Login to MyKarger

New to MyKarger? Click here to sign up.

Login with Facebook

Forgot Password? Reset your password

Authors, Editors, Reviewers

For Manuscript Submission, Check or Review Login please go to Submission Websites List.

Submission Websites List

Institutional Login (Shibboleth)

For the academic login, please select your country in the dropdown list. You will be redirected to verify your credentials.

Table of Contents
Vol. 14, No. 6, 2005
Issue release date: June 2006
Section title: Review
Neurosignals 2005;14:290–302

The Role of Opioid Receptor Phosphorylation and Trafficking in Adaptations to Persistent Opioid Treatment

Johnson E.E. · Christie M.J. · Connor M.
Pain Management Research Institute, Kolling Institute, University of Sydney at Royal North Shore Hospital, St. Leonards, Australia
email Corresponding Author

Mark Connor

Pain Management Research Institute, E25

University of Sydney at Royal North Shore Hospital

St Leonards, NSW 2065 (Australia)

Tel. +61 2 9926 5184, Fax +61 2 9926 7659, E-Mail markc@med.usyd.edu.au


  1. Hack SP, Vaughan CW, Christie MJ: Modulation of GABA release during morphine withdrawal in midbrain neurons in vitro. Neuropharmacology 2003;45:575–584.
  2. Ossipov MH, Lai J, King T, Vanderah TW, Malan Jr TP, Hruby VJ, Porecca F: Antinociceptive and nociceptive actions of opioids. J Neurobiol 2004;61:126–148.
  3. Bagley EE, Gerke MB, Vaughan CW, Hack SP, Christie MJ: GABA transporter currents activated by protein kinase A excite midbrain neurons during opioid withdrawal. Neuron 2005;45:433–445.
  4. Bie B, Pan ZZ: Increased glutamate synaptic transmission in the nucleus raphe magnus neurons from morphine-tolerant rats. Mol Pain 2005;1:7. doi:10.1 186/1744-8069-1-7.
    External Resources
  5. Saal D, Dong Y, Bonci A, Malenka RC: Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons. Neuron 2003;37:577–582.
  6. Williams JT, Christie MJ, Manzoni O: Cellular and synaptic adaptations mediating opioid dependence. Physiol Rev 2001;81:299–343.
  7. Bailey CP, Connor M: Opioids: cellular mechanisms of tolerance and physical dependence. Curr Opin Pharmacol 2005;5:60–68.
  8. Liu-Chen L-Y: Agonist-induced regulation and trafficking of κ opioid receptors. Life Sci 2004;75:511–536.
  9. Varga EV, Navratilova E, Stropova D, Jambrosic J, Roeske WR, Yamamura HI: Agonist-specific regulation of the δ-opioid receptor. Life Sci 2004;76:599–612.
  10. Gintzler AR, Chakrabarti S: Chronic morphine-induced plasticity among signalling molecules. Novartis Found Symp 2004;261:167–176.
  11. Connor M, Christie MJ: Opioid receptor signalling mechanisms. Clin Exp Pharmacol Physiol 1999;26:493–499.
  12. Maudsley S, Martin B, Luttrell LM: The origins of diversity and specificity in G protein-coupled receptor signaling. J Pharmacol Exp Ther 2005;314:485–494.
  13. Segredo V, Burford NT, Lameh J, Sadee W: A constitutively internalizing and recycling mutant of the μ-opioid receptor. J Neurochem 1997;68:2395–2404.
  14. Burford NT, Wang D, Sadee W: G-protein coupling of μ-opioid receptors (OP3): elevated basal signalling activity. Biochem J 2000;348:531–537.
  15. Ingram S, Wilding TJ, McCleskey EW, Williams JT: Efficacy and kinetics of opioid action on acutely dissociated neurons. Mol Pharmacol 1997;52:136–143.
  16. Connor M, Osborne P, Christie MJ: μ-Opioid receptor desensitization: is morphine different? Br J Pharmacol 2004;143:685–696.
  17. Kobrinsky E, Mirshahi T, Zhang H, Jin T, Logothetis DE: Receptor-mediated hydrolysis of plasma membrane messenger PIP2 leads to K+-current desensitization. Nat Cell Biol 2000;2:507–514.
  18. Nomura K, Reuveny E, Narahashi T: Opioid inhibition and desensitization of calcium channel currents in rat dorsal root ganglion neurons. J Pharmacol Exp Ther 1994;270:466–474.
  19. Von Zastrow M, Svingos A, Haberstock-Debic, Evans C: Regulated endocytosis of opioid receptors: cellular mechanisms and proposed roles in physiological adaptation to opioid drugs. Curr Opin Neurobiol 2003;13:348–353.
  20. Garzon J, Rodriguez-Munoz M, de la Torre-Madrid E, Sanchez-Blazquez P: Effector antagonism by the regulators of G protein signalling (RGS) proteins causes desensitization of mu-opioid receptors in the CNS. Psychopharmacology 2005;180:1–11.
  21. Xie G-X, Palmer PP: RGS proteins: new players in the filed of opioid signaling and tolerance mechanisms. Anesth Analg 2005;100:1034–1042.
  22. Garzon J, Rodriguez-Munoz M, Lopez-Fernando A, Sanchez-Blazquez P: Activation of μ-opioid receptors transfers control of Gα subunits to regulator of G-protein signalling RGS9–2. J Biol Chem 2005;280:8951–8960.
  23. Zachariou V, Georgescu D, Sanchez N, Rahman Z, DiLeone R, Berton O, Neve RL, Sim-Selley LJ, Selley DE, Gold SJ, Nestler EJ: Essential role for RGS9 in opiate action. Proc Natl Acad Sci USA 2003;100:13656–13661.
  24. Ferguson SSG: Evolving concepts in G protein-coupled receptor endocytosis: the role in receptor desensitisation and signaling. Pharmacol Rev 2001;53:1–24.
  25. Daaka Y, Luttrell LM, Lefkowitz RJ: Switching of the coupling of the β2-adrenergic receptor to different G proteins by protein kinase A. Nature 1997;390:88–91.
  26. Chavkin C, McLaughlin JP, Celver JP: Regulation of opioid receptor function by chronic agonist exposure: constitutive activity and desensitization. Mol Pharmacol 2001;60:20–25.
  27. El Kouhen R, Burd AL, Erickson-Herbrandson LJ, Chang C-Y, Law P-Y, Loh HH: Phosphorylation of Ser363, Thr370 and Ser375 residues within the carboxyl tail differentially regulates μ-opioid receptor internalization. J Biol Chem 2001;276:12744–12780.
  28. Schulz S, Mayer D, Pfeiffer M, Stumm R, Koch T, Hollt V: Morphine induces terminal μ-opioid receptor desensitization by sustained phosphorylation of serine-375. EMBO J 2004;23:3282–3289.
  29. Seibold A, Williams B, Huang Z-F, Friedman J, Moore RH, Knoll BJ, Clark RB: Localization of the sites mediating desensitization of the β2-adrenergic receptor by the GRK pathway. Mol Pharmacol 2000;58:1162–1173.
  30. Trester-Zedlitz M, Burlingame A, Kobilka B, von Zastrow M: Mass spectrophotometric analysis of agonist effects on posttranslational modifications of the beta-2 adrenoceptor in mammalian cells. Biochemistry 2005;44:6133–6143.
  31. Deng HB, Yu Y, Wang H, Guang W, Wang JB: Agonist-induced μ opioid receptor phosphorylation and functional desensitization in rat thalamus. Brain Res 2001;898:204–214.
  32. Arden JR, Segredo V, Wang Z, Lameh J, Sadee W: Phosphorylation and agonist-specific intracellular trafficking of an epitope-tagged μ-opioid receptor expressed in HEK 293 cells. J Neurochem 1995;65:1636–1645.
  33. Zhang L, Yu Y, Mackin S, Weight FF, Uhl GR, Wang JB: Differential μ opiate receptor phosphorylation and desensitization induced by agonists and phorbol esters. J Biol Chem 1996;271:11449–11454.
  34. Wang Z, Arden J, Sadee W: Basal phosphorylation of μ opioid receptor is agonist modulated and Ca2+-dependent. FEBS Lett 1996;386:53–57.
    External Resources
  35. Yu Y, Zhang L, Yin X, Sun H, Uhl GR, Wang JB: μ-Opioid receptor phosphorylation, desensitization and ligand efficacy. J Biol Chem 1997;272:28869–28874.
  36. Zhang J, Ferguson SSG, Barak LS, Bodduluri SR, Laporte SA, Law P-Y, Caron MG: Role for G protein-couple receptor kinase in agonist-specific regulation of μ-opioid receptor responsiveness. Proc Natl Acad Sci USA 1998;95:7157–7162.
  37. Whistler JL, Chuang HH, Chu P, Jan LY, von Zastrow M: Functional dissociation of μ-opioid receptor signaling and endocytosis: implications for the biology of opiate tolerance and addiction. Neuron 1999;23:737–746.
  38. El Kouhen R, Maestri-El Kouhen O, Law P-Y, Low HH: The absence of a direct correlation between the loss of [D-Ala2,N-MePhe4Gly5-ol]enkephalin inhibition of adenylyl cyclase activity and agonist-induced μ-opioid receptor phosphorylation. J Biol Chem 1999;274:9207–9215.
  39. Deng HB, Yu Y, Pak Y, O’Dowd BF, George SR, Surratt CK, Uhl GR, Wang JB: Role for the C-terminus in agonist-induced μ-opioid receptor phosphorylation and desensitization. Biochemistry 2000;39:5492–5499.
  40. Koch T, Schulz S, Pfeiffer M, Klutzny M, Schroder H, Kahl E, Hollt V: C-terminal splice variants of the mouse μ-opioid receptor differ in morphine-induced internalization and receptor resensitization. J Biol Chem 2001;276:31408–31414.
  41. Chakrabarti S, Law P-Y, Low HH: Distinct differences between morphine and [D-Ala2,N-MePhe4Gly5-ol]enkephalin-μ-opioid receptor complexes demonstrated by cyclic AMP-dependent protein kinase phosphorylation. J Neurochem 1998;71:231–239.
  42. McLaughlin JP, Chavkin C: Tyrosine phosphorylation of the μ-opioid receptor regulates intrinsic agonist efficacy. Mol Pharmacol 2001;59:1360–1368.
  43. Kenski DM, Zhang C, von Zastrow M, Shokat KM: Chemical genetic engineering of G protein-coupled receptor kinase 2. J Biol Chem 2005;280:35051–35061.
  44. Schulz R, Wehmeyer A, Schulz K: Opioid receptor types selectively cointernalize with G protein-coupled receptor kinases 2 and 3. J Pharmacol Exp Ther 2002;300:376–384.
  45. Sadee W, Wang D, Bilsky EJ: Basal opioid receptor activity, neutral antagonists, and therapeutic opportunities. Life Sci 2005;76:1427–1437.
  46. Strulovici B, Cerione R, Kilpatrick BF, Caron MG, Lefkowitz RJ: Direct demonstration of impaired functionality of a purified desensitized β-adrenergic receptor in an reconstituted system. Science 1984;225:837–840.
  47. Gurevich VV, Dion SB, Onorato JJ, Ptasienski J, Kim CM, Sterne-Marr R, Hosey MM, Benovic JL: Arrestin interactions with G protein-coupled receptors. J Biol Chem 1995;270:720–731.
  48. Gurevich VV, Gurevich EV: The molecular acrobatics of arrestin activation. Trends Pharmacol Sci 2004;25:105–111.
  49. Bailey CP, Kelley EP, Henderson G: Protein kinase C activation enhances morphine-induced rapid desensitization of μ-opioid receptors in mature rat locus ceruleus neurons. Mol Pharmacol 2004;66:1592–1598.
  50. Terman GW, Jin W, Cheong Y-P, Lowe J, Caron MG, Lefkowitz RJ, Chavkin C: G-protein receptor kinase 3 (GRK3) influences opioid analgesic tolerance but not opioid withdrawal. Br J Pharmacol 2004;141:55–64.
  51. Oakley RH, Laporte SA, Holt JA, Caron MG, Barak LS: Differential affinities of visual arrestin, βarrestin1 and βarrestin2 for G protein-coupled receptors delineate two major classes of receptors. J Biol Chem 2000;275:17201–17210.
  52. Bushell T, Endoh T, Simen AA, Ren D, Bindokas VP, Miller RJ: Molecular components of tolerance to opiates in single hippocampal neurons. Mol Pharmacol 2002;61:55–64.
  53. 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;66:106–112.
  54. Bohn LM, Lefkowitz RJ, Gainetdinov RR, Peppel K, Caron MG, Lin, FT: Enhanced morphine analgesia in mice lacking β-arrestin 2. Science 1999;286:2495–2498.
  55. Bohn LM, Gainetdinov RR, Lin F, Lefkowitz RJ, Caron, MG: μ-Opioid receptor desensitization by β-arrestin-2 determines morphine tolerance but not dependence. Nature 2000;408:720–723.
  56. Bohn LM, Lefkowitz RJ, Caron MG: Differential mechanisms of morphine antinociceptive tolerance revealed in βarrestin-2 knockout mice. J Neurosci 2002;22:10494–10500.
  57. Sternini C, Spann M, Anton B, Keith Jr DE, Bunnet NW, von Zastrow M, Evans C, Brecha NC: Agonist selective endocytosis of μ-opioid receptor by neurons in vivo. Proc Natl Acad Sci USA 1996;93:9421–9426.
    External Resources
  58. Trafton JA, Abbadie C, Marek K, Basbaum AI: Postsynaptic signaling via the μ-opioid receptor: responses of dorsal horn neurons to exogenous opioids and noxious stimulation. J Neurosci 2000;20:8578–8584.
  59. He L, Fong J, von Zastrow M, Whistler JL: Regulation of opioid receptor trafficking and morphine tolerance by receptor oligomerization. Cell 2002;108:271–282.
  60. Lee M-C, Cahill CM, Vincent J-P, Beaudet A: Internalization and trafficking of opioid receptor ligands in rat cortical neurons. Synapse 2002;43:102–111.
  61. Keith DE, Murray SR, Zaki PA, Chu PC, Lissin DV, Kang L, Evans CJ, von Zastrow M: Morphine activates opioid receptors without causing their rapid internalization. J Biol Chem 1996;271:19021–19024.
  62. Keith DE, Anton B, Murray SR, Zaki PA, Chu PC, Lissin DV, Monteillet-Agius G, Stewart PL, Evans CJ, von Zastrow M: μ-Opioid receptor internalization: opiate drugs have differential effects on a conserved endocytic mechanism in vitro and the mammalian brain. Mol Pharmacol 1998;53:377–384.
  63. 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;278:18776–18784.
  64. Celver J, Xu M, Jin W, Lowe J, Chavkin C: Distinct domains of the μ-opioid receptor control uncoupling and internalization. Mol Pharmacol 2004;65:528–537.
  65. Haberstock-Debic H, Kim K-A, Yu YJ, von Zastrow M: Morphine promotes rapid, arrestin-dependent endocytosis of μ-opioid receptors in striatal neurons. J Neurosci 2005;25:7847–7857.
  66. Haberstock-Debic H, Wein M, Barrot M, Colago EEO, Rahman Z, Neve RL, Pickel VM, Nestler EJ, von Zastrow M, Svingos AL: Morphine acutely regulates opioid receptor trafficking selectively in dendrites of nucleus accumbens neurons. J Neurosci 2003;23:4324–4332.
  67. Koch T, Schulz S, Schroder H, Wolf R, Raulf E, Hollt V: Carboxyl-terminal splicing of the rat μ-opioid receptor modulates agonist-mediated internalization and receptor resensitization. J Biol Chem 1998;273:13652–13667.
  68. Tanowitz M, von Zastrow M: A novel endocytic recycling signal that distinguishes the membrane trafficking of naturally occurring opioid receptors. J Biol Chem 2003;278:45978–45986.
  69. Koch T, Widera A, Bartzsch K, Schulz S, Brandenburg L-O, Wundrack N, Beyer A, Grecksch G, Hollt V: Receptor endocytosis counteracts the development of tolerance. Mol Pharmacol 2005;67:280–287.
  70. Finn AK, Whistler JL: Endocytosis of the mu opioid receptor reduces tolerance and a cellular hallmark of withdrawal. Neuron 2001;32:829–839.
  71. Dang V, Williams JT: Morphine-induced μ-opioid receptor desensitization. Mol Pharmacol 2005;68:1127–1132.
  72. Bailey CP, Couch D, Johnson E, Griffiths K, Kelly E, Henderson G: μ-Opioid receptor desensitization in mature rat neurons: lack of interaction between DAMGO and morphine. J Neurosci 2003;23:10515–10520.
  73. Blanchet C, Sollini M, Luscher C: Two distinct forms of desensitization of G-protein coupled inwardly rectifying potassium currents evoked by alkaloid and peptide μ-opioid receptor agonists. Mol Cell Neurosci 2003;24:517–523.
  74. Christie MJ, Williams JT, North RA: Cellular mechanisms of opioid tolerance: studies in single brain neurons. Mol Pharmacol 1987;32:633–638.
  75. Connor M, Borgland SL, Christie MJ: Continued morphine modulation of calcium channel currents in acutely isolated locus coeruleus neurons from morphine-dependent rats. Br J Pharmacol 1999;128:1561–1569.
  76. Dang V, Williams JT: Chronic morphine treatment reduces recovery from desensitization. J Neurosci 2004;24:7699–7706.
  77. Bagley EE, Chieng BCH, Christie MJ, Connor M: Opioid tolerance in periaqueductal gray mouse neurons isolated from mice chronically treated with morphine. Br J Pharmacol 2005;146:68–76.
  78. Dumont E, Williams JT: Noradrenaline triggers GABAA inhibition of bed nucleus of the stria terminalis neurons projecting to the ventral tegmental area. J Neurosci 2004;8198–8204.
  79. Sim LJ, Selley DE, Dworkin SI, Childers SR: Effects of chronic morphine administration on μ-opioid receptor-stimulated [35S]-GTPγS autoradiography in rat brain. J Neurosci 1996;16:2684–2692.
  80. Sim-Selley LJ, Selley DE, Vogt LJ, Childers SR, Martin TJ: Chronic heroin self-administration desensitizes μ opioid receptor-activated G-proteins in specific regions of rat brain. J Neurosci 2000;20:4555–4562.
  81. Kirschke C, Schadrack J, Zieglgansberger W, Spangler R: Effects of morphine withdrawal on μ-opioid receptor-stimulated guanylyl 5′-[γ-[35S]thio]-triphosphate autoradiography in rat brain. Eur J Pharmacol 2002;446:43–51.
  82. Narita M, Mizoguchi H, Narita M, Nagase H, Suzuki T, Tseng LF: Involvement of spinal protein kinase Cγ in the attenuation of opioid μ-receptor-mediated G-protein activation after chronic intrathecal administration of [D-Ala2,N-MePhe4,Gly-ol5]enkephalin. J Neurosci 2001;21:3715–3720.
  83. Liu JG, Ruckle MB, Prather PL: Constitutively active μ-opioid receptors inhibit adenylyl cyclase activity in intact cells and activate G-proteins differently than the agonist [D-Ala2,N-MePhe4,Gly-ol5]enkephalin. J Biol Chem 2001;276:37779–37786.
  84. Liu JG, Prather PL: Chronic exposure μ-opioid agonists produces constitutive activation of μ-opioid receptors in direct proportion to the efficacy of the agonist used for pretreatment. Mol Pharmacol 2001;60:53–62.
  85. Wang D, Raehal KM, Lin ET, Lowery JJ, Kieffer BL, Bilsky EJ, Sadee W: Basal signaling activity of μ-opioid receptor in mouse brain: role in narcotic dependence. J Pharmacol Exp Ther 2004;308:612–620.
  86. Trafton JA, Basbaum AI: [D-Ala2,N-MePhe4,Glyol5]enkephalin-induced internalization of the μ-opioid receptor in the spinal cord of morphine tolerant rats. Neuroscience 2004;125:541–543.
  87. Drake CT, Aicher SA, Montalmant FL, Milner TA: Redistribution of mu-opioid receptors in C1 adrenergic neurons following chronic administration of morphine. Exp Neurol 2005;196:365–372.
  88. Alvarez VA, Arttamangkul S, Dang V, Salem A, Whistler JL, von Zastrow M, Grandy DK, Williams JT: μ-Opioid receptors: ligand-dependent activation of potassium conductance, desensitization, and internalization. J Neurosci 2002;22:5769–5776.
  89. Terwilliger RZ, Ortiz J, Guitart X, Nestler EJ: Chronic morphine administration increases β-adrenergic receptor kinase (βARK) levels in the rat locus coeruleus. J Neurochem 1994;63:1983–1986.
  90. Patel MB, Patel CN, Rajashekara V, Yoburn BC: Opioid agonists differentially regulate μ-opioid receptor trafficking proteins in vivo. Mol Pharmacol 2002;62:1464–1470.
  91. Lefkowitz RJ, Shenoy SK: Transduction of receptor signals by β-arrestins. Science 2005;308:512–517.
  92. Werling LL, McMahon PN, Cox BM: Selective changes in μ opioid receptor properties in duced by chronic morphine exposure. Proc Natl Acad Sci USA 1989;86:6393–6397.
  93. Bhargava HN, Gulati A: Down-regulation of brain and spinal cord μ-opiate receptors in morphine tolerant-dependent rats. Eur J Pharmacol 1990;190:305–311.
  94. Yoburn BC, Purohit V, Patel K, Zhang Q: Opioid agonist and antagonist treatment differentially regulates immunoreactive μ-opioid receptors and dynamin-2 in vivo. Eur J Pharmacol 2004;498:87–96.
  95. Tao PL, Law PY, Loh HH: Decrease in delta and mu opioid receptor binding capacity in rat brain after chronic etorphine treatment. J Pharmacol Exp Ther 1987;240:809–816.
  96. Diaz A, Ruiz F, Florez J, Hurle MA, Pazos A: Mu-opioid receptor regulation during opioid tolerance and supersensitivity in rat central nervous system. J Pharmacol Exp Ther 1995;274:1545–1551.