Opioids pp 145-188 | Cite as

Opioid Receptor-G Protein Interactions: Acute and Chronic Effects of Opioids

  • B. M. Cox
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 104 / 1)


It has been accepted for several years that opioid action mediated through μ- and δ-type opioid receptors requires the interaction of the agonist- occupied receptor with a guanine nucleotide binding protein (G protein). Accumulating evidence suggests that a similar mechanism is an essential component of κ-type opioid receptor function. In this chapter, we will discuss the evidence supporting these conclusions and review similarities and differences between opioid receptor-G protein interactions and the functions of other G protein-linked receptor systems. The evidence that tolerance to opioid agonist actions and the development of dependence on opioid agonist after chronic exposure might also be related to modified interactions between receptor and G protein, and also to changes in the concentrations of individual forms of G proteins, will also be considered.


Opioid Receptor Adenylyl Cyclase Guanine Nucleotide Opiate Receptor Opioid Agonist 
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  1. Aghajanian GK (1978) Tolerance of locus coeruleus neurons to morphine and suppression of withdrawal response by clonidine. Nature 276: 186–188PubMedGoogle Scholar
  2. Aghajanian GK, Wang Y-Y (1986) Pertussis toxin blocks the outward currents evoked by opiate and α2-agonists in locus coeruleus neurons. Brain Res 371: 390–394PubMedGoogle Scholar
  3. Asano T, Ogasawara N (1986) Uncoupling of γ-aminobutyric acid B receptors from GTP-binding proteins by N-ethylmaleimide: effect of N-ethylmaleimide on purified GTP-binding proteins. Mol Pharmacol 29: 244–249PubMedGoogle Scholar
  4. Aston-Jones G, Ennis M, Pieribone VA, Nickel WT, Shipley MT (1986) The brain locus coeruleus: restricted afferent control of a broad efferent network. Science 234: 734–737PubMedGoogle Scholar
  5. Attali B, Vogel Z (1989) Long-term opiate exposure leads to reduction of the α1-1subunit of GTP-binding proteins. J Neurochem 53: 1636–1639PubMedGoogle Scholar
  6. Attali B, Saya D, Nah S-Y, Vogel Z (1989a) κ-Opiate agonists inhibit Ca2+ influx in rat spinal cord-dorsal root ganglion cocultures: involvement of a GTP-binding protein. J Biol Chem 264:347–353PubMedGoogle Scholar
  7. Attali B, Saya D, Vogel Z (1989b) K-Opiate agonists inhibit adenylate cyclase and produce heterologous desensitization in rat spinal cord. J Neurochem 52: 360–369PubMedGoogle Scholar
  8. Aub DL, Frey EA, Sekura RD, Cote TE (1986) Coupling of the thyrotropin-releasing hormone receptor to phospholipase C by a GTP-binding protein distinct from the inhibitory or stimulatory GTP binding proteins. J Biol Chem 261: 9333–9340PubMedGoogle Scholar
  9. Barchfield CC, Medzihradsky F (1984) Receptor-mediated stimulation of brain GTPase by opiates in normal and dependent rats. Biochim Biophys Acta 121: 641–648Google Scholar
  10. Beitner-Johnson D, Nestler EJ (1991) Morphine and cocaine exert common chronic actions on tyrosine hydroxylase in dopaminergic brain reward regions. J Neurochem 57: 344–347PubMedGoogle Scholar
  11. Bennett DB, Spain JW, Lakowski MB, Roth BL, Coscia CJ (1985) Stereospecific opiate binding sites occur in coated vesicles. J Neurosci 5: 3010–3015PubMedGoogle Scholar
  12. Benovic JL, Strasse RH, Caron MG, Lefkowitz RJ (1986) β-Adrenergic receptor kinase: identification of a novel protein kinase that phosphorylates the agonist- occupied form of the receptor. Proc Natl Acad Sci USA 83:2797–2801PubMedGoogle Scholar
  13. Birnbaumer L (1990) Transduction of receptor signal into modulation of effector activity by G proteins: the first 20 years or so. FASEB J 4: 3068–3078Google Scholar
  14. Bläsig J, Meyer G, Hollt V, Hengstenburg J, Dum J, Herz A (1979) Non-competitive nature of the antagonistic mechanism responsible for tolerance development to opiate-induced analgesia. Neuropharmacol 18: 473–481Google Scholar
  15. Blume A J (1978a) Interactions of ligands with opiate receptors of brain membranes; regulation by ions and nucleotides. Proc Natl Acad Sci USA 75: 1713–1717PubMedGoogle Scholar
  16. Blume AJ (1978b) Opiate binding to membrane preparations of neuroblastoma X glioma hybrid cells NG 108–15: effects of ions and nucleotides. Life Sci 22: 1843–1852PubMedGoogle Scholar
  17. Blume AJ, Lichtshtein D, Boone G (1979) Coupling of opiate receptors to adenylate cyclase: requirement for Na+ and GTP. Proc Natl Acad Sci USA 76: 5626–5630PubMedGoogle Scholar
  18. Bolger GT, Sklonick P, Rice KC, Weisman BA (1988) Differential regulation of μ-opiate receptors in heroin- and morphine-dependent rats. FEBS Lett 234: 22–26PubMedGoogle Scholar
  19. Brady LS, Herkenham M, Long JB, Rothman RB (1989) Chronic morphine increases μ-opiate receptor binding in rat brain: a quantitative autoradiographic study. Brain Res 477: 382–386PubMedGoogle Scholar
  20. Burns DL, Hewlett EL, Moss J, Vaughan M (1983) Pertussis toxin inhibits encephalin stimulation of GTPase of NG 108–15 cells. J Biol Chem 258: 1435–1438PubMedGoogle Scholar
  21. Cassel D, Selinger Z (1976) Catecholamine-stimulated GTPase activity in turkey erythrocyte membranes. Biochim Biophys Acta 252: 538–551Google Scholar
  22. Castanas E, Bourhim N, Giraud P, Boudouresque F, Cantau P, Oliver C (1985) Interaction of opiates with opioid binding sites in the bovine adrenal medulla: interaction with K sites. J Neurochem 45: 688–699PubMedGoogle Scholar
  23. Chang K-J, Eckel RW, Blanchard SG (1982) Opioid peptides induce reduction of enkephalin receptors in cultures neuroblastoma cells. Nature 296: 446–448PubMedGoogle Scholar
  24. Chang K-J, Blanchard SG, Cuatrecasas P (1983) Unmasking of magnesium- dependent high-affinity binding sites for [D-Ala2, D-Leu5] enkephalin after pre-treatment of brain membranes with guanine nucleotides. Proc Natl Acad Sci USA 80: 940–944PubMedGoogle Scholar
  25. Chang K-J, Blanchard SG, Cuatrecasas P (1984) Benzomorphan sites are ligand recognition sites of putative ε-receptors. Mol Pharmacol 26: 484–488PubMedGoogle Scholar
  26. Chavkin C, Goldstein A (1984) Opioid receptor reserve in normal and morphine- tolerant guinea pig ileum myenteric plexus. Proc Natl Acad Sci USA 81: 7253–7257PubMedGoogle Scholar
  27. Chen G-C, Chalazonitis A, Shen K-F, Crain SM (1988) Inhibitor of cyclic AMP- dependent protein kinase blocks opioid-induced prolongation of the action potential of mouse sensory ganglion neurons in dissociated cell cultures. Brain Res 462: 372–377PubMedGoogle Scholar
  28. Childers SR (1984) Interaction of opiate receptor binding sites and guanine nucleotide regulatory sites: selective protection from N-ethylmaleimide. J Pharmacol Exp Ther 230: 684–691PubMedGoogle Scholar
  29. Childers SR, Snyder SH (1978) Guanine nucleotides differentiate agonist and antagonist interactions with opiate receptors. Life Sci 23: 759–762PubMedGoogle Scholar
  30. Childers SR, Snyder SH (1980) Differential regulation by guanine nucleotides of opiate agonist and antagonist receptor interactions. J Neurochem 34: 583–593PubMedGoogle Scholar
  31. Christie MJ, Williams JT, North RA (1987) Cellular mechanisms of opioid tolerance; studies in single brain neurons. Mol Pharmacol 32: 632–638Google Scholar
  32. Clark JA, Lui L, Price M, Hersh B, Edelson M, Pasternak GW (1989) Kappa opiate receptor multiplicity: evidence for two U50488-sensitive κ1 subtypes and a novel κ3 subtype. J Pharmacol Exp Ther 251: 461–468PubMedGoogle Scholar
  33. Clark MJ, Medzihradsky F (1987) Coupling of multiple opioid receptors to GTPase following selective receptor alkylation in brain membranes. Neuropharmacology 26: 1763–1770PubMedGoogle Scholar
  34. Clark MJ, Levenson SD, Medzihradsky F (1986) Evidence for coupling of the κ opioid receptor to brain GTPase. Life Sci 39: 1721–1727PubMedGoogle Scholar
  35. Costa T, Herz A (1989) Antagonists with negative intrinsic activity at delta opioid receptors coupled to GTP-binding proteins. Proc Natl Acad Sci USA 86: 7321–7325PubMedGoogle Scholar
  36. Costa T, Aktories K, Schultz G, Wüster M (1983) Pertussis toxin decreases opiate receptor binding and adenylate inhibition in a neuroblastoma X glioma hybrid cell line. Life Sci 33 [Suppl 1]: 219–222PubMedGoogle Scholar
  37. Costa T, Wüster M, Gramsch C, Herz A (1985) Multiple states of opioid receptor may modulate adenylate cyclase in intact neuroblastoma X glioma hybrid cells. Mol Pharmacol 28: 146–154PubMedGoogle Scholar
  38. Costa T, Lang G, Gless C, Herz A (1990) Spontaneous association between opioid receptors and GTP-binding regulatory proteins in native membranes: specific regulation by antagonists and sodium. Mol Pharmacol 37: 383–394PubMedGoogle Scholar
  39. Cox BM (1978) Multiple mechanisms in opiate tolerance. In: van Ree J, Terenius L (eds) Characteristics and functions of opioids. Elsevier /North-Holland, Amsterdam, pp 13–23Google Scholar
  40. Cox BM (1990) Drug tolerance and physical dependence. In: Pratt WB, Taylor P (eds) Principles of drug action: the basis of pharmacology. Churchill Livingstone, New York, pp 639–690Google Scholar
  41. Cox BM, Werling LL (1988) Regulation of norepinephrine release by opioids: role of noradrenergic pathways in opiate withdrawal. In: Illes P, Farsang C (eds) Regulatory roles of opioid peptides. VCH, Weinheim, pp 259–267Google Scholar
  42. Dingledine R, Valentino RJ, Bostock E, King ME, Chang K-J (1983) Down- regulation of δ but not μ opioid receptors in the hippocampal slice associated with loss of physiological response. Life Sci 33 [Suppl 1]: 333–336PubMedGoogle Scholar
  43. Dum J, Meyer G, Hollt V, Herz A (1979) In vivo opiate binding unchanged in tolerant/dependent mice. Eur J Pharmacol 58: 453–460PubMedGoogle Scholar
  44. Duman RS, Tallman JF, Nestler EJ (1988) Acute and chronic opiate-regulation of adenylate cyclase in brain: specific effects in locus coeruleus. J Pharmacol Exp Ther 246: 1033–1039PubMedGoogle Scholar
  45. Frances B, Moisand C, Meunier J-C (1985) Na+ ions and Gpp ( NH) p selectively inhibit agonist interactions at K opioid receptor sites in rabbit and guinea-pig cerebellum membranes. Eur J Pharmacol 117: 223–232Google Scholar
  46. Frances B, Puget A, Moisand C, Meunier J-C (1990) Apparent precoupling of κ- but not μ-opioid receptors with a G protein in the absence of agonist. Eur J Pharmacol 189: 1–9PubMedGoogle Scholar
  47. Frey E, Kebabian J (1984) A μ-opiate receptor in 7315c tumor tissue mediates inhibition of immunoreactive prolactin release and adenylate cyclase activity. Endocrinology 115: 1797–1804PubMedGoogle Scholar
  48. Furchgott RF (1978) Pharmacological characterization of receptors: its relation to radioligand binding studies. Fed Proc 37: 115–120PubMedGoogle Scholar
  49. Gairin JE, Botanch C, Cros J, Meunier J-C (1989) Binding of dynorphin A and related peptides to κ- and μ-opioid receptors: sensitivity to Na+ and Gpp ( NH)p. Eur J Pharmacol 172: 381–384Google Scholar
  50. Gintzler AR, Xu H (1991) Different G proteins mediate the opioid inhibition or enhancement of evoked [5-methionine] enkephalin release. Proc Natl Acad Sci USA 88: 4741–4745PubMedGoogle Scholar
  51. Giordano AL, Nock B, Cicero TJ (1991) 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 255: 536–540Google Scholar
  52. Glossman H, Baukal AJ, Catt KJ (1974) Properties of angiotensin II receptors in bovine and rat adrenal cortex. J Biol Chem 249: 825–834Google Scholar
  53. Green DA, Clark RB (1982) Specific mucarinic-cholinergic desensitization in the neuroblastoma-glioma hybrid NG108-15. J Neurochem 39: 1125–1131PubMedGoogle Scholar
  54. Griffin MT, Law P-Y, Loh HH (1985) Involvement of both inhibitory and stimulatory guanine nucleotide binding proteins in the expression of chronic opiate regulation of adenylate cyclase activity in NG108-15 cells. J Neurochem 45: 1585–1589PubMedGoogle Scholar
  55. Guitart X, Nestler EJ (1989) Identification of morphine- and cyclic AMP-regulated phosphoproteins (MARPPs) in the locus coeruleus and other regions of rat brain: regulation by acute and chronic morphine. J Neurosci 9: 4371–4387PubMedGoogle Scholar
  56. Guitart X, Hayward M, Nisenbaum LK, Beitner-Johnson DB, Haycock JW, Nestler EJ (1990) Identification of MARPP-58, a morphine- and cyclic AMP-regulated phosphoprotein of 58 KDa, as tyrosine hydroxylase: evidence for regulation of its expression by chronic morphine in rat locus coeruleus. J Neurosci 10: 2649–2659PubMedGoogle Scholar
  57. Hadcock JR, Ros M, Malbon CC (1989) Agonist regulation of β-adrenergic receptor mRN A: analysis in S49 mouse lymphoma mutants. J Biol Chem 264: 13956–13961PubMedGoogle Scholar
  58. Hadcock JR, Ros M, Watkins DC, Malbon CC (1990) Cross-regulation between G-protein-mediated pathways: stimulation of adenylyl cyclase increases expression of the inhibitory G-protein, Gid2. J Biol Chem 265: 14784–14790PubMedGoogle Scholar
  59. Harada H, Ueda H, Wada Y, Katada T, Ui M, Satoh M (1989) Phosphorylation of μ-opioid receptors — a putative mechanism of selective uncoupling of receptor- Gi interaction, measured with low Km GTPase and nucleotide-sensitive agonist binding. Neurosci Lett 100: 221–226PubMedGoogle Scholar
  60. Harada H, Ueda H, Katada T, Ui M, Satoh M (1990) Phosphorylated μ-opioid receptor purified from rat brains lacks functional coupling with Gi1, a GTP- binding protein in reconstituted lipid vesicles. Neurosci Lett 113: 47–49PubMedGoogle Scholar
  61. Hazum E, Chang K-J, Cuatrecasas P (1979) Opiate (enkephalin) receptors of neuroblastoma cells: occurrence in clusters on the cell surface. Science 206: 1077–1079PubMedGoogle Scholar
  62. Horstman DA, Brandon S, Wilson AL, Guyer CA, Cragoe EJ Jr, Limbird LE (1990) An aspartate conserved among G-protein receptors confers allosteric regulation of α2 adrenergic receptors by sodium. J Biol Chem 265: 21590–21595PubMedGoogle Scholar
  63. Huganir RL, Greengard P (1990) Regulation of neurotransmitter receptor desensitization by protein phosphorylation. Neuron 5: 555–567PubMedGoogle Scholar
  64. Johnson GL, Kaslow HR, Bourne HR (1978) Genetic evidence that cholera toxin substrates are regulatory components of adenylyl cyclase. J Biol Chem 253: 7120–7123PubMedGoogle Scholar
  65. Johnson SM, Costa M, Humphreys CMS (1989) Opioid dependence in myenteric neurons innervating the circular muscle of guinea-pig ileum. Naunyn- Schmiedeberg’s Arch Pharmacol 339: 166–172PubMedGoogle Scholar
  66. Johnson SM, Fleming WW (1989) Mechanisms of cellular adaptive sensitivity changes: applications to opioid tolerance and dependence. Pharmacol Rev 41: 435–488PubMedGoogle Scholar
  67. Johnson SM, Westfall DP, Howard SA, Fleming WW (1978) Sensitivities of the isolated ileal longitudinal smooth muscle-myenteric plexus and hypogastric nerve-vas deferens of the guinea pig after chronic morphine pellet implantation. J Pharmacol Exp Ther 204: 54–66PubMedGoogle Scholar
  68. Katada T, Ui M (1982) Direct modification of the membrane adenylate cyclase system by islet-activating protein due to ADP-ribosylation of a membrane protein. Proc Natl Acad Sci USA 79: 3129–3133PubMedGoogle Scholar
  69. Klee WA, Streaty RA (1974) Narcotic receptor sites in morphine-dependent rats. Nature 248: 61–63PubMedGoogle Scholar
  70. Konkoy CS, Childers SR (1989) Dynorphin-selective inhibition of adenylyl cyclase in guinea pig cerebellum membranes. J Pharmacol Exp Ther 36: 627–633Google Scholar
  71. Koski G, Klee WA (1981) Opiates inhibit adenylate cyclase by stimulating GTP hydrolysis. Proc Natl Acad Sci USA 78: 4185–4189PubMedGoogle Scholar
  72. Kurose H, Katada T, Ui M (1983) 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 258: 4870–4875PubMedGoogle Scholar
  73. Lahti R, Collins R (1978) Chronic naloxone results in prolonged increases in opiate binding sites in rat brain. Eur J Pharmacol 51: 185–186PubMedGoogle Scholar
  74. Lang J, Costa T (1989) Chronic exposure of NG 108-15 cells to opiate agonists does not alter the amount of the guanine nucleotide-binding proteins Gi and G0. J Neurochem 53: 1500–1506PubMedGoogle Scholar
  75. Lang J, Schulz R (1989) Chronic opiate receptor activation in vivo alters the level of G-protein subunits in guinea-pig myenteric plexus. Neuroscience 32: 503–510PubMedGoogle Scholar
  76. Larsen NE, Mulliken-Kilpatrick D, Blume AJ (1981) Two different modifications of the neuroblastoma x glioma hybrid opiate receptors induced by N-ethylmaleimide. Mol Pharmacol 20: 255–262PubMedGoogle Scholar
  77. Law P-Y, Horn DS, Loh HH (1982) Loss of opiate receptor activity in neuroblastoma x glioma NG108-15 hybrid cells after chronic opiate treatment: a multistep process. Mol Pharmacol 22: 1–4PubMedGoogle Scholar
  78. Law P-Y, Horn DS, Loh HH (1983) Opiate receptor down-regulation and desensitization in neuroblastoma x glioma NG108-15 hybrid cells are two separate cellular adaptation processes. Mol Pharmacol 24: 413–424PubMedGoogle Scholar
  79. Law P-Y, Horn DS, Loh HH (1984) Down-regulation of opioid receptor in neuroblastoma x glioma NG108-15 hybrid cells: chloroquine promotes accumulation of tritiated enkephalin in the lysosomes. J Biol Chem 259: 4096–4104PubMedGoogle Scholar
  80. Law P-Y, Horn DS, Loh HH (1985a) Multiple affinity states of opiate receptor in neuroblastoma x glioma NG108–15 hybrid cells. J Biol Chem 260: 3561–3569PubMedGoogle Scholar
  81. Law P-Y, Louie AK, Loh HH (1985b) Effect of pertussis toxin treatment on the down-regulation of opiate receptors in neuroblastoma x glioma NG108-15 hybrid cells. J Biol Chem 260: 14818–23PubMedGoogle Scholar
  82. Lee S, Rosenberg CR, Musacchio JM (1988) Cross-dependence to opioid and α2-adrenergic receptor agonists in NG1208-15 cells. FASEB J 2: 52–55PubMedGoogle Scholar
  83. Leff P, Harper D, Dainty IA, Dougall IG (1990) Harmacological estimation of agonist affinity; detection of errors that may be caused by the operation of receptor isomerization or ternary complex mechanism. Br J Pharmacol 101: 55–60PubMedGoogle Scholar
  84. Lefkowitz RJ, Mullikan D, Caron MG (1976) Regulation of β-adrenergic receptors by guanyl-5’-yl imidophosphate and other purine nucleotides. J Biol Chem 254: 44686–44692Google Scholar
  85. Lenoir D, Barg J, Simantov R (1984) Characterization and downregulation of opiate receptors in aggregating fetal rat brain cells. Brain Res 304: 295–290Google Scholar
  86. Longabaugh JP, Didbury J, Spiegal A, Stiles GL (1989) Modification of rat adipocyte A1 adenosine receptor-adenylate cyclase system during chronic exposure to an A1 adenosine receptor agonist: alterations in the quantity of Gsa and Giot are not associated with changes in their mRNAS. Mol Pharmacol 36: 681–688PubMedGoogle Scholar
  87. Mack KJ, Lee MF, Weyhenmeyer JA (1985) Effects of guanyl nucleotides and ions on kappa opioid binding. Brain Res Bull 14: 301–306PubMedGoogle Scholar
  88. Mackay D (1990) Agonist potency and apparent affinity: interpretation using classical and steady-state ternary-complex models. Trends Pharmacol Sci 11: 17–22PubMedGoogle Scholar
  89. Maguire ME, van Arsdale PM, Gilman AG (1976) An agonist-specific effect of guanine nucleotides on binding to the beta adrenergic receptor. Mol Pharmacol 12: 335–339PubMedGoogle Scholar
  90. Makman MH, Dvorkin B, Crain SM (1988) Modulation of adenylate cyclase activity of mouse spinal cord-ganglion explants by opioids, serotonin and pertussis toxin. Brain Res 445: 303–313PubMedGoogle Scholar
  91. Maloteaux JM, Octave JN, Laterre EC, Laduron PM (1989) Downregulation of 3H-lofentanil binding to opiate receptors in different cultured neuronal cells. Naunyn Schmiedebergs Arch Pharmacol 339: 192–199PubMedGoogle Scholar
  92. McKenzie FR, Milligan G (1990) δ-Opioid receptor mediated inhibition of adenylate cyclase is transduced specifically by the guanine nucleotide binding protein Gi2. Biochem J 267:391–398PubMedGoogle Scholar
  93. Milligan G, Green A (1991) Agonist control of G-protein levels. Trends Pharmacol Sci 12: 207–209PubMedGoogle Scholar
  94. Misawa H, Ueda H, Satoh M (1990) κ-Opioid agonist inhibits phospholipase C, possibly via an inhibition of G-protein activity. Neurosci Lett 112:324–327PubMedGoogle Scholar
  95. Morris BJ, Herz A (1989) In vivo regulation of opioid receptors: simultaneous down-regulation of kappa sites and up-regulation of mu sites following chronic agonist /antagonist treatment. Neuroscience 29: 433–442PubMedGoogle Scholar
  96. Morris BJ, Millan MJ (1990) Inability of an opioid antagonist lacking negative intrinsic activity to induce opioid receptor up-regulation in vivo. Br J Pharmacol 102: 883–886Google Scholar
  97. Moses MA, Snell CR (1984) The regulation of δ-opiate receptor density on 108ccl5 neuroblastoma X glioma hybrid cells. Br J Pharmacol 81: 169–174PubMedGoogle Scholar
  98. Musacchio JM, Greenspan DL (1986) The adenylate cyclase rebound response to naloxone in the NG 108-15 cells: effects of etorphine and other opiates. Neuropharmacology 25: 833–837PubMedGoogle Scholar
  99. Nagamatsu K, Suzuki K, Teshima R, Ikebuchi H, Terao T (1989) Morphine enhances the phosphorylation of a 58kDa protein in mouse brain membranes. Biochem J 257: 165–171PubMedGoogle Scholar
  100. Nestler EJ, Tallman JF (1988) Chronic morphine treatment increases cyclic AMP- dependent protein kinase activity in the rat locus coeruleus. Mol Pharmacol 33: 127–132PubMedGoogle Scholar
  101. Nestler EJ, Erdos JJ, Terwilliger R, Duman RS, Tallman JF (1989) Regulation of G proteins by chronic morphine in the rat locus coeruleus. Brain Res 476: 230–239PubMedGoogle Scholar
  102. Nishino K, Su YF, Wong C-S, Watkins WD, Chang K-J (1990) Dissociation of μ-opioid tolerance from receptor downregulation in rat spinal cord. J Pharmacol Exp Ther 253: 67–72PubMedGoogle Scholar
  103. Nock B, Giodano AL, Cicero TJ, O’Connor LH (1990) Affinity of drugs and peptides for U-69593-sensitive and -insensitive kappa opiate binding sites: the U-69593-insensitive site appears to be the beta-endorphin-specific epsilon receptor. J Pharmacol 254: 412–419Google Scholar
  104. North RA, Karras PJ (1978) Opiate tolerance and dependence induced in vitro in single myenteric neurons. Nature 272: 73–75PubMedGoogle Scholar
  105. Ott S, Costa T, Herz A (1989) Opioid receptors of neuroblastoma cells are in tow domains of the plasma membrane that differ in content of G protein. J Neurochem 52: 619–626PubMedGoogle Scholar
  106. Paterson SJ, Robson LE, Kosterlitz HW (1986) Control by cations of opioid binding in guinea pig brain membranes. Proc Natl Acad Sci USA 83: 6216–6220PubMedGoogle Scholar
  107. Pert CB, Snyder SH (1974) Opiate receptor binding of agonists and antagonists affected differentially by sodium. Mol Pharmacol 10: 868–879Google Scholar
  108. Porreca F, Burks TF (1983) Affinity of normorphine for its pharmacologic receptor in the naive and morphine-tolerant guinea pig isolated ileum. J Pharmacol Exp Ther 225: 688–693PubMedGoogle Scholar
  109. Puttfarcken PS, Cox BM (1989) Morphine-induced desensitization and down- regulation at mu-receptors in 7315c pituitary tumor cells. Life Sci 45: 1937–1942PubMedGoogle Scholar
  110. Puttfarcken P, Werling LL, Brown SR, Cote TE, Cox BM (1986) Sodium regulation of agonist binding at opioid receptors. I. Effects of sodium replacement on binding to μ- and δ-type opioid receptors in 7315c and NG 108-15 cells and cell membranes. Mol Pharmacol 30: 81–89PubMedGoogle Scholar
  111. Puttfarcken PS, Werling LL, Cox BM (1988) Effects of chronic morphine exposure on opioid inhibition of adenylyl cyclase in 7315c cell membranes: a useful model for the study of tolerance at μ opioid receptors. Mol Pharmacol 33: 520–527PubMedGoogle Scholar
  112. Rasmussen K, Aghajanian GK (1989) Withdrawal-induced activation of locus coeruleus neurons in opiate-dependent rats: attentuation by lesions of the nucleus paragigantocellularis. Brain Res 505: 346–350PubMedGoogle Scholar
  113. Rasmussen K, Beitner-Johnson DB, Krystal JH, Aghajanian GK, Nestler EJ (1990) Opiate withdrawal and the rat locus coeruleus: behavioral, electrophsiological and biochemical correlates. J Neurosci 10: 2308–2317PubMedGoogle Scholar
  114. Robson LE, Foote RW, Maurer R, Kosterlitz HW (1984) Opioid binding sites of the κ-type in guinea pig cerebellum. Neuroscience 12: 621–627PubMedGoogle Scholar
  115. Rodbell M (1980) The role of hormone receptors and GTP-regulatory proteins in membrane transduction. Nature 284: 17–22PubMedGoogle Scholar
  116. Rodbell M, Lin MC, Salomon Y (1974) Evidence for interdependent action of glucagon and nucleotides of the hepatic adenylate cyclase system. J Biol Chem 249: 59 - 65PubMedGoogle Scholar
  117. Roth RL, Laskowski MB, Coscia CJ (1981) Evidence for distinct subcellular sites of opiate receptors: demonstration of opiate receptors in smooth microsomal fractions isolated from rat brain. J Biol Chem 256: 10117–10123Google Scholar
  118. Rothman RB, Danks JA, Jacobson AE, Burke TR Jr, Rice KC, Tortella FC, Holaday JW (1986) Morphine tolerance increases μ-non-competitive δ binding sites. Eur J Pharmacol 124: 113–119PubMedGoogle Scholar
  119. Pothman RB, Bykov V, de Costa BR, Jacobson AE, Rice KC, Brady LS (1990) Interaction of endogenous opioid peptides and other drugs with four kappa opioid binding sites in guinea pig brain. Peptides 11: 311–331Google Scholar
  120. Scheideler MA, Zukin RS (1990) Reconstitution of solubilized delta-opiate receptor binding sites in lipid vesicles. J Biol Chem 265: 15176–15182PubMedGoogle Scholar
  121. Schulz R, Herz A (1976) Aspects of opiate dependence in the myenteric plexus of the guinea pig. Life Sci 19: 1117–1128PubMedGoogle Scholar
  122. Schulz R, Wüster M, Herz A (1980) Pharmacological characterization of the epsilon sopiate receptor. J Pharmacol Exp Ther 216: 604–606Google Scholar
  123. Sharma SK, Klee WA, Nirenberg M (1975) Dual regulation of adenylate cycclase accounts for narcotic dependence and tolerance. Proc Natl Acad Sci USA 72: 3092–3096PubMedGoogle Scholar
  124. Sharma SK, Klee WA, Nirenberg M (1977) Opiate-dependent modulation of adenylate cyclase. Proc Natl Acad Sci USA 74: 3365–3369PubMedGoogle Scholar
  125. Shen K-F, Crain SM (1989) Dual opioid modulation of the action potential duration of mouse dorsal root ganglion neurons in culture. Brain Res 491: 227–242PubMedGoogle Scholar
  126. Shen K-F, Crain SM (1990a) Cholera toxin-A subunit blocks opioid excitatory effects on sensory neuron action potentials indicating mediation by Gs-linked opioid receptors. Brain Res 525: 225–231PubMedGoogle Scholar
  127. Shen K-F, Crain SM (1990b) Cholera toxin-B subunit blocks opioid excitatory effects on sensory neuron action potentials indicating that GM1 ganglioside may regulate Gs-linked opioid receptor functions. Brain Res 531: 1–7PubMedGoogle Scholar
  128. Simon EJ, Hiller JM, Edelman I (1973) Stereospecific binding of the potent narcotic analgesic [3H]etorphine to rat brain homogenate. Proc Natl Acad Si USA 70: 1947–1949Google Scholar
  129. Smith JAM, Hunter JC, Hill RG, Hughes J (1989) A kinetic analysis of K-opioid agonist binding using the selective radioligand [3H]U69593. J Neurochem 53: 27–36PubMedGoogle Scholar
  130. Spain JW, Coscia CJ (1987) Multiple interconvertible affinity states for the δ opioid agonist receptor complex. J Biol Chem 262: 8948–8951PubMedGoogle Scholar
  131. Steece KA, DeLeon-Jones FA, Meyerson LR, Lee JM, Fields JZ, Ritzman RF (1986) In vivo down-regulation of rat striatal opioid receptors by chronic enkephalin. Brain Res Bull 17: 255–257PubMedGoogle Scholar
  132. Sullivan KA, Miller RT, Masters SB, Beidermann B, Heidman W, Bourne HR (1987) Identification of receptor contact site involved in receptor-G protein coupling. Nature 330: 758–762PubMedGoogle Scholar
  133. Tao P-L, Chang L-R, Law PY, Loh HH (1988) Decrease in δ-receptor density in rat brain after chronic [D-Ala2, D-Leu5]enkephalin treatment. Brain Res 462: 313–320PubMedGoogle Scholar
  134. Tao P-L, Lee H-Y, Chang L-R, Loh HH (1990) Decrease in μ-opioid receptor binding capacity in rat brain after chronic PL017 treatment. Brain Res 526: 270–275PubMedGoogle Scholar
  135. Tempel A, Crain SM, Peterson ER, Simon EJ, Zukin RS (1986) Antagonist-induced opiate receptor upregulation in cultures of fetal mouse spinal cord-ganglion explants. Dev Brain Res 25: 287–291Google Scholar
  136. Tempel A, Habas JE, Paredes W, Barr GA (1988) Morphine-induced down- regulation of μ-opioid receptors in neonatal rat brain. Dev Brain Res 41: 129–133Google Scholar
  137. Terwilliger R, Beitner-Johnson D, Sevarino KA, Crain SM, Nestler EJ (1991) A general model for adaptations in G proteins and the cyclic AMP system in mediating the chronic actions of morphine and cocaine on neuronal function. Brain Res 548: 100–110PubMedGoogle Scholar
  138. Thomas JM, Vagelos R, Hoffman BB (1990) Decreased cyclic AMP degradation in NG 108-15 neuroblastoma X glioma hybrid cells and S49 lymphoma cells chronically treated with drugs that inhibit adenylate cyclase. J Neurochem 54: 402–410PubMedGoogle Scholar
  139. Tiberi M, Magnan J (1990) Quantitative analysis of multiple K-opioid receptors by selective and non-selective ligand binding in guinea pig spinal cord: resolution of high and low affinity states of the κ2 receptors by a computerized model-fitting technique. Mol Pharmacol 37: 694–703PubMedGoogle Scholar
  140. Tucker JF (1984) Effects of pertussis toxin on normorphine dependence and on acute inhibitory effects of normorphine and clonidine in guinea pig isolated ileum. Br J Pharmacol 83: 326–328PubMedGoogle Scholar
  141. Tung C-S, Grenhoff J, Svennson TH (1990) Morphine withdrawal responses of rat locus coeruleus neurons are blocked by an excitatory amino acid antagonist. Acta Physiol Scand 138: 581–582PubMedGoogle Scholar
  142. Ueda H, Misawa H, Fukushima N, Takagi H (1987) The specific opioid κ-agonist U50488H inhibits low Km GTPase. Eur J Pharmacol 138: 129–132PubMedGoogle Scholar
  143. Ueda H, Harada H, Nozaki M, Katada T, Ui M, Satoh M, Takagi H (1988) Reconstitution of rat brain μ opioid receptors with purified guanine nucleotide- binding regulatory proteins. Gi and GO. Proc Natl Acad Sci USA 85: 7013–7017PubMedGoogle Scholar
  144. Ueda H, Misawa H, Katada T, Ui M, Takagi H, Satoh M (1990a) Functional reconstitution of purified Gi and GO with μ-opioid receptors in guinea pig striatal membranes pretreated with micromolar concentrations of N-ethylmaleimide. J Neurochem 54: 841–848PubMedGoogle Scholar
  145. Ueda H, Uno S, Harada J, Kobayashi I, Katada T, Ui M, Satoh M (1990b) Evidence for receptor-mediated inhibition of intrinsic activity of GTP-binding protein, Gi1 and Gi2, but not GO in reconstitution experiments FEBS Lett 266: 178–182PubMedGoogle Scholar
  146. Vachon L, Costa T, Herz A (1986) Differential sensitivity of basal and opioid- stimulated low Km GTPase to guanine nucleotide analogs. J Neurochem 47: 1361–1369PubMedGoogle Scholar
  147. Vachon L, Costa T, Herz A (1987) GTPase and adenylate cyclase desensitize at different rates in NG 108-15 cells. Mol Pharmacol 31: 159–168PubMedGoogle Scholar
  148. Vogel Z, Barg J, Attali B, Simantov R (1990) Differential effect of μ, δ, and κ ligands on G protein a subunits in cultured brain cells. J Neurosci Res 27: 106–111PubMedGoogle Scholar
  149. Wang H-Y, Berrios M, Malbon CC (1989) Localization of P-adrenergic receptors in A431 cells in situ: effect,of chronic exposure to agonist. Biochem J 263: 533–538PubMedGoogle Scholar
  150. Werling LL, Brown SR, Cox BM (1984) The sensitivity of opioid receptor types to regulation by sodium and GTP. Neuropeptides 5: 137–140PubMedGoogle Scholar
  151. Werling LL, Brown SR, Puttfarcken P, Cox BM (1986) Sodium regulation of agonist binding at opioid receptors. II. Effects of sodium replacement on opioid binding in guinea pig cortical membranes. Mol Pharmacol 30: 90–95Google Scholar
  152. Werling LL, McMahon PN, Cox BM (1988a) Selective tolerance at mu and kappa opioid receptors modulating norepinephrine release in guinea pig cortex. J Pharmacol Exp Ther 247: 1103–1106PubMedGoogle Scholar
  153. Werling LL, Puttfarcken PS, Cox BM (1988b) Multiple agonist-affinity states of opioid receptors: regulation of binding by guanyl nucleotides in guinea pig cortical, NG 108-15, and 7315c cell membranes. Mol Pharmacol 33: 423–431PubMedGoogle Scholar
  154. Werling LL, McMahon PN, Cox BM (1989a) Effects of pertussis toxin on opioid regulation of catecholamine release from rat and guinea pig brain slices. Naunyn Schmiedebergs Arch Pharmacol 339: 509–513PubMedGoogle Scholar
  155. Werling LL, McMahon PN, Cox BM (1989b) Selective changes in μ opioid receptor properties induced by chronic morphine exposure. Proc Natl Acad Sci USA 86: 6393–6397PubMedGoogle Scholar
  156. Williams JT, North RA (1984) Opiate-receptor interactions on single locus coeruleus neurones. Mol Pharmacol 26: 489–497PubMedGoogle Scholar
  157. Wong YH, Demohou-Mason CD, Hanley MR, Barnard EA (1990) Agonist-selective protection of the opioid receptor-coupled G proteins from inactivation by 5’-p-fluorosulphonylbenzoyl guanosine. J Neurochem 54: 39–45PubMedGoogle Scholar
  158. Wüster M, Costa T (1984) The opioid-induced desensitization (tolerance) in neuroblastoma X glioma NG 108-15 hybrid cells: results from receptor uncoupling. NIDA Res Monogr 54: 136–145PubMedGoogle Scholar
  159. Wüster M, Costa T, Gramsch C (1983) Uncoupling of receptors is essential for opiate-induced desensitization (tolerance) in neuroblastoma X glioma hybrid cells NG 108-15. Life Sci 33 [Suppl l]: 341–344PubMedGoogle Scholar
  160. Wüster M, Costa T, Aktories K, Jacobs KH (1984) Sodium regulation of opioid agonist binding is potentiated by pertussis toxin. Biochem Biophys Res Commun 123: 1107–1115PubMedGoogle Scholar
  161. Zazac J-M, Roques B (1985) Differences in binding properties of μ and δ opioid receptor subtypes from rat brain: kinetic analysis and effects of ions and nucleotides. J Neurochem 44: 1605–1614Google Scholar
  162. Zukin RS, Gintzler AR (1980) Guanyl nucleotide interactions with opiate receptors in guinea pig brain and ileum. Brain Res 186: 486–491PubMedGoogle Scholar
  163. Zukin RS, Sugarman JR, Fitz-Syage ML, Gardner EL, Zukin SR, Gintzler AR (1982) Naltrexone-induced opiate-receptor supersensitivity. Brain Res 25: 287–291Google Scholar
  164. Zukin RS, Eghbali M, Olive D, Unterwald EM, Tempel A (1988) Characterization and visualization of rat and guinea pig brain κ opioid receptors: evidence for κ1 and κ2 opioid receptors. Proc Natl Acad Sci USA 85: 4061–4065PubMedGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 1993

Authors and Affiliations

  • B. M. Cox

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