Behavior Genetics

, Volume 38, Issue 4, pp 390–395

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

  • Eric J. Vallender
  • Cassandra M. Priddy
  • Guo-Lin Chen
  • Gregory M. Miller
Original Research


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.


OPRM1 Opioid receptor Rhesus macaque Functional polymorphism 


  1. 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):369–376PubMedCrossRefGoogle Scholar
  2. 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):3130–3137PubMedCrossRefGoogle Scholar
  3. 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):553–560PubMedCrossRefGoogle Scholar
  4. 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):9608–9613PubMedCrossRefGoogle Scholar
  5. 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):914–928PubMedCrossRefGoogle Scholar
  6. 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):645–657PubMedCrossRefGoogle Scholar
  7. Contet C, Kieffer BL, Befort K (2004) Mu opioid receptor: a gateway to drug addiction. Curr Opin Neurobiol 14(3):370–378PubMedCrossRefGoogle Scholar
  8. 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):729–741PubMedCrossRefGoogle Scholar
  9. 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):289–297PubMedCrossRefGoogle Scholar
  10. 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):60–65CrossRefGoogle Scholar
  11. 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):2895–2908PubMedCrossRefGoogle Scholar
  12. 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 1025:316–324PubMedCrossRefGoogle Scholar
  13. 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):1–26PubMedCrossRefGoogle Scholar
  14. 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):77–87PubMedGoogle Scholar
  15. Mayer P, Hollt V (2001) Allelic and somatic variations in the endogenous opioid system of humans. Pharmacol Ther 91(3):167–177PubMedCrossRefGoogle Scholar
  16. Mayer P, Hollt V (2006) Pharmacogenetics of opioid receptors and addiction. Pharmacogenet Genomics 16(1):1–7PubMedCrossRefGoogle Scholar
  17. 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):99–108PubMedCrossRefGoogle Scholar
  18. Pan YX (2005) Diversity and complexity of the mu opioid receptor gene: alternative pre-mRNA splicing and promoters. DNA Cell Biol 24(11):736–750PubMedCrossRefGoogle Scholar
  19. 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):1057–1061PubMedCrossRefGoogle Scholar
  20. 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):209–220PubMedCrossRefGoogle Scholar
  21. 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–D65PubMedCrossRefGoogle Scholar
  22. Skarke C, Kirchhof A, Geisslinger G, Lotsch J (2004) Comprehensive mu-opioid-receptor genotyping by pyrosequencing. Clin Chem 50(3):640–644PubMedCrossRefGoogle Scholar
  23. 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):7752–7755PubMedCrossRefGoogle Scholar
  24. 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):106–114PubMedCrossRefGoogle Scholar
  25. Wise RA (1998) Drug-activation of brain reward pathways. Drug Alcohol Depend 51(1–2):13–22PubMedCrossRefGoogle Scholar
  26. Xin L, Wang ZJ (2002) Bioinformatic analysis of the human mu opioid receptor (OPRM1) splice and polymorphic variants. AAPS PharmSci 4(4):E23PubMedCrossRefGoogle Scholar
  27. 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):32618–32624PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Eric J. Vallender
    • 1
  • Cassandra M. Priddy
    • 1
  • Guo-Lin Chen
    • 1
  • Gregory M. Miller
    • 1
  1. 1.Division of NeurochemistryNew England Primate Research Center, Harvard Medical SchoolSouthboroughUSA

Personalised recommendations