Encyclopedia of Signaling Molecules

2012 Edition
| Editors: Sangdun Choi

Opioid Receptors: Cellular and Molecular Mechanisms Underlying Opioid Receptor Function

  • Vladana Vukojević
  • Yu Ming
  • Lars Terenius
Reference work entry
DOI: https://doi.org/10.1007/978-1-4419-0461-4_596


Historical Background

The existence of opioid receptors (OR) was postulated in 1954 (Beckett and Casy 1954), at a time when evidence for specific drug-responsive substances was evasive and the concept of biochemical receptors was still in its infancy. Unequivocal confirmation of specific binding sites for opioids in the brain was first reported in 1973 (Pert and Snyder 1973; Simon et al. 1973; Terenius 1973). This breakthrough was shortly followed by evidence that opioid ligands bind specifically to different anatomical locations and show different pharmacological activity, suggesting that several types of opioid receptors exist (Martin et al. 1976; Lord et al. 1977). Based on extensive pharmacological and animal model studies that followed, opioid receptors were originally classed in four types: mu (μ), kappa (κ), sigma (σ) and delta (δ). They were named after specific ligands used for...

This is a preview of subscription content, log in to check access.


  1. Allen JA, Halverson-Tamboli RA, Rasenick MM. Lipid raft microdomains and neurotransmitter signalling. Nat Rev Neurosci. 2007;8:128–40.PubMedCrossRefGoogle Scholar
  2. Anton RF, Oroszi G, O'Malley S, Couper D, Swift R, Pettinati H, Goldman D. An evaluation of mu-opioid receptor (OPRM1) as a predictor of naltrexone response in the treatment of alcohol dependence: results from the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) study. Arch Gen Psychiatry. 2008;65:135–44.PubMedCrossRefGoogle Scholar
  3. Baker A, Saulière A, Dumas F, Millot C, Mazères S, Lopez A, Salomé L. Functional membrane diffusion of G-protein coupled receptors. Eur Biophys J. 2007;36:849–60.PubMedCrossRefGoogle Scholar
  4. Beckett AH, Casy AF. Synthetic analgesics: stereochemical considerations. J Pharm Pharmacol. 1954;6:986–1001.PubMedCrossRefGoogle Scholar
  5. Bodnar RJ. Endogenous opiates and behavior. Peptides. 2010;31:2325–59.PubMedCrossRefGoogle Scholar
  6. Dean R, Bilsky EJ, Stevens Negus S. Opiate receptors and antagonists. From Bench to Clinic. New York: Humana Press; 2009.CrossRefGoogle Scholar
  7. Dreborg S, Sundström G, Larsson TA, Larhammar D. Evolution of vertebrate opioid receptors. Proc Natl Acad Sci USA. 2008;105:15487–92.PubMedCrossRefGoogle Scholar
  8. Evans CJ, Keith Jr DE, Morrison H, Magendzo K, Edwards RH. Cloning of a delta opioid receptor by functional expression. Science. 1992;258:1952–5.PubMedCrossRefGoogle Scholar
  9. Flicek P, Amode MR, Barrell D, Beal K, Brent S, Chen Y, Clapham P, Coates G, Fairley S, Fitzgerald S, Gordon L, Hendrix M, Hourlier T, Johnson N, Kähäri A, Keefe D, Keenan S, Kinsella R, Kokocinski F, Kulesha E, Larsson P, Longden I, McLaren W, Overduin B, Pritchard B, Riat HS, Rios D, Ritchie GR, Ruffier M, Schuster M, Sobral D, Spudich G, Tang YA, Trevanion S, Vandrovcova J, Vilella AJ, White S, Wilder SP, Zadissa A, Zamora J, Aken BL, Birney E, Cunningham F, Dunham I, Durbin R, Fernández-Suarez XM, Herrero J, Hubbard TJ, Parker A, Proctor G, Vogel J, Searle SM. Ensembl 2011. Nucleic Acids Res. 2011;39:D800–6.PubMedCrossRefGoogle Scholar
  10. Fortin JP, Ci L, Schroeder J, Goldstein C, Montefusco MC, Peter I, Reis SE, Huggins GS, Beinborn M, Kopin AS. The μ-opioid receptor variant N190K is unresponsive to peptide agonists yet can be rescued by small-molecule drugs. Mol Pharmacol. 2010;78:837–45.PubMedCrossRefGoogle Scholar
  11. Hanyaloglu AC, von Zastrow M. Regulation of GPCRs by endocytic membrane trafficking and its potential implications. Annu Rev Pharmacol Toxicol. 2008;48:537–68.PubMedCrossRefGoogle Scholar
  12. Huang P, Chen C, Xu W, Yoon SI, Unterwald EM, Pintar JE, Wang Y, Chong PL, Liu-Chen LY. Brain region-specific N-glycosylation and lipid rafts association of the rat mu opioid receptor. Biochem Biophys Res Commun. 2008;365:82–8.PubMedCrossRefGoogle Scholar
  13. Kane BE, Svensson B, Ferguson DM. Molecular recognition of opioid receptor ligands. AAPS J. 2006;8:E126–37.PubMedCrossRefGoogle Scholar
  14. Kieffer BL, Befort K, Gaveriaux-Ruff C, Hirth CG. The delta-opioid receptor: Isolation of a cDNA by expression cloning and pharmacological characterization. Proc Natl Acad Sci USA. 1992;89:12048–52.PubMedCrossRefGoogle Scholar
  15. Levac BA, O'Dowd BF, George SR. Oligomerization of opioid receptors: generation of novel signaling units. Curr Opin Pharmacol. 2002;2:76–81.PubMedCrossRefGoogle Scholar
  16. Lord JAH, Waterfield AA, Hughes J, Kosterlitz HW. Endogenous opioid peptides: multiple agonists and receptors. Nature. 1977;267:495–9.PubMedCrossRefGoogle Scholar
  17. Martin WR, Eades CG, Thompson JA, Huppler RE, Gilbert PE. The effects of morphine- and nalorphine-like drugs in the nondependent and morphine-dependent chronic spinal dog. J Pharmacol Exp Ther. 1976;197:517–32.PubMedGoogle Scholar
  18. Meunier J-C, Mollereau C, Toll L, Suaudeau C, Moisand C, Alvinerie P, Butour J-L, Guillemot JC, Ferrara P, Monsarrat B. Isolation and structure of the endogenous agonist of opioid receptorlike ORL1 receptor. Nature. 1995;377:532–5.PubMedCrossRefGoogle Scholar
  19. Milligan G. The role of dimerisation in the cellular trafficking of G-protein-coupled receptors. Curr Opin Pharmacol. 2010;10:23–9.PubMedCrossRefGoogle Scholar
  20. Pan YX, Xu J, Mahurter L, Xu M, Gilbert AK, Pasternak GW. Identification and characterization of two new human mu opioid receptor splice variants, hMOR-1O and hMOR-1X. Biochem Biophys Res Commun. 2003;301:1057–61.PubMedCrossRefGoogle Scholar
  21. Pert CB, Snyder SH. Opiate receptor: demonstration in nervous tissue. Science. 1973;179:1011–4.PubMedCrossRefGoogle Scholar
  22. Reinscheid RK, Nothacker HP, Bourson A, Ardati A, Henningsen RA, Bunzow JR, Grandy DK, Langen H, Monsma FJ, Civelli O. Orphanin FQ: a neuropeptide that activates an opioidlike G protein-coupled receptor. Science. 1995;270:792–4.PubMedCrossRefGoogle Scholar
  23. Simon EJ, Hiller JM, Edelman I. Stereospecific binding of the potent narcotic analgesic (3 H) Etorphine to rat-brain homogenate. Proc Natl Acad Sci USA. 1973;70:1947–9.PubMedCrossRefGoogle Scholar
  24. Terenius L. Stereospecific interaction between narcotic analgesics and a synaptic plasma membrane fraction of rat cerebral cortex. Acta Pharmacol Toxicol (Copenh). 1973;32:317–20.CrossRefGoogle Scholar
  25. Vukojević V, Ming Y, D'Addario C, Hansen M, Langel U, Schulz R, Johansson B, Rigler R, Terenius L. Mu-opioid receptor activation in live cells. FASEB J. 2008;22:3537–48.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of Clinical NeuroscienceKarolinska InstituteStockholmSweden