindell SG, Chen SA, Goldman D, Suomi SJ, Higley JD, Heilig M (2007) Association of a functional polymorphism in the mu-opioid receptor gene with alcohol response and consumption in male rhesus macaques. Arch Gen Psychiatry 64(3):369–376

    PubMed  Article  CAS  Google Scholar 

  • Befort K, Filliol D, Decaillot FM, Gaveriaux-Ruff C, Hoehe MR, Kieffer BL (2001) A single nucleotide polymorphic mutation in the human mu-opioid receptor severely impairs receptor signaling. J Biol Chem 276(5):3130–3137

    PubMed  Article  CAS  Google Scholar 

  • Beyer A, Koch T, Schroder H, Schulz S, Hollt V (2004) Effect of the A118G polymorphism on binding affinity, potency and agonist-mediated endocytosis, desensitization, and resensitization of the human mu-opioid receptor. J Neurochem 89(3):553–560

    PubMed  Article  CAS  Google Scholar 

  • Bond C, LaForge KS, Tian M, Melia D, Zhang S, Borg L, Gong J, Schluger J, Strong JA, Leal SM, Tischfield JA, Kreek MJ, Yu L (1998) Single-nucleotide polymorphism in the human mu opioid receptor gene alters beta-endorphin binding and activity: possible implications for opiate addiction. Proc Natl Acad Sci USA 95(16):9608–9613

    PubMed  Article  CAS  Google Scholar 

  • Chen GL, Novak MA, Hakim S, Xie Z, Miller GM (2006) Tryptophan hydroxylase-2 gene polymorphisms in rhesus monkeys: association with hypothalamic-pituitary-adrenal axis function and in vitro gene expression. Mol Psychiatry 11(10):914–928

    PubMed  Article  CAS  Google Scholar 

  • Chen GL, Vallender EJ, Miller GM (2008) Functional characterization of the human TPH2 5′ regulatory region: untranslated region and polymorphisms modulate gene expression in vitro. Hum Genet 122(6):645–657

    PubMed  Article  CAS  Google Scholar 

  • Contet C, Kieffer BL, Befort K (2004) Mu opioid receptor: a gateway to drug addiction. Curr Opin Neurobiol 14(3):370–378

    PubMed  Article  CAS  Google Scholar 

  • Drolet G, Dumont EC, Gosselin I, Kinkead R, Laforest S, Trottier JF (2001) Role of endogenous opioid system in the regulation of the stress response. Prog Neuropsychopharmacol Biol Psychiatry 25(4):729–741

    PubMed  Article  CAS  Google Scholar 

  • Gelernter J, Kranzler H, Lacobelle J (1998) Population studies of polymorphisms at loci of neuropsychiatric interest (tryptophan hydroxylase (TPH), dopamine transporter protein (SLC6A3), D3 dopamine receptor (DRD3), apolipoprotein E (APOE), mu opioid receptor (OPRM1), and ciliary neurotrophic factor (CNTF)). Genomics 52(3):289–297

    PubMed  Article  CAS  Google Scholar 

  • Hernandez-Avila CA, Wand G, Luo X, Gelernter J, Kranzler HR (2003) Association between the cortisol response to opioid blockade and the Asn40Asp polymorphism at the mu-opioid receptor locus (OPRM1). Am J Med Genet B Neuropsychiatr Genet 118(1):60–65

    Article  Google Scholar 

  • Hoehe MR, Kopke K, Wendel B, Rohde K, Flachmeier C, Kidd KK, Berrettini WH, Church GM (2000) Sequence variability and candidate gene analysis in complex disease: association of mu opioid receptor gene variation with substance dependence. Hum Mol Genet 9(19):2895–2908

    PubMed  Article  CAS  Google Scholar 

  • Ide S, Kobayashi H, Tanaka K, Ujike H, Sekine Y, Ozaki N, Inada T, Harano M, Komiyama T, Yamada M, Iyo M, Ikeda K, Sora I (2004) Gene polymorphisms of the mu opioid receptor in methamphetamine abusers. Ann N Y Acad Sci 1025:316–324

    PubMed  Article  CAS  Google Scholar 

  • Kreek MJ, Bart G, Lilly C, LaForge KS, Nielsen DA (2005) Pharmacogenetics and human molecular genetics of opiate and cocaine addictions and their treatments. Pharmacol Rev 57(1):1–26

    PubMed  Article  CAS  Google Scholar 

  • Kroslak T, Laforge KS, Gianotti RJ, Ho A, Nielsen DA, Kreek MJ (2007) The single nucleotide polymorphism A118G alters functional properties of the human mu opioid receptor. J Neurochem 103(1):77–87

    PubMed  CAS  Google Scholar 

  • Mayer P, Hollt V (2001) Allelic and somatic variations in the endogenous opioid system of humans. Pharmacol Ther 91(3):167–177

    PubMed  Article  CAS  Google Scholar 

  • Mayer P, Hollt V (2006) Pharmacogenetics of opioid receptors and addiction. Pharmacogenet Genomics 16(1):1–7

    PubMed  CAS  Article  Google Scholar 

  • Miller GM, Bendor J, Tiefenbacher S, Yang H, Novak MA, Madras BK (2004) A mu-opioid receptor single nucleotide polymorphism in rhesus monkey: association with stress response and aggression. Mol Psychiatry 9(1):99–108

    PubMed  Article  CAS  Google Scholar 

  • Pan YX (2005) Diversity and complexity of the mu opioid receptor gene: alternative pre-mRNA splicing and promoters. DNA Cell Biol 24(11):736–750

    PubMed  Article  CAS  Google Scholar 

  • Pan YX, Xu J, Mahurter L, Xu M, Gilbert AK, Pasternak GW (2003) Identification and characterization of two new human mu opioid receptor splice variants, hMOR-1O and hMOR-1X. Biochem Biophys Res Commun 301(4):1057–1061

    PubMed  Article  CAS  Google Scholar 

  • Pan L, Xu J, Yu R, Xu MM, Pan YX, Pasternak GW (2005) Identification and characterization of six new alternatively spliced variants of the human mu opioid receptor gene, Oprm. Neuroscience 133(1):209–220

    PubMed  Article  CAS  Google Scholar 

  • Pruitt KD, Tatusova T, Maglott DR (2007) NCBI reference sequences (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins. Nucleic Acids Res 35(Database issue):D61–D65

    PubMed  Article  CAS  Google Scholar 

  • Skarke C, Kirchhof A, Geisslinger G, Lotsch J (2004) Comprehensive mu-opioid-receptor genotyping by pyrosequencing. Clin Chem 50(3):640–644

    PubMed  Article  CAS  Google Scholar 

  • Uhl GR, Sora I, Wang Z (1999) The mu opiate receptor as a candidate gene for pain: polymorphisms, variations in expression, nociception, and opiate responses. Proc Natl Acad Sci USA 96(14):7752–7755

    PubMed  Article  CAS  Google Scholar 

  • Wand GS, McCaul M, Yang X, Reynolds J, Gotjen D, Lee S, Ali A (2002) The mu-opioid receptor gene polymorphism (A118G) alters HPA axis activation induced by opioid receptor blockade. Neuropsychopharmacology 26(1):106–114

    PubMed  Article  CAS  Google Scholar 

  • Wise RA (1998) Drug-activation of brain reward pathways. Drug Alcohol Depend 51(1–2):13–22

    PubMed  Article  CAS  Google Scholar 

  • Xin L, Wang ZJ (2002) Bioinformatic analysis of the human mu opioid receptor (OPRM1) splice and polymorphic variants. AAPS PharmSci 4(4):E23

    PubMed  Article  Google Scholar 

  • Zhang Y, Wang D, Johnson AD, Papp AC, Sadee W (2005) Allelic expression imbalance of human mu opioid receptor (OPRM1) caused by variant A118G. J Biol Chem 280(38):32618–32624

    PubMed  Article  CAS  Google Scholar 

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Acknowledgements

The authors would like to thank the NEPRC Primate Genetics Core and Sequencing Core for all their help. We would also like to thank the NEPRC Division of Primate Medicine, and in particular Angela Carville, for their help in obtaining rhesus macaque samples and reviewers and editors for constructive advice. This study was supported by AA016194 (GMM), MH082507 (EJV), DA021180 (GMM), DA06303 (GMM), DA016606 (GMM), and RR00168.

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  1. Division of Neurochemistry, New England Primate Research Center, Harvard Medical School, One Pine Hill Drive, Southborough, MA, 01772, USA

    Eric J. Vallender, Cassandra M. Priddy, Guo-Lin Chen & Gregory M. Miller

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  1. Eric J. Vallender
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  2. Cassandra M. Priddy
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  3. Guo-Lin Chen
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  4. Gregory M. Miller
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Correspondence to Gregory M. Miller.

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Edited by Tamara Phillips.

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Vallender, E.J., Priddy, C.M., Chen, GL. et al. Human Expression Variation in the Mu-Opioid Receptor is Paralleled in Rhesus Macaque. Behav Genet 38, 390–395 (2008). https://doi.org/10.1007/s10519-008-9207-2

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  • DOI: https://doi.org/10.1007/s10519-008-9207-2

Keywords

  • OPRM1
  • Opioid receptor
  • Rhesus macaque
  • Functional polymorphism