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Functional Selectivity at Opioid Receptors

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Functional Selectivity of G Protein-Coupled Receptor Ligands

Part of the book series: The Receptors ((REC))

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Abstract

Opiate drugs are among the most effective analgesics available but their clinical use is restricted by tolerance, physical dependence, respiratory depression, nausea, and constipation. As a class, opioid ligands produce their effects by acting upon G protein coupled receptors (GPCRs). In this class of membrane receptors, agonist binding induces a series of conformational changes, which propagate to intracellular signaling partners as GPCRs switch from a resting to an active conformation. This active state had been classically considered unique and responsible for regulation of all signaling pathways controlled by any given receptor. However, recent studies have challenged this classical notion, calling for an alternative paradigm where receptors would exist in more than one active conformation with distinct signaling properties. Ligand ability to stablize different active states of the same receptors is currently referred to as functional selectivity. In this review, we summarize evidence supporting the existence of ligand-selective conformations for μ and δ-opioid receptors and analyze how functional selectivity may contribute to the production of longer lasting, better tolerated opiate analgesics.

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References

  1. Goldstein FJ. Adjuncts to opioid therapy. J Am Osteopath Assoc 2002;102(9 Suppl 3):S15–21.

    PubMed  Google Scholar 

  2. Grunkemeier DM, Cassara JE, Dalton CB, Drossman DA. The narcotic bowel syndrome: clinical features, pathophysiology, and management. Clin Gastroenterol Hepatol 2007;5(10):1126–39; quiz 1–2.

    PubMed  CAS  Google Scholar 

  3. Walker JM, Farney RJ, Rhondeau SM, et al. Chronic opioid use is a risk factor for the development of central sleep apnea and ataxic breathing. J Clin Sleep Med 2007;3(5):455–61.

    PubMed  Google Scholar 

  4. Ballantyne JC, LaForge KS. Opioid dependence and addiction during opioid treatment of chronic pain. Pain 2007;129(3):235–55.

    PubMed  CAS  Google Scholar 

  5. Noble M, Schoelles K. Opioid treatment for chronic back pain and its association with addiction. Ann Intern Med 2007;147(5):348–9; author reply 9–50.

    PubMed  Google Scholar 

  6. Kieffer BL, Gaveriaux-Ruff C. Exploring the opioid system by gene knockout. Prog Neurobiol 2002;66(5):285–306.

    PubMed  CAS  Google Scholar 

  7. Rapaka RS, Porreca F. Development of delta opioid peptides as nonaddicting analgesics. Pharm Res 1991;8(1):1–8.

    PubMed  CAS  Google Scholar 

  8. Dickenson AH. Plasticity: implications for opioid and other pharmacological interventions in specific pain states. Behav Brain Sci 1997;20(3):392–403; discussion 35–513.

    PubMed  CAS  Google Scholar 

  9. Cheng PY, Wu D, Soong Y, McCabe S, Decena JA, Szeto HH. Role of mu 1- and delta-opioid receptors in modulation of fetal EEG and respiratory activity. Am J Physiol 1993;265(2 Pt 2):R433–8.

    PubMed  CAS  Google Scholar 

  10. Coop A, Rice KC. Role of delta-opioid receptors in biological processes. Drug News Perspect 2000;13(8):481–7.

    PubMed  CAS  Google Scholar 

  11. Cowan A, Zhu XZ, Mosberg HI, Omnaas JR, Porreca F. Direct dependence studies in rats with agents selective for different types of opioid receptor. J Pharmacol Exp Ther 1988;246(3):950–5.

    PubMed  CAS  Google Scholar 

  12. Gainetdinov RR, Premont RT, Bohn LM, Lefkowitz RJ, Caron MG. Desensitization of G protein-coupled receptors and neuronal functions. Annu Rev Neurosci 2004;27:107–44.

    PubMed  CAS  Google Scholar 

  13. von Zastrow M. A cell biologist's perspective on physiological adaptation to opiate drugs. Neuropharmacology 2004;47 Suppl 1:286–92.

    PubMed  CAS  Google Scholar 

  14. Jutkiewicz EM, Baladi MG, Folk JE, Rice KC, Woods JH. The convulsive and electroencephalographic changes produced by nonpeptidic delta-opioid agonists in rats: comparison with pentylenetetrazol. J Pharmacol Exp Ther 2006;317:1337–48.

    PubMed  CAS  Google Scholar 

  15. Furchgott RF. Metabolic factors that influence contractility of vascular smooth muscle. Bull N Y Acad Med 1966;42(11):996–1006.

    PubMed  CAS  Google Scholar 

  16. Azzi M, Charest PG, Angers S, et al. Beta-arrestin-mediated activation of MAPK by inverse agonists reveals distinct active conformations for G protein-coupled receptors. Proc Natl Acad Sci USA 2003;100(20):11406–11.

    PubMed  CAS  Google Scholar 

  17. Audet N, Paquin-Gobeil M, Landry-Paquet O, Schiller PW, Pineyro G. Internalization and Src activity regulate the time course of ERK activation by delta opioid receptor ligands. J Biol Chem 2005;280(9):7808–16.

    PubMed  CAS  Google Scholar 

  18. Urban JD, Clarke WP, von Zastrow M, et al. Functional selectivity and classical concepts of quantitative pharmacology. J Pharmacol Exp Ther 2007;320(1):1–13.

    PubMed  CAS  Google Scholar 

  19. Mailman RB. GPCR functional selectivity has therapeutic impact. Trends Pharmacol Sci 2007;28(8):390–6.

    PubMed  CAS  Google Scholar 

  20. Gilchrist A, Blackmer T. G-protein-coupled receptor pharmacology: examining the edges between theory and proof. Curr Opin Drug Discov Devel 2007;10(4):446–51.

    PubMed  CAS  Google Scholar 

  21. Kenakin T. Principles: receptor theory in pharmacology. Trends Pharmacol Sci 2004;25(4):186–92.

    PubMed  CAS  Google Scholar 

  22. Kenakin T. Functional selectivity through protean and biased agonism: who steers the ship? Mol Pharmacol 2007;72(6):1393–401.

    PubMed  CAS  Google Scholar 

  23. Bosier B, Hermans E. Versatility of GPCR recognition by drugs: from biological implications to therapeutic relevance. Trends Pharmacol Sci 2007;28(8):438–46.

    PubMed  CAS  Google Scholar 

  24. Hubbell WL, Altenbach C, Hubbell CM, Khorana HG. Rhodopsin structure, dynamics, and activation: a perspective from crystallography, site-directed spin labeling, sulfhydryl reactivity, and disulfide cross-linking. Adv Protein Chem 2003;63:243–90.

    PubMed  CAS  Google Scholar 

  25. Gether U, Lin S, Kobilka BK. Fluorescent labeling of purified beta 2 adrenergic receptor. Evidence for ligand-specific conformational changes. J Biol Chem 1995;270(47):28268–75.

    PubMed  CAS  Google Scholar 

  26. Gether U, Lin S, Ghanouni P, Ballesteros JA, Weinstein H, Kobilka BK. Agonists induce conformational changes in transmembrane domains III and VI of the beta2 adrenoceptor. Embo J 1997;16(22):6737–47.

    PubMed  CAS  Google Scholar 

  27. Schwartz TW, Frimurer TM, Holst B, Rosenkilde MM, Elling CE. Molecular mechanism of 7TM receptor activation–a global toggle switch model. Annu Rev Pharmacol Toxicol 2006;46:481–519.

    PubMed  CAS  Google Scholar 

  28. Swaminath G, Steenhuis J, Kobilka B, Lee TW. Allosteric modulation of beta2-adrenergic receptor by Zn(2+). Mol Pharmacol 2002;61(1):65–72.

    PubMed  CAS  Google Scholar 

  29. Yao X, Parnot C, Deupi X, et al. Coupling ligand structure to specific conformational switches in the beta2-adrenoceptor. Nat Chem Biol 2006;2(8):417–22.

    PubMed  CAS  Google Scholar 

  30. Li JH, Han SJ, Hamdan FF, et al. Distinct structural changes in a G protein-coupled receptor caused by different classes of agonist ligands. J Biol Chem 2007;282(36):26284–93.

    PubMed  CAS  Google Scholar 

  31. Hoffmann C, Zurn A, Bunemann M, Lohse MJ. Conformational changes in G-protein-coupled receptors-the quest for functionally selective conformations is open. Br J Pharmacol 2008;153 Suppl 1:S358–66.

    PubMed  CAS  Google Scholar 

  32. Law SF, Reisine T. Changes in the association of G protein subunits with the cloned mouse delta opioid receptor on agonist stimulation. J Pharmacol Exp Ther 1997;281(3):1476–86.

    PubMed  CAS  Google Scholar 

  33. Alves ID, Ciano KA, Boguslavski V, et al. Selectivity, cooperativity and reciprocity in the interactions between the delta opioid receptor, its ligands and G-proteins. J Biol Chem 2004;17:17.

    Google Scholar 

  34. Garzon J, Garcia-Espana A, Sanchez-Blazquez P. Opioids binding mu and delta receptors exhibit diverse efficacy in the activation of Gi2 and G(x/z) transducer proteins in mouse periaqueductal gray matter. J Pharmacol Exp Ther 1997b;281(1):549–57.

    CAS  Google Scholar 

  35. McKenzie FR, Milligan G. Delta-opioid-receptor-mediated inhibition of adenylate cyclase is transduced specifically by the guanine-nucleotide-binding protein Gi2. Biochem J 1990;267(2):391–8.

    PubMed  CAS  Google Scholar 

  36. Offermanns S, Schultz G, Rosenthal W. Evidence for opioid receptor-mediated activation of the G-proteins, Go and Gi2, in membranes of neuroblastoma x glioma (NG108-15) hybrid cells. J Biol Chem 1991;266(6):3365–8.

    PubMed  CAS  Google Scholar 

  37. Prather PL, Loh HH, Law PY. Interaction of delta-opioid receptors with multiple G proteins: a non-relationship between agonist potency to inhibit adenylyl cyclase and to activate G proteins. Mol Pharmacol 1994;45(5):997–1003.

    PubMed  CAS  Google Scholar 

  38. Laugwitz KL, Offermanns S, Spicher K, Schultz G. mu and delta opioid receptors differentially couple to G protein subtypes in membranes of human neuroblastoma SH-SY5Y cells. Neuron 1993;10(2):233–42.

    PubMed  CAS  Google Scholar 

  39. Allouche S, Polastron J, Hasbi A, Homburger V, Jauzac P. Differential G-protein activation by alkaloid and peptide opioid agonists in the human neuroblastoma cell line SK-N-BE. Biochem J 1999;342 (Pt 1):71–8.

    PubMed  CAS  Google Scholar 

  40. Prather PL, McGinn TM, Erickson LJ, Evans CJ, Loh HH, Law PY. Ability of delta-opioid receptors to interact with multiple G-proteins is independent of receptor density. J Biol Chem 1994;269(33):21293–302.

    PubMed  CAS  Google Scholar 

  41. Prather PL, Song L, Piros ET, Law PY, Hales TG. delta-Opioid receptors are more efficiently coupled to adenylyl cyclase than to L-type Ca(2+) channels in transfected rat pituitary cells. J Pharmacol Exp Ther 2000;295(2):552–62.

    PubMed  CAS  Google Scholar 

  42. Moon HE, Cavalli A, Bahia DS, Hoffmann M, Massotte D, Milligan G. The human delta opioid receptor activates G(i1)alpha more efficiently than G(o1)alpha. J Neurochem 2001;76(6):1805–13.

    PubMed  CAS  Google Scholar 

  43. Sanchez-Blazquez P, Garcia-Espana A, Garzon J. In vivo injection of antisense oligodeoxynucleotides to G alpha subunits and supraspinal analgesia evoked by mu and delta opioid agonists. J Pharmacol Exp Ther 1995;275(3):1590–6.

    PubMed  CAS  Google Scholar 

  44. Sanchez-Blazquez P, Garzon J. delta Opioid receptor subtypes activate inositol-signaling pathways in the production of antinociception. J Pharmacol Exp Ther 1998;285(2):820–7.

    PubMed  CAS  Google Scholar 

  45. Standifer KM, Rossi GC, Pasternak GW. Differential blockade of opioid analgesia by antisense oligodeoxynucleotides directed against various G protein alpha subunits. Mol Pharmacol 1996;50(2):293–8.

    PubMed  CAS  Google Scholar 

  46. Audet N, Gales C, Archer-Lahlou E, et al. BRET assays reveal ligand-specific conformational changes within preformed signalling complexes containing delta opioid receptor (DOR) and heterotrimeric G proteins. J Biol Chem 2008;283:15078–88.

    PubMed  CAS  Google Scholar 

  47. Bunemann M, Frank M, Lohse MJ. Gi protein activation in intact cells involves subunit rearrangement rather than dissociation. Proc Natl Acad Sci USA 2003;100(26):16077–82.

    PubMed  Google Scholar 

  48. Gales C, Rebois RV, Hogue M, et al. Real-time monitoring of receptor and G-protein interactions in living cells. Nat Methods 2005;2(3):177–84.

    PubMed  CAS  Google Scholar 

  49. George SR, O'Dowd BF, Lee SP. G-protein-coupled receptor oligomerization and its potential for drug discovery. Nat Rev Drug Discov 2002;1(10):808–20.

    PubMed  CAS  Google Scholar 

  50. Gupta A, Decaillot FM, Devi LA. Targeting opioid receptor heterodimers: strategies for screening and drug development. Aaps J 2006;8(1):E153–9.

    PubMed  CAS  Google Scholar 

  51. Davare MA, Avdonin V, Hall DD, et al. A beta2 adrenergic receptor signaling complex assembled with the Ca2 + channel Cav1.2. Science 2001;293(5527):98–101.

    PubMed  CAS  Google Scholar 

  52. Lavine N, Ethier N, Oak JN, et al. G protein-coupled receptors form stable complexes with inwardly rectifying potassium channels and adenylyl cyclase. J Biol Chem 2002;277(48):46010–9.

    PubMed  CAS  Google Scholar 

  53. Rebois RV, Robitaille M, Gales C, et al. Heterotrimeric G proteins form stable complexes with adenylyl cyclase and Kir3.1 channels in living cells. J Cell Sci 2006;119(Pt 13):2807–18.

    PubMed  CAS  Google Scholar 

  54. Abramow-Newerly M, Roy AA, Nunn C, Chidiac P. RGS proteins have a signalling complex: interactions between RGS proteins and GPCRs, effectors, and auxiliary proteins. Cell Signal 2006;18(5):579–91.

    PubMed  CAS  Google Scholar 

  55. Jordan BA, Devi LA. G-protein-coupled receptor heterodimerization modulates receptor function. Nature 1999;399(6737):697–700.

    PubMed  CAS  Google Scholar 

  56. George SR, Fan T, Xie Z, et al. Oligomerization of mu- and delta-opioid receptors. Generation of novel functional properties. J Biol Chem 2000;275(34):26128–35.

    PubMed  CAS  Google Scholar 

  57. Gomes I, Gupta A, Filipovska J, Szeto HH, Pintar JE, Devi LA. A role for heterodimerization of mu and delta opiate receptors in enhancing morphine analgesia. Proc Natl Acad Sci USA 2004;101(14):5135–9.

    PubMed  CAS  Google Scholar 

  58. Hasbi A, Nguyen T, Fan T, et al. Trafficking of preassembled opioid mu-delta heterooligomer-Gz signaling complexes to the plasma membrane: coregulation by agonists. Biochemistry 2007;46(45):12997–3009.

    PubMed  CAS  Google Scholar 

  59. Garzon J, Rodriguez-Munoz M, Sanchez-Blazquez P. Morphine alters the selective association between mu-opioid receptors and specific RGS proteins in mouse periaqueductal gray matter. Neuropharmacology 2005a;48(6):853–68.

    CAS  Google Scholar 

  60. Garzon J, Rodriguez-Munoz M, Lopez-Fando A, Sanchez-Blazquez P. Activation of mu-opioid receptors transfers control of Galpha subunits to the regulator of G-protein signaling RGS9-2: role in receptor desensitization. J Biol Chem 2005b;280(10):8951–60.

    CAS  Google Scholar 

  61. Chalecka-Franaszek E, Weems HB, Crowder AT, Cox BM, Cote TE. Immunoprecipitation of high-affinity, guanine nucleotide-sensitive, solubilized mu-opioid receptors from rat brain: coimmunoprecipitation of the G proteins G(alpha o), G(alpha i1), and G(alpha i3). J Neurochem 2000;74(3):1068–78.

    PubMed  CAS  Google Scholar 

  62. Georgoussi Z, Leontiadis L, Mazarakou G, Merkouris M, Hyde K, Hamm H. Selective interactions between G protein subunits and RGS4 with the C-terminal domains of the mu- and delta-opioid receptors regulate opioid receptor signaling. Cell Signal 2006;18(6):771–82.

    PubMed  CAS  Google Scholar 

  63. Dupre DJ, Hebert TE. Biosynthesis and trafficking of seven transmembrane receptor signalling complexes. Cell Signal 2006;18(10):1549–59.

    PubMed  CAS  Google Scholar 

  64. Dupre DJ, Robitaille M, Ethier N, Villeneuve LR, Mamarbachi AM, Hebert TE. Seven transmembrane receptor core signaling complexes are assembled prior to plasma membrane trafficking. J Biol Chem 2006;281(45):34561–73.

    PubMed  CAS  Google Scholar 

  65. Kreienkamp HJ. Organisation of G-protein-coupled receptor signalling complexes by scaffolding proteins. Curr Opin Pharmacol 2002;2(5):581–6.

    PubMed  CAS  Google Scholar 

  66. Nikolaev VO, Hoffmann C, Bunemann M, Lohse MJ, Vilardaga JP. Molecular basis of partial agonism at the neurotransmitter alpha2A-adrenergic receptor and Gi-protein heterotrimer. J Biol Chem 2006;281(34):24506–11.

    PubMed  CAS  Google Scholar 

  67. Milligan G, Bouvier M. Methods to monitor the quaternary structure of G protein-coupled receptors. Febs J 2005;272(12):2914–25.

    PubMed  CAS  Google Scholar 

  68. Gupta A, Decaillot FM, Gomes I, et al. Conformation state-sensitive antibodies to G-protein-coupled receptors. J Biol Chem 2007;282(8):5116–24.

    PubMed  CAS  Google Scholar 

  69. Gupta A, Rozenfeld R, Gomes I, et al. Post-activation-mediated changes in opioid receptors detected by N-terminal antibodies. J Biol Chem 2008;283(16):10735–44.

    PubMed  CAS  Google Scholar 

  70. Murthy KS, Makhlouf GM. Opioid mu, delta, and kappa receptor-induced activation of phospholipase C-beta 3 and inhibition of adenylyl cyclase is mediated by Gi2 and G(o) in smooth muscle. Mol Pharmacol 1996;50(4):870–7.

    PubMed  CAS  Google Scholar 

  71. Clark MJ, Furman CA, Gilson TD, Traynor JR. Comparison of the relative efficacy and potency of mu-opioid agonists to activate G{alpha}i/o proteins containing a pertussis toxin-insensitive mutation. J Pharmacol Exp Ther 2006;317:858–64.

    PubMed  CAS  Google Scholar 

  72. Burford NT, Tolbert LM, Sadee W. Specific G protein activation and mu-opioid receptor internalization caused by morphine, DAMGO and endomorphin I. Eur J Pharmacol 1998;342(1):123–6.

    PubMed  CAS  Google Scholar 

  73. Burford NT, Wang D, Sadee W. G-protein coupling of mu-opioid receptors (OP3): elevated basal signalling activity. Biochem J 2000;348 Pt 3:531–7.

    PubMed  CAS  Google Scholar 

  74. Chakrabarti S, Prather PL, Yu L, Law PY, Loh HH. Expression of the mu-opioid receptor in CHO cells: ability of mu-opioid ligands to promote alpha-azidoanilido[32P]GTP labeling of multiple G protein alpha subunits. J Neurochem 1995;64(6):2534–43.

    PubMed  CAS  Google Scholar 

  75. Massotte D, Brillet K, Kieffer B, Milligan G. Agonists activate Gi1 alpha or Gi2 alpha fused to the human mu opioid receptor differently. J Neurochem 2002;81(6):1372–82.

    PubMed  CAS  Google Scholar 

  76. Stanasila L, Lim WK, Neubig RR, Pattus F. Coupling efficacy and selectivity of the human mu-opioid receptor expressed as receptor-Galpha fusion proteins in Escherichia coli. J Neurochem 2000;75(3):1190–9.

    PubMed  CAS  Google Scholar 

  77. Sanchez-Blazquez P, Rodriguez-Diaz M, DeAntonio I, Garzon J. Endomorphin-1 and endomorphin-2 show differences in their activation of mu opioid receptor-regulated G proteins in supraspinal antinociception in mice. J Pharmacol Exp Ther 1999;291(1):12–8.

    PubMed  CAS  Google Scholar 

  78. Sanchez-Blazquez P, Gomez-Serranillos P, Garzon J. Agonists determine the pattern of G-protein activation in mu-opioid receptor-mediated supraspinal analgesia. Brain Res Bull 2001;54(2):229–35.

    PubMed  CAS  Google Scholar 

  79. Berg KA, Stout BD, Cropper JD, Maayani S, Clarke WP. Novel actions of inverse agonists on 5-HT2C receptor systems. Mol Pharmacol 1999;55(5):863–72.

    PubMed  CAS  Google Scholar 

  80. Kenakin T. Drug efficacy at G protein-coupled receptors. Annu Rev Pharmacol Toxicol 2002;42:349–79.

    PubMed  CAS  Google Scholar 

  81. Polastron J, Mur M, Mazarguil H, Puget A, Meunier JC, Jauzac P. SK-N-BE: a human neuroblastoma cell line containing two subtypes of delta-opioid receptors. J Neurochem 1994;62(3):898–906.

    PubMed  CAS  Google Scholar 

  82. Hosohata Y, Varga EV, Stropova D, et al. Mutation W284L of the human delta opioid receptor reveals agonist specific receptor conformations for G protein activation. Life Sci 2001;68(19–20):2233–42.

    PubMed  CAS  Google Scholar 

  83. Chaipatikul V, Loh HH, Law PY. Ligand-selective activation of mu-oid receptor: demonstrated with deletion and single amino acid mutations of third intracellular loop domain. J Pharmacol Exp Ther 2003;305(3):909–18.

    PubMed  CAS  Google Scholar 

  84. Surratt CK, Johnson PS, Moriwaki A, et al. -mu opiate receptor. Charged transmembrane domain amino acids are critical for agonist recognition and intrinsic activity. J Biol Chem 1994;269(32):20548–53.

    PubMed  CAS  Google Scholar 

  85. Prather PL. Inverse agonists: tools to reveal ligand-specific conformations of G protein-coupled receptors. Sci STKE 2004;2004(215):pe1.

    PubMed  Google Scholar 

  86. Zheng H, Loh HH, Law PY. Beta-arrestin-dependent mu-opioid receptor-activated extracellular signal-regulated kinases (ERKs) translocate to nucleus in contrast to G protein-dependent ERK activation. Mol Pharmacol 2008;73(1):178–90.

    PubMed  CAS  Google Scholar 

  87. Pineyro G, Azzi M, De Lean A, Schiller P, Bouvier M. Short-term inverse-agonist treatment induces reciprocal changes in delta-opioid agonist and inverse-agonist binding capacity. Mol Pharmacol 2001;60(4):816–27.

    PubMed  CAS  Google Scholar 

  88. Archer-Lahlou E, Audet N, Amraei MG, Huard K, Paquin-Gobeil M, Pineyro G. Src promotes delta opioid receptor (DOR) desensitization by interfering with receptor recycling. J Cell Mol Med 2008.

    Google Scholar 

  89. Whistler JL, Chuang HH, Chu P, Jan LY, von Zastrow M. Functional dissociation of mu opioid receptor signaling and endocytosis: implications for the biology of opiate tolerance and addiction. Neuron 1999;23(4):737–46.

    PubMed  CAS  Google Scholar 

  90. Williams JT, Christie MJ, Manzoni O. Cellular and synaptic adaptations mediating opioid dependence. Physiol Rev 2001;81(1):299–343.

    PubMed  CAS  Google Scholar 

  91. Nestler EJ, Alreja M, Aghajanian GK. Molecular control of locus coeruleus neurotransmission. Biol Psychiatry 1999;46(9):1131–9.

    PubMed  CAS  Google Scholar 

  92. Nicholson D, Reid A, Sawynok J. Effects of forskolin and phosphodiesterase inhibitors on spinal antinociception by morphine. Pharmacol Biochem Behav 1991;38(4):753–8.

    PubMed  CAS  Google Scholar 

  93. Bradaia A, Berton F, Ferrari S, Luscher C. beta-Arrestin2, interacting with phosphodiesterase 4, regulates synaptic release probability and presynaptic inhibition by opioids. Proc Natl Acad Sci USA 2005;102(8):3034–9.

    PubMed  CAS  Google Scholar 

  94. Mitrovic I, Margeta-Mitrovic M, Bader S, Stoffel M, Jan LY, Basbaum AI. Contribution of GIRK2-mediated postsynaptic signaling to opiate and alpha 2-adrenergic analgesia and analgesic sex differences. Proc Natl Acad Sci USA 2003;100(1):271–6.

    PubMed  CAS  Google Scholar 

  95. Gilman AG. G proteins: transducers of receptor-generated signals. Annu Rev Biochem 1987;56:615–49.

    PubMed  CAS  Google Scholar 

  96. Bourne HR. How receptors talk to trimeric G proteins. Curr Opin Cell Biol 1997;9(2):134–42.

    PubMed  CAS  Google Scholar 

  97. Vilardaga JP, Nikolaev VO, Lorenz K, Ferrandon S, Zhuang Z, Lohse MJ. Conformational cross-talk between alpha2A-adrenergic and mu-opioid receptors controls cell signaling. Nat Chem Biol 2008;4(2):126–31.

    PubMed  CAS  Google Scholar 

  98. Mazarakou G, Georgoussi Z. STAT5A interacts with and is phosphorylated upon activation of the mu-opioid receptor. J Neurochem 2005;93(4):918–31.

    PubMed  CAS  Google Scholar 

  99. Koch T, Brandenburg LO, Schulz S, Liang Y, Klein J, Hollt V. ADP-ribosylation factor-dependent phospholipase D2 activation is required for agonist-induced mu-opioid receptor endocytosis. J Biol Chem 2003;278(11):9979–85.

    PubMed  CAS  Google Scholar 

  100. Wang D, Sadee W, Quillan JM. Calmodulin binding to G protein-coupling domain of opioid receptors. J Biol Chem 1999;274(31):22081–8.

    PubMed  CAS  Google Scholar 

  101. Parenty G, Appelbe S, Milligan G. CXCR2 chemokine receptor antagonism enhances DOP opioid receptor function via allosteric regulation of the CXCR2-DOP receptor hetero-dimer. Biochem J 2008;412:245–56.

    PubMed  CAS  Google Scholar 

  102. Pello OM, Martinez-Munoz L, Parrillas V, et al. Ligand stabilization of CXCR4/delta-opioid receptor heterodimers reveals a mechanism for immune response regulation. Eur J Immunol 2008;38(2):537–49.

    PubMed  CAS  Google Scholar 

  103. Jordan BA, Gomes I, Rios C, Filipovska J, Devi LA. Functional interactions between mu opioid and alpha 2A-adrenergic receptors. Mol Pharmacol 2003;64(6):1317–24.

    PubMed  CAS  Google Scholar 

  104. Rios C, Gomes I, Devi LA. Interactions between delta opioid receptors and alpha-adrenoceptors. Clin Exp Pharmacol Physiol 2004;31(11):833–6.

    PubMed  CAS  Google Scholar 

  105. Pfeiffer M, Kirscht S, Stumm R, et al. Heterodimerization of substance P and mu-opioid receptors regulates receptor trafficking and resensitization. J Biol Chem 2003;278(51):51630–7.

    PubMed  CAS  Google Scholar 

  106. Mackie K. Cannabinoid receptor homo- and heterodimerization. Life Sci 2005;77(14):1667–73.

    PubMed  CAS  Google Scholar 

  107. Fan T, Varghese G, Nguyen T, Tse R, O'Dowd BF, George SR. A role for the distal carboxyl tails in generating the novel pharmacology and G protein activation profile of mu and delta opioid receptor hetero-oligomers. J Biol Chem 2005;280(46):38478–88.

    PubMed  CAS  Google Scholar 

  108. Marie N, Aguila B, Allouche S. Tracking the opioid receptors on the way of desensitization. Cell Signal 2006;18(11):1815–33.

    PubMed  CAS  Google Scholar 

  109. Pineyro G, Archer-Lahlou E. Ligand-specific receptor states: implications for opiate receptor signalling and regulation. Cell Signal 2007;19(1):8–19.

    PubMed  CAS  Google Scholar 

  110. Mestek A, Hurley JH, Bye LS, et al. The human mu opioid receptor: modulation of functional desensitization by calcium/calmodulin-dependent protein kinase and protein kinase C. J Neurosci 1995;15(3 Pt 2):2396–406.

    PubMed  CAS  Google Scholar 

  111. Koch T, Kroslak T, Mayer P, Raulf E, Hollt V. Site mutation in the rat mu-opioid receptor demonstrates the involvement of calcium/calmodulin-dependent protein kinase II in agonist-mediated desensitization. J Neurochem 1997;69(4):1767–70.

    PubMed  CAS  Google Scholar 

  112. Bailey CP, Smith FL, Kelly E, Dewey WL, Henderson G How important is protein kinase C in mu-opioid receptor desensitization and morphine tolerance? Trends Pharmacol Sci 2006;27(11):558–65.

    PubMed  CAS  Google Scholar 

  113. Johnson EA, Oldfield S, Braksator E, et al. Agonist-selective mechanisms of mu-opioid receptor desensitization in human embryonic kidney 293 cells. Mol Pharmacol 2006;70(2):676–85.

    PubMed  CAS  Google Scholar 

  114. Schmidt H, Schulz S, Klutzny M, Koch T, Handel M, Hollt V. Involvement of mitogen-activated protein kinase in agonist-induced phosphorylation of the mu-opioid receptor in HEK 293 cells. J Neurochem 2000;74(1):414–22.

    PubMed  CAS  Google Scholar 

  115. Polakiewicz RD, Schieferl SM, Dorner LF, Kansra V, Comb MJ. A mitogen-activated protein kinase pathway is required for mu-opioid receptor desensitization. J Biol Chem 1998;273(20):12402–6.

    PubMed  CAS  Google Scholar 

  116. Pak Y, O'Dowd BF, Wang JB, George SR. Agonist-induced, G protein-dependent and -independent down-regulation of the mu opioid receptor. The receptor is a direct substrate for protein-tyrosine kinase. J Biol Chem 1999;274(39):27610–6.

    PubMed  CAS  Google Scholar 

  117. Kovoor A, Celver JP, Wu A, Chavkin C. Agonist induced homologous desensitization of mu-opioid receptors mediated by G protein-coupled receptor kinases is dependent on agonist efficacy. Mol Pharmacol 1998;54(4):704–11.

    PubMed  CAS  Google Scholar 

  118. Borgland SL, Connor M, Osborne PB, Furness JB, Christie MJ. Opioid agonists have different efficacy profiles for G protein activation, rapid desensitization, and endocytosis of mu-opioid receptors. J Biol Chem 2003;278(21):18776–84.

    Google Scholar 

  119. Woolf PJ, Linderman JJ. Untangling ligand induced activation and desensitization of G-protein-coupled receptors. Biophys J 2003;84(1):3–13.

    PubMed  CAS  Google Scholar 

  120. Okura T, Cowell SM, Varga E, et al. Differential down-regulation of the human delta-opioid receptor by SNC80 and [D-Pen(2),D-Pen(5)]enkephalin. Eur J Pharmacol 2000;387(2):R11–3.

    PubMed  CAS  Google Scholar 

  121. Okura T, Varga EV, Hosohata Y, et al. Agonist-specific down-regulation of the human delta-opioid receptor. Eur J Pharmacol 2003;459(1):9–16.

    PubMed  CAS  Google Scholar 

  122. Celver J, Xu M, Jin W, Lowe J, Chavkin C. Distinct domains of the mu-opioid receptor control uncoupling and internalization. Mol Pharmacol 2004;65(3):528–37.

    PubMed  CAS  Google Scholar 

  123. Whistler JL, von Zastrow M. Morphine-activated opioid receptors elude desensitization by beta-arrestin. Proc Natl Acad Sci USA 1998;95(17):9914–9.

    PubMed  CAS  Google Scholar 

  124. Zhang J, Ferguson SS, Barak LS, et al. Role for G protein-coupled receptor kinase in agonist-specific regulation of mu-opioid receptor responsiveness. Proc Natl Acad Sci U S A 1998;95(12):7157–62.

    PubMed  CAS  Google Scholar 

  125. Bohn LM, Dykstra LA, Lefkowitz RJ, Caron MG, Barak LS. Relative opioid efficacy is determined by the complements of the G protein-coupled receptor desensitization machinery. Mol Pharmacol 2004;66(1):106–12.

    PubMed  CAS  Google Scholar 

  126. Keith DE, Murray SR, Zaki PA, et al. Morphine activates opioid receptors without causing their rapid internalization. J Biol Chem 1996;271(32):19021–4.

    PubMed  CAS  Google Scholar 

  127. Keith DE, Anton B, Murray SR, et al. mu-Opioid receptor internalization: opiate drugs have differential effects on a conserved endocytic mechanism in vitro and in the mammalian brain. Mol Pharmacol 1998;53(3):377–84.

    PubMed  CAS  Google Scholar 

  128. Harding WW, Tidgewell K, Schmidt M, et al. Salvinicins A and B, new neoclerodane diterpenes from Salvia divinorum. Org Lett 2005;7(14):3017–20.

    PubMed  CAS  Google Scholar 

  129. Groer CE, Tidgewell K, Moyer RA, et al. An opioid agonist that does not induce micro-opioid receptor--arrestin interactions or receptor internalization. Mol Pharmacol 2007;71(2):549–57.

    PubMed  CAS  Google Scholar 

  130. Aguila B, Coulbault L, Boulouard M, et al. In vitro and in vivo pharmacological profile of UFP-512, a novel selective delta-opioid receptor agonist; correlations between desensitization and tolerance. Br J Pharmacol 2007;152(8):1312–24.

    PubMed  CAS  Google Scholar 

  131. Koch T, Brandenburg LO, Liang Y, et al. Phospholipase D2 modulates agonist-induced mu-opioid receptor desensitization and resensitization. J Neurochem 2004;88(3):680–8.

    PubMed  CAS  Google Scholar 

  132. Koch T, Wu DF, Yang LQ, Brandenburg LO, Hollt V. Role of phospholipase D2 in the agonist-induced and constitutive endocytosis of G-protein coupled receptors. J Neurochem 2006;97(2):365–72.

    PubMed  CAS  Google Scholar 

  133. Liscovitch M, Cantley LC. Signal transduction and membrane traffic: the PITP/phosphoinositide connection. Cell 1995;81(5):659–62.

    PubMed  CAS  Google Scholar 

  134. De Camilli P, Emr SD, McPherson PS, Novick P. Phosphoinositides as regulators in membrane traffic. Science 1996;271(5255):1533–9.

    PubMed  CAS  Google Scholar 

  135. Koch T, Hollt V. Role of receptor internalization in opioid tolerance and dependence. Pharmacol Ther 2008;117(2):199–206.

    PubMed  Google Scholar 

  136. Whistler JL, Enquist J, Marley A, et al. Modulation of postendocytic sorting of G protein-coupled receptors. Science 2002;297(5581):615–20.

    PubMed  CAS  Google Scholar 

  137. Tanowitz M, von Zastrow M. A novel endocytic recycling signal that distinguishes the membrane trafficking of naturally occurring opioid receptors. J Biol Chem 2003;278(46):45978–86.

    PubMed  CAS  Google Scholar 

  138. Koch T, Schulz S, Schroder H, Wolf R, Raulf E, Hollt V. Carboxyl-terminal splicing of the rat mu opioid receptor modulates agonist-mediated internalization and receptor resensitization. J Biol Chem 1998;273(22):13652–7.

    PubMed  CAS  Google Scholar 

  139. Wang W, Loh HH, Law PY. The intracellular trafficking of opioid receptors directed by carboxyl tail and a di-leucine motif in Neuro2A cells. J Biol Chem 2003;278(38):36848–58.

    PubMed  CAS  Google Scholar 

  140. Chaturvedi K, Bandari P, Chinen N, Howells RD. Proteasome involvement in agonist-induced down-regulation of mu and delta opioid receptors. J Biol Chem 2001;276(15):12345–55.

    PubMed  CAS  Google Scholar 

  141. Tanowitz M, Von Zastrow M. Ubiquitination-independent trafficking of G protein-coupled receptors to lysosomes. J Biol Chem 2002;277(52):50219–22.

    PubMed  CAS  Google Scholar 

  142. Hislop JN, Marley A, Von Zastrow M. Role of mammalian vacuolar protein-sorting proteins in endocytic trafficking of a non-ubiquitinated G protein-coupled receptor to lysosomes. J Biol Chem 2004;279(21):22522–31.

    PubMed  CAS  Google Scholar 

  143. Heydorn A, Sondergaard BP, Ersboll B, et al. A library of 7TM receptor C-terminal tails. Interactions with the proposed post-endocytic sorting proteins ERM-binding phosphoprotein 50 (EBP50), N-ethylmaleimide-sensitive factor (NSF), sorting nexin 1 (SNX1), and G protein-coupled receptor-associated sorting protein (GASP). J Biol Chem 2004;279(52):54291–303.

    PubMed  CAS  Google Scholar 

  144. Simonin F, Karcher P, Boeuf JJ, Matifas A, Kieffer BL. Identification of a novel family of G protein-coupled receptor associated sorting proteins. J Neurochem 2004;89(3):766–75.

    PubMed  CAS  Google Scholar 

  145. Koch T, Schulz S, Pfeiffer M, et al. C-terminal splice variants of the mouse mu-opioid receptor differ in morphine-induced internalization and receptor resensitization. J Biol Chem 2001;276(33):31408–14.

    PubMed  CAS  Google Scholar 

  146. Thompson D, Pusch M, Whistler JL. Changes in G protein-coupled receptor sorting protein affinity regulate postendocytic targeting of G protein-coupled receptors. J Biol Chem 2007;282(40):29178–85.

    PubMed  CAS  Google Scholar 

  147. Marie N, Lecoq I, Jauzac P, Allouche S. Differential sorting of human delta-opioid receptors after internalization by peptide and alkaloid agonists. J Biol Chem 2003;278(25):22795–804.

    PubMed  CAS  Google Scholar 

  148. Quock RM, Burkey TH, Varga E, et al. The delta-opioid receptor: molecular pharmacology, signal transduction, and the determination of drug efficacy. Pharmacol Rev 1999;51(3):503–32.

    PubMed  CAS  Google Scholar 

  149. Bohn LM, Lefkowitz RJ, Gainetdinov RR, Peppel K, Caron MG, Lin FT. Enhanced morphine analgesia in mice lacking beta-arrestin 2. Science 1999;286(5449):2495–8.

    PubMed  CAS  Google Scholar 

  150. Finn AK, Whistler JL. Endocytosis of the mu opioid receptor reduces tolerance and a cellular hallmark of opiate withdrawal. Neuron 2001;32(5):829–39.

    PubMed  CAS  Google Scholar 

  151. Grecksch G, Bartzsch K, Widera A, Becker A, Hollt V, Koch T. Development of tolerance and sensitization to different opioid agonists in rats. Psychopharmacology (Berl) 2006;186(2):177–84.

    CAS  Google Scholar 

  152. Martini L, Whistler JL. The role of mu opioid receptor desensitization and endocytosis in morphine tolerance and dependence. Curr Opin Neurobiol 2007;17(5):556–64.

    PubMed  CAS  Google Scholar 

  153. Bailey CP, Connor M. Opioids: cellular mechanisms of tolerance and physical dependence. Curr Opin Pharmacol 2005;5(1):60–8.

    PubMed  CAS  Google Scholar 

  154. He L, Fong J, von Zastrow M, Whistler JL. Regulation of opioid receptor trafficking and morphine tolerance by receptor oligomerization. Cell 2002;108(2):271–82.

    PubMed  CAS  Google Scholar 

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  1. Chercheure Agrégée, Département de Psychiatrie, Université de Montréal, 7331 Rue Hochelaga, Montréal, Qc, H1N3V2

    Graciela Piñeyro

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    Kim A. Neve

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Piñeyro, G. (2009). Functional Selectivity at Opioid Receptors. In: Neve, K.A. (eds) Functional Selectivity of G Protein-Coupled Receptor Ligands. The Receptors. Humana Press. https://doi.org/10.1007/978-1-60327-335-0_12

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