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Upregulation of Opioid Receptors

  • Chapter
Opiate Receptors and Antagonists

Part of the book series: Contemporary Neuroscience ((CNEURO))

Abstract

It is well established that chronic exposure to opioid receptor antagonists can result in opioid receptor upregulation. The phenomenon of antagonist-induced receptor upregulation is not unique to the opioid system but is common to many receptor systems including adenergic, cholinergic, serotinergic, and dopaminergic receptors. Chronic administration of naloxone or naltrexone reliably produces increases in binding to opioid receptors both in vivo and in vitro. This receptor upregulation is associated with functional supersensitivity to subsequent agonist administration. Thus, the analgesic potency of morphine is increased following prior exposure to opioid receptor antagonists. The three opioid receptor types show different degrees of upregulation in response to in vivo antagonist administration, with μ opioid receptors showing the largest increases in binding in response to any given dose of naloxone or naltrexone, followed by more modest increases in δ and k receptors. Antagonist-induced receptor upregulation appears to vary between brain regions, and the reason for this is not clear. Although the first demonstration of antagonist-induced opioid receptor upregulation occurred more than 30 years ago, the mechanisms mediating this effect remained elusive for much of this time. Recent data have provided new insights into potential molecular mechanisms of opioid receptor upregulation. Data are presented that support the hypothesis that naloxone and nal-trexone are acting as pharmacological chaperones, stabilizing intracellular receptor protein molecules and facilitating their trafficking and insertion into the cell membrane. Finally, heterologous opioid receptor upregulation occurs in response to repeated exposure to cocaine and ethanol, and the resulting opioid receptor regulation may play an important role in craving and reinforcement induced by these agents. Given the multiple potential clinical uses of opioid receptor antagonists described in other chapters of this volume, opioid receptor upregulation and the accompanying functional supersensitivity that results from antagonist exposure needs to be further explored in the clinical setting.

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References

  1. Hitzemann RJ, Hitzemann BA, Loh HH. Binding of 3H-naloxone in the mouse brain: effect of ions and tolerance development. Life Sci. 1974;14:2393–2404.

    CAS  PubMed  Google Scholar 

  2. Tang AH, Collins RJ. Enhanced analgesic effects of morphine after chronic administration of naloxone in the rat. Eur. J. Pharmacol. 1978;47:473–474.

    CAS  PubMed  Google Scholar 

  3. Lahti RA, Collins RJ. Chronic naloxone results in prolonged increases in opiate binding sites in brain. Eur. J. Pharmacol. 1978;51:185–186.

    CAS  PubMed  Google Scholar 

  4. Schulz R, Wuster M, Herz A. Supersensitivity to opioids following the chronic blockade of endorphine action by naloxone. Naunyn Schmiedebergs Arch. Pharmacol. 1979;306:93–96.

    CAS  PubMed  Google Scholar 

  5. 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.

    CAS  PubMed  Google Scholar 

  6. Castelli MP, Melis M, Mameli M, Fadda P, Diaz G, Gessa GL. Chronic morphine and naltrexone fail to modify μ-opioid receptor mRNA levels in the rat brain. Mol. Brain Res. 1997;45:149–153.

    CAS  PubMed  Google Scholar 

  7. Tempel A, Zukin RS, Gardner EL. Supersensitivity of brain opiate receptor subtypes after chronic naltrexone treatment. Life Sci. 1982;31:1401–1404.

    CAS  PubMed  Google Scholar 

  8. Zukin RS, Sugarman JR, Fitz-Syage ML, Gardner EL, Zukin SR, Gintzler AR. Naltrexone-induced opiate receptor supersensitivity. Brain Res. 1982;245:285–292.

    CAS  PubMed  Google Scholar 

  9. Yoburn BC, Nunes FA, Adler B, Pasternak GW, Inturrisi CE. Pharmacodynamic supersensitivity and opioid receptor upregulation in the mouse. J. Pharmacol. Exp. Ther. 1986;239:132–135.

    CAS  PubMed  Google Scholar 

  10. Tempel A, Gardner EL, Zukin RS. Neurochemical and functional correlates of naltrexone-induced opiate receptor up-regulation. J. Pharmacol. Exp. Ther. 1985;232:439–444.

    CAS  PubMed  Google Scholar 

  11. Attali B, Vogel Z. Characterization of kappa opiate receptors in rat spinal cord-dorsal root ganglion co-cultures and their regulation by chronic opiate treatment. Brain Res. 1990;517: 182–188.

    CAS  PubMed  Google Scholar 

  12. Bhargava HN, Matwyshyn GA, Reddy PL, Veeranna. Effects of naltrexone on the binding of [3H]D-Ala2, MePhe4, Gly-ol5-enkepahlin to brain regions and spinal cord and pharmacological responses to morphine in the rat. Gen. Pharmacol. 1993;24:1351–1357.

    CAS  PubMed  Google Scholar 

  13. Yoburn BC, Shah S, Chan K, Duttaroy A, Davis T. Supersensitivity to opioid analgesics following chronic opioid antagonist treatment: relationship to receptor selectivity. Pharmacol. Biochem. Behav. 1995;51:535–539.

    CAS  PubMed  Google Scholar 

  14. Unterwald EM, Rubenfeld JM, Imai Y, Wang J-B, Uhl GR, Kreek MJ. Chronic opioid antagonist administration upregulated mu opioid receptor binding without altering mu opioid receptor mRNA levels. Mol. Brain Res. 1995;33:351–355.

    CAS  PubMed  Google Scholar 

  15. Tempel A, Crain SM, Peterson ER, Simon EJ, Zukin RS. Antagonist-induced opiate receptor upregulation in cultures of fetal mouse spinal cord-ganglion explants. Dev. Brain Res. 1986;25:287–291.

    CAS  Google Scholar 

  16. Cote TE, Izenwasser S, Weems HB. Naltexone-induced upregulation of mu opioid receptors on 7315c cell and brain membranes: enhancement of opioid efficacy in inhibiting adenylyl cyclase. J. Pharmacol. Exp. Ther. 1993;267:238–244.

    CAS  PubMed  Google Scholar 

  17. Giordano AL, Nock B, Cicero TJ. Antagonist-induced up-regulation of the putative epsilon opioid receptor in rat brain: comparison with kappa, mu and delta opioid receptors. J. Pharmacol. Exp. Ther. 1990;255:536–540.

    CAS  PubMed  Google Scholar 

  18. Morris BJ, Millan MJ, Herz A. Antagonist-induced opioid receptor up-regulation. II. Regionally specific modulation of mu, delta and kappa binding sites in rat brain revealed by quantitative autoradiography. J. Pharmacol. Exp. Ther. 1988;247:729–736.

    CAS  PubMed  Google Scholar 

  19. Yoburn BC, Luke MC, Pasternak GW, Inturrisi CE. Upregulation of opioid receptor subtypes correlates with potency changes of morphine and DADLE. Life Sci. 1988;43:1319 –1324.

    CAS  PubMed  Google Scholar 

  20. Lesscher HMB, Bailey A, Burbach JPH, van Ree JM, Kitchen I, Gerrits MAFM. Receptor-selective changes in μ-, 4- and K-opioid receptors after chronic naltrexone treatment in mice. Eur. J. Neurosci. 2003;17:1006–1012.

    PubMed  Google Scholar 

  21. Hummel M, Ansonoff MA, Pintar JE, Unterwald EM. Genetic and pharmacological manipulation of μ opioid receptors in mice reveals a differential effect on behavioral sensitization to cocaine. Neurosci. 2004;125:211 –220.

    CAS  Google Scholar 

  22. Millan MJ, Morris BJ, Herz A. Antagonist-induced opioid receptor up-regulation. I. Characterization of supersensitivity to selective mu and kappa agonists. J. Pharmacol. Exp. Ther. 1988;247:721 –728.

    CAS  PubMed  Google Scholar 

  23. Goldstein A, Naidu A. Multiple opioid receptors: ligand selectivity profiles and binding site signatures. Mol. Pharmacol. 1989;36:265 –272.

    CAS  PubMed  Google Scholar 

  24. Raynor K, Kong H, Chen Y, Yasuda K, Yu L, Bell GI, Reisine T. Pharmacological characterization of the cloned kappa-, delta-, and mu-opioid receptors. Mol. Pharmacol. 1994; 45:330 –334.

    CAS  PubMed  Google Scholar 

  25. Tempel A, Gardner EL, Zukin RS. Visualization of opiate receptor upregulation by light microscopy autoradiography. Proc. Natl. Acad. Sci. USA 1984;81:3893 –3897.

    CAS  PubMed  Google Scholar 

  26. Unterwald EM, Anton B, To T, Lam H, Evans CJ. Quantitative immuno-localization of mu-opioid receptors: regulation by naltrexone. Neuroscience 1998;85:897 –905.

    CAS  PubMed  Google Scholar 

  27. Morris BJ, Herz A. Control of opiate receptor number in vivo: simultaneous K-receptor down-regulation and μ-receptor up-regulation following chronic agonist/antagonist treatment. Neuroscience 1989;29:433 –442.

    CAS  PubMed  Google Scholar 

  28. Corbett AD, Kosterlitz HW. Bremazocine is an agonist at K-opioid receptors and an antagonist at μ-opioid receptors in the guinea-pig myenteric plexus. Br. J. Pharmacol. 1986; 89:245–249.

    CAS  PubMed  Google Scholar 

  29. Miller L, Shaw JS, Whiting EM. The contribution of intrinsic activity to the action of opioids in vitro. Br. J. Pharmacol. 1986;87:595–601.

    CAS  PubMed  Google Scholar 

  30. Hayes A, Kelly A. Profile of activity of K receptor agonists in the rabbit vas deferens. Eur. J. Pharmacol. 1985;111:317–322.

    Google Scholar 

  31. Baram D, Simantov R. Enkephalins and opiate antagonists control calmodulin distribution in neuroblastoma-glioma cells. J. Neurochem. 1983;40:55–63.

    CAS  PubMed  Google Scholar 

  32. Barg J, Levy R, Simantov R. Up-regulation of opiate receptors by opiate antagonists in neuroblastoma-glioma cell culture: the possibility of interaction with guanosine triphosphate-binding proteins. Neurosci. Lett. 1984;50:133–137.

    CAS  PubMed  Google Scholar 

  33. Law PY, Hom DS, Loh HH. Opiate receptor down-regulation and desensitization in neuroblastoma X glioma NG108-15 hybrid cells are two separate cellular adaptation processes. Mol. Pharmacol. 1983;24:413–424.

    CAS  PubMed  Google Scholar 

  34. Belcheva MM, Barg J, McHale RJ, Gao XM, Chuang DM, Coscia CJ. Up-regulation of delta opioid receptors in neuroblastoma hybrid cells: evidence for differences in the mechanisms of action of sodium butyrate and naltrexone. J. Pharmacol. Exp. Ther. 1991;259:302–309.

    CAS  PubMed  Google Scholar 

  35. Zadina JE, Harrison LM, Ge LJ, Kastin AJ, Chang SL. Differential regulation of mu and delta opiate receptors by morphine selective agonists and antagonists and differentiating agents in SH-SY5Y human neuroblastoma cells. J. Pharmacol. Exp. Ther. 1994;270:1086–1096.

    CAS  PubMed  Google Scholar 

  36. Zadina JE, Chang SL, Ge LJ, Kastin AJ. Mu opiate receptor down-regulation by morphine and up-regulation by naloxone in SH-SY5Y human neuroblastoma cells. J. Pharmacol. Exp. Ther. 1993;265:254–262.

    CAS  PubMed  Google Scholar 

  37. Kramer T, Shook J, Kazmierski W, Ayres E, Wire W, Hruby V, Burks T. Novel peptidic mu opioid antagonists: pharmacologic characterization in vitro and in vivo. J. Pharmacol. Exp. Ther. 1989;249:544–548.

    CAS  PubMed  Google Scholar 

  38. Zaki PA, Keith DE, Brine GA, Carroll FI, Evans CJ. Ligand-induced changes in surface μ-opioid receptor number: relationship to G protein activation. J. Pharmacol. Exp. Ther. 2000;292:1127–1134.

    CAS  PubMed  Google Scholar 

  39. Kurose H, Katada T, Amano T, Ui M. Specific uncoupling by islet-activating protein, pertussis toxin, of negative signal transduction via α-adrenergic, cholinergic, and opiate receptors in neuroblastoma x glioma hybrid cells. J. Biol. Chem. 1983;258:4870–4875.

    CAS  PubMed  Google Scholar 

  40. Li J, Chen C, Huang P, Liu-Chen LY. Inverse agonist up-regulates the constitutively active D3.49(164)Q mutant of the rat μ-opioid receptor by stabilizing the structure and blocking constitutive internalization and down-regulation. Mol. Pharmacol. 2001;60:1064–1075.

    CAS  PubMed  Google Scholar 

  41. Yoburn BC, Sierra V, Lutfy K. Chronic opioid antagonist treatment: assessment of receptor upregulation. Eur. J. Pharmacol. 1989;170:193–200.

    CAS  PubMed  Google Scholar 

  42. Stevens CW, Yaksh TL. Chronic antagonist infusion does not increase morphine antinocicep-tion in rat spinal cord. Brain Res. 1987;425:388–390.

    CAS  PubMed  Google Scholar 

  43. Volterra BN, DiGiulio AM, Cuomo V, Racagni G. Modulation of opioid system in C57 mice after repeated treatment with morphine and naloxone: biochemical and behavioral correlates. Life Sci. 1984;34:1669–1678.

    PubMed  Google Scholar 

  44. Bardo MT, Bhatnagar RK, Gebhart GF. Chronic naltrexone increases binding in brain and produces supersensitivity to morphine in the locus coeruleus of the rat. Brain Res. 1983; 289:223–234.

    CAS  PubMed  Google Scholar 

  45. Suzuki T, Fukagawa Y, Misawa M. Enhancement of morphine withdrawal signs in the rat after chronic treatment with naloxone. Eur. J. Pharmacol. 1990;178:239–242.

    CAS  PubMed  Google Scholar 

  46. Yoburn BC, Nunes FA, Adler B, Pasternak GW, Inturrisi CE. Pharmacodynamic supersen-sitivity and opioid receptor upregulation in the mouse. J. Pharmacol. Exp. Ther. 1986;239: 132–135.

    CAS  PubMed  Google Scholar 

  47. Narita M, Mizoguchi H, Nagase H, Suzuki T, Tseng LF. Up-regulation of spinal μ-opioid receptor function to activate G-protein by chronic naloxone treatment. Brain Res. 2001;913: 170–173.

    CAS  PubMed  Google Scholar 

  48. McQuay H. Opioids in pain management. Lancet 1999;353:2229–2232.

    CAS  PubMed  Google Scholar 

  49. Chang SC, Lutfy K, Sierra V, Yoburn BC. Dissociation of opioid receptor upregulation and functional supersensitivity. Pharmacol. Biochem. Behav. 1991;38:853–859.

    CAS  Google Scholar 

  50. Jenab S, Inturrisi CE. Ethanol and naloxone differentially upregulate delta opioid receptor gene expression in neuroblastoma hybrid (NG108–15) cells. Mol. Brain Res. 1994;27:95–102.

    CAS  PubMed  Google Scholar 

  51. Jenab S, Kest B, Inturrisi CE. Assessment of delta opioid antinociception and receptor mRNA levels in mouse after chronic naltrexone treatment. Brain Res. 1995;691:69–75.

    CAS  PubMed  Google Scholar 

  52. Thomas PJ, Qu B, Pederson PI. Defective protein folding as a basis of human disease. Trends Biochem. Sci. 1995;20:456–459.

    CAS  PubMed  Google Scholar 

  53. Welch WJ, Howard M. Antagonists to the rescue. J. Clin. Invest. 2000;105:853–854.

    CAS  PubMed  Google Scholar 

  54. Sato S, Ward CL, Krouse ME, Wine JJ, Kopito RR. Glycerol reverses the misfolding pheno-type of the most common cystic fibrosis mutation. J. Biol. Chem. 1996;271:635–638.

    CAS  PubMed  Google Scholar 

  55. Burrows JA, Willis LK, Perlmutter DH. Chemical chaperones mediate increased secretion of mutant alpha 1-antitrypsin (alpha 1-AT) Z: a potential pharmacological strategy for prevention of liver injury and emphysema in alpha 1-AT deficiency. Proc. Natl. Acad. Sci. USA 2000;97:1796–1801.

    CAS  PubMed  Google Scholar 

  56. Brown CR, Hong-Brown LQ, Welch WJ. Correcting temperature-sensitive protein folding defects. J. Clin. Invest. 1997;99:1432–44.

    CAS  PubMed  Google Scholar 

  57. Tatzelt J, Prusiner SB, Welch WJ. Chemical chaperones interfere with the formation of scrapie prion protein. EMBO J. 1996;15:6363–6373.

    CAS  PubMed  Google Scholar 

  58. Tamarappoo BK, Verkman AS. Defective aquaporin-2 trafficking in nephrogenic diabetes insipidus and correction by chemical chaperones. J. Clin. Invest. 1998;101:2257–2267.

    CAS  PubMed  Google Scholar 

  59. Fan J-Q, Ishii S, Asano N, Suzuki Y. Accelerated transport and maturation of lysosomal α-galactosidase A in Fabry lymphoblasts by an enzyme inhibitor. Nat. Med. 1999;5(1):112–115.

    CAS  PubMed  Google Scholar 

  60. Sung C-H, Schneider BG, Agarwal N, Papermaster DS, Nathans J. Functional heterogeneity of mutant rhodopsins responsible for autosomal dominant retinitis pigmentosa. Proc. Natl. Acad. Sci. USA 1991;88:8840–8844.

    CAS  PubMed  Google Scholar 

  61. Latronico AC, Segaloff DL. Naturally occurring mutations of the luteinizing hormone receptor: lessons learned about reproductive physiology and G protein-coupled receptors. Am. J. Hum. Genet. 1999;65:949–958.

    CAS  PubMed  Google Scholar 

  62. Leanos-Miranda A, Ulloa-Aguirre A, Janovick JA, Conn PM. In vitro coexpression and pharmacological rescue of mutant gonadotropin-releasing hormone receptors causing hypogonadotropic hypogonadism in humans expressing compound heterozygous alleles. J. Clin. Endocrinol. Metab. 2005;90:3001–3008.

    CAS  PubMed  Google Scholar 

  63. Oksche A, Rosenthal W. The molecular basis of nephrogenic diabetes insipidus. J. Mol. Med. 1998;76:327–337.

    Google Scholar 

  64. Ellgaard L, Helenius A. Quality control in the endoplasmic reticulum. Nat. Rev. Mol. Cell. Biol. 2003;4:181–191.

    CAS  PubMed  Google Scholar 

  65. Morello J-P, Salahpour A, Laperriere A, Bernier V, Arthus M-F, Lonergan M, Petaja-Repo U, Angers S, Morin D, Bichet DG, Bouvier M. Pharmacological chaperones rescue cell-surface expression and function of misfolded V2 vasopressin receptor mutants. J. Clin. Invest. 2000; 105:887–895.

    CAS  PubMed  Google Scholar 

  66. Cohen GB, Yang T, Robinson PR, Oprian DD. Constitutive activation of opsin: influence of charge at position 134 and size at position 296. Biochemistry 1993;32:6111–6115.

    CAS  PubMed  Google Scholar 

  67. Scheer A, Fanelli F, Costa T, De Benedetti PG, Cotecchia S. Constitutively active mutants of the α1B-adrenergic receptor: role of highly conserved polar amino acids in receptor activation. EMBO J. 1996;15:3566–3578.

    CAS  PubMed  Google Scholar 

  68. Rasmussen SGF, Jensen AD, Liapakis G, Ghanouni P, Javitch JA, Gether U. Mutation of a highly conserved aspartic acid in the ß2-adrenergic receptor: constitutive activation, structural instability, and conformational rearrangement of transmembrane segment 6. Mol. Pharmacol. 1999;56:175–184.

    CAS  PubMed  Google Scholar 

  69. Li J, Huang P, Chen C, de Riel JK, Weinstein H, Liu-Chen LY. Constitutive activation of the μ opioid receptor by mutation of D3.49(164), but not D3.32(147): D3.49(164) is critical for stabilization of the inactive form of the receptor and for its expression. Biochemistry 2001;40:12039–12050.

    CAS  PubMed  Google Scholar 

  70. Hawtin SR. Pharmacological chaperone activity of SR49059 to functionally recover mis-folded mutations of the vasopressin V1a receptor. J. Biol. Chem. 2006;281:14604–14614.

    CAS  PubMed  Google Scholar 

  71. Schubert U, Anton LC, Gibbs J, Norbury CC, Yewdell JW, Bennink JR. Rapid degradation of a large fraction of newly synthesized proteins by the proteasome. Nature 2000;404:770–774.

    CAS  PubMed  Google Scholar 

  72. Petaja-Repo UE, Hogue M, Laperriere A, Walker P, Bouvier M. Export from the endoplasmic reticulum represents the limiting step in the maturation and cell surface expression of the human δ opioid receptor. J. Biol. Chem. 2000;275:13727–13736.

    CAS  PubMed  Google Scholar 

  73. Petaja-Repo UE, Hogue M, Laperriere A, Bhalla S, Walker P, Bouvier M. Newly synthesized human δ opioid receptors retained in the endoplasmic reticulum are retrotranslocated to the cytosol, deglycosylated, ubiquitinated and degraded by the proteasome. J. Biol. Chem. 2001;276:4416–4423.

    CAS  PubMed  Google Scholar 

  74. 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;276:12345–12355.

    CAS  PubMed  Google Scholar 

  75. Petaja-Repo UE, Hogue M, Bhalla S, Laperriere A, Morello JP, Bouvier M. Ligands act as pharmacological chaperones and increase the efficiency of δ opioid receptor maturation. EMBO J. 2002;21:1628–1637.

    CAS  PubMed  Google Scholar 

  76. Lippincott-Schwartz J, Yuan LC, Bonifacino JS, Klausner RD. Rapid redistribution of Golgi proteins into the ER in cells treated with brefeldin A: evidence for membrane cycling from Golgi to ER. Cell 1989;56:801–813.

    CAS  PubMed  Google Scholar 

  77. Chaipatikul V, Erickson-Herbrandson LJ, Loh HH, Law P-Y Rescuing the traffic-deficient mutants of rat μ-opioid receptors with hydrophobic ligands. Mol. Pharmacol. 2003;64:32–41.

    CAS  PubMed  Google Scholar 

  78. Keith DE, Anton B, Murray SR, Zaki PA, Chu PC, Lissin DV, Montellet-Agius G, Stewart PI, Evans CJ, von Zastrow M. μ-Opioid receptor internalization: opiate drugs have differential effects on conserved endocytic mechanism in vitro and in the mammalian brain. Mol. Pharmacol. 1998;53:377–384.

    CAS  PubMed  Google Scholar 

  79. Wannemacher K, Yadav P, Doligosa M, Howells RD. Antagonist-induced opioid receptor up-regulation. Soc. Neurosci. Abst. Prog. No. 490.15, online; 2005.

    Google Scholar 

  80. Wannemacher K, Yadav P, Howells RD. Opioid antagonists up-regulate delta opioid receptor binding without increasing immunoreactive receptor protein. Int. Narcotic Res. Conf. abstract Th-42, p. 65; 2006.

    Google Scholar 

  81. Wannemacher K, Yadav P, Howells RD. A select set of opioid ligands induce up-regulation by promoting the maturation and stability of the rat kappa opioid receptor in human embryonic kidney 293 cells. J. Pharmacol. Exp. Ther. 2007; 323:614–625, eprint DOI:10.1124/ jpet.107.125500.

    CAS  PubMed  Google Scholar 

  82. Li J-G, Benovic JL, Liu-Chen LY. Mechanisms of agonist-induced down-regulation of the human ? opioid receptor: internalization is required for down-regulation. Mol. Pharmacol. 2000;58:795–801.

    CAS  PubMed  Google Scholar 

  83. Chen Y, Chen C, Wang Y, Liu-Chen L-Y. Ligands regulate cell surface level of the human ? opioid receptor (hKOR) by activation-induced down-regulation and pharmacological chaperone-mediated enhancement: differential effects of non-peptide and peptide agonists. J. Pharmacol. Exp. Ther. 2006;319:765–775.

    CAS  PubMed  Google Scholar 

  84. Schwartz RD, Keller KJ. Nicotinic cholinergic receptor binding sites in the brain: regulation in vivo. Science 1983;220:214–216.

    CAS  PubMed  Google Scholar 

  85. Benwell ME, Balfour DJ, Anderson JM. Evidence that tobacco smoking increases the density of (−)-[3H]nicotine binding sites in human brain. J. Neurochem. 1988;50:1243–1247.

    CAS  PubMed  Google Scholar 

  86. Perry DC, Davila-Garcia MI, Stockmeier CA, Keller KJ. Increased nicotinic receptors in brains from smokers: membrane binding and autoradiography studies. J. Pharmacol. Exp. Ther. 1999;289:1545–1552.

    CAS  PubMed  Google Scholar 

  87. Sallette J, Pons S, Devillers-Thiery A, Soudant M, Prado de Carvalho L, Changeux J-P, Corringer PJ. Nicotine upregulates its own receptors through enhanced intracellular maturation. Neuron 2005;46:595–607.

    CAS  PubMed  Google Scholar 

  88. Kuryatov A, Luo J, Cooper J, Lindstrom J. Nicotine acts as a pharmacological chaperone to up-regulate human alpha4beta2 acetylcholine receptors. Mol. Pharmacol. 2005;68: 1839–51.

    CAS  PubMed  Google Scholar 

  89. Vallejo YF, Buisson B, Bertrand D, Green WN. Chronic nicotine exposure upregulates nico-tinic receptors by a novel mechanism. J. Neurosci. 2005;25:5563–5572.

    CAS  PubMed  Google Scholar 

  90. Unterwald EM, Horne-King J, Kreek MJ. Chronic cocaine alters brain mu opioid receptors. Brain Res. 1992;584:314–318.

    CAS  PubMed  Google Scholar 

  91. Unterwald EM, Rubenfeld JM, Kreek MJ. Repeated cocaine administration upregulates kappa and mu, but not delta, opioid receptors. NeuroReport 1994;5:1613–1616.

    CAS  PubMed  Google Scholar 

  92. Unterwald EM. Regulation of opioid receptors by cocaine. Ann. N. Y. Acad. Sci. 2001;937:74–92.

    CAS  PubMed  Google Scholar 

  93. Chen JF, Aloyo VJ, Weiss B. Continuous treatment with the D2 dopamine receptor agonist quinpirole decreases D2 dopamine receptors, D2 dopamine receptor messenger RNA and proenkephalin messenger RNA, and increases mu opioid receptors in mouse striatum. Neuroscience 1993;54:669–680.

    CAS  PubMed  Google Scholar 

  94. Chen JF, Aloyo VJ, Qin ZH, Weiss B. Irreversible blockade of D2 dopamine receptors by fluphenazine-N-mustard increases D2 dopamine receptor mRNA and proenkephalin mRNA and decreases D1 dopamine receptor mRNA and mu and delta opioid receptors in rat stria-tum. Neurochem. Int. 1994;25:355–366.

    CAS  PubMed  Google Scholar 

  95. George SR, Kertesz M. Met-enkephalin concentrations in striatum respond reciprocally to alterations in dopamine neurotransmission. Peptides 1987;8:487–492.

    CAS  PubMed  Google Scholar 

  96. Steiner H, Gerfen CR. Enkephalin regulates acute D2 dopamine receptor antagonist-induced immediate-early gene expression in striatal neurons. Neuroscience 1999;88:795–810.

    CAS  PubMed  Google Scholar 

  97. Ambrose LM, Unterwald EM, Van Bockstaele EJ. Ultrastructural evidence for co- localization of dopamine D2 and mu opioid receptors in the rat dorsolateral striatum. Anat. Rec. 2004;279A:583–591.

    CAS  Google Scholar 

  98. Rosin A, Kitchen I, Georgieva J. Effects of single and dual administration of cocaine and ethanol on opioid and ORL1 receptor expression in rat CNS: an autoradiographic study. Brain Res. 2003;978:1–13.

    CAS  PubMed  Google Scholar 

  99. Schroeder JA, Niculescu M, Unterwald EM. Cocaine alters mu but not delta or kappa opioid receptor-stimulated in situ [35S]GTPγS binding in rat brain. Synapse 2003;47:26–32.

    CAS  PubMed  Google Scholar 

  100. Bailey A, Gianotti R, Ho A, Kreek MJ. Persistent upregulation of mu-opioid, but not adenos-ine, receptors in brains of long-term withdrawn escalating dose “binge” cocaine-treated rats. Synapse 2005;57:160–166.

    CAS  PubMed  Google Scholar 

  101. Unterwald EM, Kreek MJ, Cuntapay M. The frequency of cocaine administration impacts cocaine-induced receptor alterations. Brain Res. 2001;900:103–109.

    CAS  PubMed  Google Scholar 

  102. Hammer RP. Cocaine alters opiate receptor binding in critical brain reward regions. Synapse 1989;3:55–60.

    CAS  PubMed  Google Scholar 

  103. Izenwasser S, Heller B, Cox BM. Continuous cocaine administration enhances mu- but not delta-opioid receptor-mediated inhibition of adenylyl cyclase activity in nucleus accumbens. Eur. J. Pharmacol. 1996;297:187–91.

    CAS  PubMed  Google Scholar 

  104. Zubieta JK, Gorelick DA, Stauffer R, Ravert HT, Dannals RF, Frost JJ. Increased mu opioid receptor binding detected by PET in cocaine-dependent men is associated with cocaine craving. Nat. Med. 1996;2:1225–1229.

    CAS  PubMed  Google Scholar 

  105. Gorelick DA, Kim YK, Bencherif B, Boyd SJ, Newson R, Copersino M, Endres CJ, Dannals RF, Frost JJ. Imaging brain mu-opioid receptors in abstinent cocaine users: time course and relation to cocaine craving. Biol. Psychiatry 2005;57:1573–1582.

    CAS  PubMed  Google Scholar 

  106. Hurd YL, Herkenham M. Molecular alterations in the neostriatum of human cocaine addicts. Synapse 1993;13:347–369.

    Google Scholar 

  107. Bencherif B, Wand GS, McCaul ME, Kim YK, Ilgin Nm Dannais RF, et al. Mu-opioid receptor binding measured by [11C]carfentanil positron emission tomography is related to craving and mood in alcohol dependence. Biol. Psychiatry 2004;55:255–262.

    CAS  PubMed  Google Scholar 

  108. Staley JK, Rothman RB, Rice KC, Partilla J, Mash DC. Kappa2 opioid receptors in limbic areas of the human brain are upregulated by cocaine in fatal overdose victims. J. Neurosci. 1997;17:8225–8233.

    CAS  PubMed  Google Scholar 

  109. Hynes MD, Lochner MA, Bemis KG, Hymson DL. Chronic ethanol alters the receptor binding characteristics of the delta opioid receptor lignad, d-Ala2-d-Leu5 enkephalin in mouse brain. Life Sci. 1983;33:2331–2337.

    CAS  PubMed  Google Scholar 

  110. Charness ME, Gordon AS, Diamond I. Ethanol modulation of opiate receptors in cultured neural cells. Science 1983;222:1246–1248.

    CAS  PubMed  Google Scholar 

  111. Charness ME, Querimit LA, Diamond I. Ethanol increases the expression of functional delta-opioid receptors in neuroblastoma x glioma NG108-15 hybrid cells. J. Biol. Chem. 1986;261:3164–3169.

    CAS  PubMed  Google Scholar 

  112. Charness ME, Hu G, Edwards RH, Querimit LA. Ethanol increases delta-opioid receptor gene expression in neuronal cell lines. Mol. Pharmacol. 1993;44:1119–1127.

    CAS  PubMed  Google Scholar 

  113. Mendez M, Morales-Mulia M, Leriche M. [3H]DPDPE binding to δ opioid receptors in the rat mesocorticolimbic and nigrostriatal pathways is transiently increased by acute ethanol administration. Brain Res. 2004;1028:180–190.

    CAS  PubMed  Google Scholar 

  114. Turchan J, Przewlocka B, Toth G, Lason W, Borsodi A, Przewlocki R. The effect of repeated administration of morphine, cocaine and ethanol on mu and delta opioid receptor density in the nucleus accumbens and striatum of the rat. Neuroscience 1999;91:971–999.

    CAS  PubMed  Google Scholar 

  115. Shah S, Duttaroy A, Sehba F, Chen B, Philippe J, Monderson T, Lau-Cam C, Carroll J, Yoburn BC. The effect of ethanol drinking on opioid analgesia and receptors in mice. Alcohol 1997;14:361–366.

    CAS  PubMed  Google Scholar 

  116. Shen J, Chan KW, Chen BT, Philippe J, Sehba F, Duttaroy A, Carroll J, Yoburn BC. The effect of in vivo ethanol consumption on cyclic AMP and delta-opioid receptors in mouse striatum. Brain Res. 1997;770:65–71.

    CAS  PubMed  Google Scholar 

  117. Sim-Selley LJ, Sharpe AL, Vogt LJ, Brunk LK, Selley DE, Samson HH. Effect of ethanol self-administration on mu- and dalta-opioid receptor-mediated G-protein activity. Alcohol. Clin. Exp. Res. 2002;26:688–694.

    CAS  PubMed  Google Scholar 

  118. Saland LC, Hastings CM, Abeyta A, Chavez JB. Chronic ethanol modulates delta and mu-opioid receptor expression in rat CNS: immunohistochemical analysis with quantitative confocal microscopy. Neurosci. Lett. 2005;381:163–168.

    CAS  PubMed  Google Scholar 

  119. Herz A. Endogenous opioid systems and alcohol addiction. Psychopharmacology 1997;129:99–111.

    CAS  PubMed  Google Scholar 

  120. Gianoulakis C. Endogenous opioids and addiction to alcohol and other drugs of abuse. Curr. Top. Med. Chem. 2004;4:39–50.

    CAS  PubMed  Google Scholar 

  121. Volpicelli JR, Alterman AI, Hayashida M, O'Brien CP. Naltrexone in the treatment of alcohol dependence. Arch. Gen. Psychiatry 1992;49:876–880.

    CAS  PubMed  Google Scholar 

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Acknowledgments

Acknowledgments We thank the editors, Drs. Dean, Bilsky, and Negus, for their efforts in assembling this vast volume of scientific literature. E. M. Unterwald acknowledges Dr. Mary Jeanne Kreek for her role in many of the studies presented herein. R. D. Howells acknowledges the contributions of Kenneth Wannemacher and Prem Yadav to the research performed in his laboratory. This work was supported in part from grants from NIH/NIDA, P50 DA05130 (MJK), DA09580 (EMU), and DA09113 (RDH).

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Authors and Affiliations

  1. Department of Pharmacology and Center for Substance Abuse Research, Temple School of Medicine, and The Rockefeller University, Biology of Addictive Diseases Laboratory, 19140, Philadelphia, PA, 10021, New York

    Ellen M. Unterwald

  2. Department of Biochemistry and Molecular Biology,University of Medicine and Dentistry of New Jersey, New Jersey Medical School, NJ, Newark, 07103

    Richard D. Howells

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  1. Ellen M. Unterwald
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  2. Richard D. Howells
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Editors and Affiliations

  1. Life Sciences/Toxicology, Alkermes, Inc., Cambridge, MA, 02139, USA

    Reginald L. Dean III

  2. Department of Pharmacology, College of Osteopathic Medicine, University of New England, Biddleford, ME, 04005, USA

    Edward J. Bilsky

  3. Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, 23298, USA

    S. Stevens Negus

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Unterwald, E.M., Howells, R.D. (2009). Upregulation of Opioid Receptors. In: Dean, R.L., Bilsky, E.J., Negus, S.S. (eds) Opiate Receptors and Antagonists. Contemporary Neuroscience. Humana Press. https://doi.org/10.1007/978-1-59745-197-0_2

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