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Psychopharmacology

, Volume 210, Issue 2, pp 137–147 | Cite as

Kinase cascades and ligand-directed signaling at the kappa opioid receptor

  • Michael R. Bruchas
  • Charles ChavkinEmail author
Review

Abstract

Background and Rationale

The dynorphin/kappa opioid receptor (KOR) system has been implicated as a critical component of the stress response. Stress-induced activation of dynorphin-KOR is well known to produce analgesia, and more recently, it has been implicated as a mediator of stress-induced responses including anxiety, depression, and reinstatement of drug seeking.

Objective

Drugs selectively targeting specific KOR signaling pathways may prove potentially useful as therapeutic treatments for mood and addiction disorders.

Results

KOR is a member of the seven transmembrane spanning (7TM) G-protein coupled receptor (GPCR) superfamily. KOR activation of pertussis toxin-sensitive G proteins leads to Gαi/o inhibition of adenylyl cyclase production of cAMP and releases Gβγ, which modulates the conductances of Ca+2 and K+ channels. In addition, KOR agonists activate kinase cascades including G-protein coupled Receptor Kinases (GRK) and members of the mitogen-activated protein kinase (MAPK) family: ERK1/2, p38 and JNK. Recent pharmacological data suggests that GPCRs exist as dynamic, multi-conformational protein complexes that can be directed by specific ligands towards distinct signaling pathways. Ligand-induced conformations of KOR that evoke β-arrestin-dependent p38 MAPK activation result in aversion; whereas ligand-induced conformations that activate JNK without activating arrestin produce long-lasting inactivation of KOR signaling.

Conclusions

In this review, we discuss the current status of KOR signal transduction research and the data that support two novel hypotheses: (1) KOR selective partial agonists that do not efficiently activate p38 MAPK may be useful analgesics without producing the dysphoric or hallucinogenic effects of selective, highly efficacious KOR agonists and (2) KOR antagonists that do not activate JNK may be effective short-acting drugs that may promote stress-resilience.

Keywords

Kappa opioid receptor Dynorphin Kinase MAPK GPCR Ligand-directed signaling p38 ERK 1/2 JNK Relapse Stress Opioid Arrestin Depression Addiction Therapeutics 

Notes

Acknowledgements

This work was supported by National Institute on Drug Abuse U.S. Public Health Service Grants DA25970, DA20570, and DA25182 and the Hope for Depression Research Foundation.

References

  1. Appleyard SM, Patterson TA, Jin W, Chavkin C (1997) Agonist-induced phosphorylation of the kappa-opioid receptor. J Neurochem 69:2012–2405Google Scholar
  2. Appleyard SM, Celver J, Pineda V, Kovoor A, Wayman GA, Chavkin C (1999) Agonist-dependent desensitization of the kappa opioid receptor by G protein receptor kinase and beta-arrestin. J Biol Chem 274:23802–23807CrossRefPubMedGoogle Scholar
  3. Ariens EJ (1954) Affinity and intrinsic activity in the theory of competitive inhibition I Problems and theory. Arch Int Pharmacodyn Ther 99:32–49PubMedGoogle Scholar
  4. Ashwell JD (2006) The many paths to p38 mitogen-activated protein kinase activation in the immune system. Nat Rev Immunol 6:532–540CrossRefPubMedGoogle Scholar
  5. Avidor-Reiss T, Nevo I, Saya D, Bayewitch M, Vogel Z (1997) Opiate-induced adenylyl cyclase superactivation is isozyme-specific. J Biol Chem 272:5040–5047CrossRefPubMedGoogle Scholar
  6. Baker SJ, Reddy EP (1998) Modulation of life and death by the TNF receptor superfamily. Oncogene 17:3261–3270CrossRefPubMedGoogle Scholar
  7. Barchfeld CC, Medzihradsky F (1984) Receptor-mediated stimulation of brain GTPase by opiates in normal and dependent rats. Biochem Biophys Res Commun 121:641–648CrossRefPubMedGoogle Scholar
  8. Beardsley PM, Howard JL, Shelton KL, Carroll FI (2005) Differential effects of the novel kappa opioid receptor antagonist, JDTic, on reinstatement of cocaine-seeking induced by footshock stressors vs cocaine primes and its antidepressant-like effects in rats. Psychopharmacology (Berl.) 183:118–126Google Scholar
  9. Belcheva MM, Vogel Z, Ignatova E, Avidor-Reiss T, Zippel R, Levy R, Young EC, Barg J, Coscia CJ (1998) Opioid modulation of extracellular signal-regulated protein kinase activity is ras-dependent and involves Gbetagamma subunits. Biochemistry 48:6898–6908Google Scholar
  10. Belcheva MM, Clark AL, Haas PD, Serna JS, Hahn JW, Kiss A, Coscia CJ (2005) Mu and kappa opioid receptors activate ERK/MAPK via different protein kinase C isoforms and secondary messengers in astrocytes. J Biol Chem 280:27662–27669CrossRefPubMedGoogle Scholar
  11. Bhargava HN, Gulati A, Ramarao P (1989) Effect of chronic administration of U-50, 488H on tolerance to its pharmacological actions and on multiple opioid receptors in rat brain regions and spinal cord. J Pharmacol Exp Ther 251:21–26PubMedGoogle Scholar
  12. Blake AD, Bot G, Freeman JC, Reisine T (1997) Differential opioid agonist regulation of the mouse mu opioid receptor. J Biol Chem 272:782–790CrossRefPubMedGoogle Scholar
  13. Bruchas MR, Macey TA, Lowe JD, Chavkin C (2006) Kappa opioid receptor activation of p38 MAPK is GRK3- and arrestin-dependent in neurons and astrocytes. J Biol Chem 281:18081–18089CrossRefPubMedGoogle Scholar
  14. Bruchas MR, Land BB, Aita M, Xu M, Barot SK, Li S, Chavkin C (2007a) Stress-induced p38 mitogen-activated protein kinase activation mediates kappa-opioid-dependent dysphoria. J Neurosci 27:11614–11623CrossRefPubMedGoogle Scholar
  15. Bruchas MR, Yang T, Schreiber S, Defino M, Kwan SC, Li S, Chavkin C (2007b) Long-acting kappa opioid antagonists disrupt receptor signaling and produce noncompetitive effects by activating c-Jun N-terminal kinase. J Biol Chem 282:29803–29811CrossRefPubMedGoogle Scholar
  16. Bruchas MR, Xu M, Chavkin C (2008) Repeated swim stress induces kappa opioid-mediated activation of extracellular signal-regulated kinase 1/2. Neuroreport 19:1417–1422CrossRefPubMedGoogle Scholar
  17. Bruchas MR, Land BB, Lemos J, Chavkin C (2009a) CRF1-R activation of the dynorphin/kappa opioid system in the mouse basolateral amygdala mediates anxiety-like behavior. PLoS One 4(12):e8528CrossRefPubMedGoogle Scholar
  18. Bruchas MR, Land BB, Chavkin C (2009b) The dynorphin/kappa opioid system as a modulator of stress-induced and pro-addictive behaviors. Brain Res 1314C:44–55Google Scholar
  19. Carlezon WA, Thome J, Olson VG, Lane-Ladd SB, Brodkin ES, Hiroi N, Duman RS, Neve RL, Nestler EJ (1998) Regulation of cocaine reward by CREB. Science 282:2272–2275Google Scholar
  20. Carlezon WA Jr, Duman RS, Nestler EJ (2005) The many faces of CREB. Trends Neurosci 28:436–445CrossRefPubMedGoogle Scholar
  21. Carroll I, Thomas JB, Dykstra LA, Granger AL, Allen RM, Howard JL, Pollard GT, Aceto MD, Harris LS (2004) Pharmacological properties of JDTic: a novel kappa-opioid receptor antagonist. Eur J Pharmacol 501:111–119CrossRefPubMedGoogle Scholar
  22. Chan AS, Yeung WW, Wong YH (2005) Integration of G protein signals by extracellular signal-regulated protein kinases in SK-N-MC neuroepithelioma cells. Cell Mol Life Sci 55:1230–1254Google Scholar
  23. Chavkin C, James IF, Goldstein A (1982) Dynorphin is a specific endogenous ligand of the kappa opioid receptor. Science 215:413–415Google Scholar
  24. Chavkin C, Sud S, Jin W, Stewart J, Zjawiony JK, Siebert DJ, Toth BA, Hufeisen SJ, Roth BL (2004) Salvinorin A, an active component of the hallucinogenic sage salvia divinorum is a highly efficacious kappa-opioid receptor agonist: structural and functional considerations. J Pharmacol Exp Ther 308:1197–1203CrossRefPubMedGoogle Scholar
  25. Chen Y, Chen C, Liu-Chen LY (2007) Dynorphin peptides differentially regulate the human kappa opioid receptor. Life Sci 80:1439–1448CrossRefPubMedGoogle Scholar
  26. Cheng ZJ, Yu QM, Wu YL, Ma L, Pei G (1998) Selective interference of beta-arrestin 1 with kappa and delta but not mu opioid receptor/G protein coupling. J Biol Chem 273:24328–24333CrossRefPubMedGoogle Scholar
  27. Childers SR, Snyder SH (1978) Guanine nucleotides differentiate agonist and antagonist interactions with opiate receptors. Life Sci 23:759–761CrossRefPubMedGoogle Scholar
  28. Clark AJ (1926) The reaction between acetyl choline and muscle cells. J Physiol 61:530–546PubMedGoogle Scholar
  29. Clayton CC, Xu M, Chavkin C (2009) Tyrosine phosphorylation of Kir3 following kappa-opioid receptor activation of p38 MAPK causes heterologous desensitization. J Biol Chem 284:31872–31881CrossRefPubMedGoogle Scholar
  30. Crain SM, Shen KF (1990) Opioids can evoke direct receptor-mediated excitatory as well as inhibitory effects on sensory neuron action potentials. NIDA Res Monogr 105:34–39PubMedGoogle Scholar
  31. Della Rocca GJ, Maudsley S, Daaka Y, Lefkowitz RJ, Luttrell LM (1999) Pleiotropic coupling of G protein-coupled receptors to the mitogen-activated protein kinase cascade Role of focal adhesions and receptor tyrosine kinases. J Biol Chem 274:13978–13984CrossRefPubMedGoogle Scholar
  32. Dhawan BN, Cesselin F, Raghubir R, Reisine T, Bradley PB, Portoghese PS, Hamon M (1996) International Union of Pharmacology. XII. Classification of opioid receptors. Pharmacol Rev 48:567–592Google Scholar
  33. Gesty-Palmer D, Chen M, Reiter E, Ahn S, Nelson CD, Wang S, Eckhardt AE, Cowan CL, Spurney RF, Luttrell LM, Lefkowitz RJ (2006) Distinct beta-arrestin- and G protein-dependent pathways for parathyroid hormone receptor-stimulated ERK1/2 activation. J Biol Chem 281:10856–10864CrossRefPubMedGoogle Scholar
  34. Grudt TJ, Williams JT (1995) Opioid receptors and the regulation of ion conductances. Rev Neurosci 6:279–286PubMedGoogle Scholar
  35. Gurwell JA, Duncan MJ, Maderspach K, Stiene-Martin A, Elde RP, Hauser KF (1996) Kappa-opioid receptor expression defines a phenotypically distinct subpopulation of astroglia: relationship to Ca2+ mobilization, development, and the antiproliferative effect of opioids. Brain Res 737:175–187CrossRefPubMedGoogle Scholar
  36. Horan P, Taylor J, Yamamura HI, Porreca F (1992) Extremely long-lasting antagonistic actions of nor-binaltorphimine (nor-BNI) in the mouse tail-flick test. J Pharmacol Exp Ther 260:1237–1243Google Scholar
  37. Hsia JA, Moss J, Hewlett EL, Vaughan M (1984) ADP-ribosylation of adenylate cyclase by pertussis toxin: effects on inhibitory agonist binding. J Biol Chem 25:1086–1090Google Scholar
  38. Hudmon A, Choi JS, Tyrrell L, Black JA, Rush AM, Waxman SG, Dib-Hajj SD (2008) Phosphorylation of sodium channel Na(v)18 by p38 mitogen-activated protein kinase increases current density in dorsal root ganglion neurons. J Neurosci 28:3190–3201CrossRefPubMedGoogle Scholar
  39. Hunton DL, Barnes WG, Kim J, Ren XR, Violin JD, Reiter E, Milligan G, Patel DD, Lefkowitz RJ (2005) Beta-arrestin 2-dependent angiotensin II type 1A receptor-mediated pathway of chemotaxis. Mol Pharmacol 67:1229–1236CrossRefPubMedGoogle Scholar
  40. Jordan BA, Cvejic S, Devi LA (2000) Kappa opioid receptor endocytosis by dynorphin peptides. DNA Cell Biol 19:19–27CrossRefPubMedGoogle Scholar
  41. Kam AY, Chan AS, Wong YH (2004) Phosphatidylinositol-3 kinase is distinctively required for mu-, but not kappa-opioid receptor-induced activation of c-Jun N-terminal kinase. J Neurochem 89:391–402CrossRefPubMedGoogle Scholar
  42. Karandikar M, Cobb MH (1999) Scaffolding and protein interactions in MAP kinase modules. Cell Calcium 26:219–226CrossRefPubMedGoogle Scholar
  43. Kenakin T (2003) Ligand-selective receptor conformations revisited: the promise and the problem. Trends Pharmacol Sci 24:346–354CrossRefPubMedGoogle Scholar
  44. Kenakin T (2007) Collateral efficacy in drug discovery: taking advantage of the good (allosteric) nature of 7TM receptors. Trends Pharmacol Sci 28:407–415CrossRefPubMedGoogle Scholar
  45. Kim E, Clark AL, Kiss A, Hahn JW, Wesselschmidt R, Coscia CJ, Belcheva MM (2006) Mu- and kappa-opioids induce the differentiation of embryonic stem cells to neural progenitors. J Biol Chem 281:33749–33760Google Scholar
  46. Knoll AT, Carlezon WA (2010) Dynorphin, stress, and depression. Brain Res 1314:56–73Google Scholar
  47. Kohout TA, Lefkowitz RJ (2003) Regulation of G protein-coupled receptor kinases and arrestins during receptor desensitization. Mol Pharmacol 63:9–18CrossRefPubMedGoogle Scholar
  48. Kreek MJ, Koob GF (1998) Drug dependence: stress and dysregulation of brain reward pathways. Drug Alcohol Depend 51:23–47Google Scholar
  49. Kreek MJ, Zhou Y, Butelman ER, Levran O (2009) Opiate and cocaine addiction: from bench to clinic and back to the bench. Curr Opin Pharmacol 9(1):74–80CrossRefPubMedGoogle Scholar
  50. Kreibich AS, Blendy JA (2004) cAMP response element-binding protein is required for stress but not cocaine-induced reinstatement. J Neurosci 24:6686–6692CrossRefPubMedGoogle Scholar
  51. Kukkonen JP, Näsman J, Rinken A, Dementjev A, Akerman KE (1998) Pseudo-noncompetitive antagonism of M1, M3, and M5 muscarinic receptor-mediated Ca2+ mobilization by muscarinic antagonists. Biochem Biophys Res Commun 243:41–46CrossRefPubMedGoogle Scholar
  52. Land BB, Bruchas MR, Lemos JC, Xu M, Melief EJ, Chavkin C (2008) The dysphoric component of stress is encoded by activation of the dynorphin kappa-opioid system. J Neurosci 28:407–414CrossRefPubMedGoogle Scholar
  53. Land BB, Bruchas MR, Schattauer S, Giardino WJ, Aita M, Messinger D, Hnasko TS, Palmiter RD, Chavkin C (2009) Activation of the kappa opioid receptor in the dorsal raphe nucleus mediates the aversive effects of stress and reinstates drug seeking. Proc Natl Acad Sci USA 106:19168–19173CrossRefPubMedGoogle Scholar
  54. Lefkowitz RJ, Shenoy SK (2005) Transduction of receptor signals by beta-arrestins. Science 308:512–517CrossRefPubMedGoogle Scholar
  55. Li JG, Luo LY, Krupnick JG, Benovic JL, Liu-Chen LY (1999) U50, 488H-induced internalization of the human kappa opioid receptor involves a beta-arrestin- and dynamin-dependent mechanism Kappa receptor internalization is not required for mitogen-activated protein kinase activation. J Biol Chem 274:12087–12094CrossRefPubMedGoogle Scholar
  56. Li J, Li JG, Chen C, Zhang F, Liu-Chen LY (2002) Molecular basis of differences in (-)(trans)-3, 4-dichloro-N-methyl-N-[2-(1-pyrrolidiny)-cyclohexyl]benzeneacetamide-induced desensitization and phosphorylation between human and rat kappa-opioid receptors expressed in Chinese hamster ovary cells. Mol Pharmacol 61:73–84CrossRefPubMedGoogle Scholar
  57. Li JG, Zhang F, Jin XL, Liu-Chen LY (2003) Differential regulation of the human kappa opioid receptor by agonists: etorphine and levorphanol reduced dynorphin A- and U50, 488H-induced internalization and phosphorylation. J Pharmacol Exp Ther 305:531–540CrossRefPubMedGoogle Scholar
  58. Liu-Chen LY (2004) Agonist-induced regulation and trafficking of kappa opioid receptors. Life Sci 75:511–536CrossRefPubMedGoogle Scholar
  59. Lopez-Ilasaca M (1998) Signaling from G-protein-coupled receptors to mitogen-activated protein (MAP)-kinase cascades. Biochem Pharmacol 56:269–277CrossRefPubMedGoogle Scholar
  60. Lozama A, Prisinzano TE (2009) Chemical methods for the synthesis and modification of neoclerodane diterpenes. Bioorg Med Chem Lett 19:5490–5495CrossRefPubMedGoogle Scholar
  61. Marinissen MJ, Gutkind JS (2001) G-protein-coupled receptors and signaling networks: emerging paradigms. Trends Pharmacol Sci 22:368–376CrossRefPubMedGoogle Scholar
  62. McDonald PH, Chow CW, Miller WE, Laporte SA, Field ME, Lin FT, Davis RJ, Lefkowitz RJ (2000) Beta-arrestin 2: a receptor-regulated MAPK scaffold for the activation of JNK3. Science 290:1574–1577CrossRefPubMedGoogle Scholar
  63. McLaughlin JP, Marton-Popovici M, Chavkin C (2003a) Kappa opioid receptor antagonism and prodynorphin gene disruption block stress-induced behavioral responses. J Neurosci 23:5674–5683PubMedGoogle Scholar
  64. McLaughlin JP, Xu M, Mackie K, Chavkin C (2003b) Phosphorylation of a carboxyl-terminal serine within the kappa-opioid receptor produces desensitization and internalization. J Biol Chem 278:34631–34640CrossRefPubMedGoogle Scholar
  65. McLaughlin JP, Myers LC, Zarek PE, Caron MG, Lefkowitz RJ, Czyzyk TA, Pintar JE, Chavkin C (2004) Prolonged kappa opioid receptor phosphorylation mediated by G-protein receptor kinase underlies sustained analgesic tolerance. J Biol Chem 279:1810–1818CrossRefPubMedGoogle Scholar
  66. McLaughlin JP, Li S, Valdez J, Chavkin TA, Chavkin C (2006) Social defeat stress-induced behavioral responses are mediated by the endogenous kappa opioid system. Neuropsychopharmacology 31:1241–1248Google Scholar
  67. McLennan GP, Kiss A, Miyatake M, Belcheva MM, Chambers KT, Pozek JJ, Mohabbat Y, Moyer RA, Bohn LM, Coscia CJ (2008) Kappa opioids promote the proliferation of astrocytes via Gbetagamma and beta-arrestin 2-dependent MAPK-mediated pathways. J Neurochem 107:1753–1765CrossRefPubMedGoogle Scholar
  68. Minden A, Karin M (1998) Regulation and function of the JNK subgroup of MAP kinases. Biochim Biophys Acta 1333:F85–F104Google Scholar
  69. Minneman KP, Iversen IL (1976) Enkephalin and opiate narcotics increase cyclic GMP accumulation in slices of rat neostriatum. Nature 262:313–314CrossRefPubMedGoogle Scholar
  70. Negus SS, Mello NK, Linsenmayer DC, Jones RM, Portoghese PS (2002) Kappa opioid antagonist effects of the novel kappa antagonist 5′-guanidinonaltrindole (GNTI) in an assay of schedule-controlled behavior in rhesus monkeys. Psychopharmacology (Berl) 163:412–419CrossRefGoogle Scholar
  71. Nobes C, Hall A (1994) Regulation and function of the Rho subfamily of small GTPases. Curr Opin Genet Dev 4:77–81CrossRefPubMedGoogle Scholar
  72. Pan ZZ (2003) Kappa-opioid receptor-mediated enhancement of the hyperpolarization-activated current (I(h)) through mobilization of intracellular calcium in rat nucleus raphe magnus. J Physiol 548:765–775CrossRefPubMedGoogle Scholar
  73. Perez DM, Karnik SS (2005) Multiple signaling states of G-protein-coupled receptors. Pharmacol Rev 57:147–161CrossRefPubMedGoogle Scholar
  74. Pfeiffer A, Brantl V, Herz A, Emrich HM (1986) Psychotomimesis mediated by kappa opiate receptors. Science 233:774–776CrossRefPubMedGoogle Scholar
  75. Pierce KL, Lefkowitz RJ (2001) Classical and new roles of beta-arrestins in the regulation of G-protein-coupled receptors. Nat Rev Neurosci 2:727–733CrossRefPubMedGoogle Scholar
  76. Pierce KL, Tohgo A, Ahn S, Field ME, Luttrell LM, Lefkowitz RJ (2001) Epidermal growth factor (EGF) receptor-dependent ERK activation by G protein-coupled receptors: a co-culture system for identifying intermediates upstream and downstream of heparin-binding EGF shedding. J Biol Chem 276:23155–23160CrossRefPubMedGoogle Scholar
  77. Piñeyro G (2009) Membrane signalling complexes: implications for development of functionally selective ligands modulating heptahelical receptor signalling. Cell Signal 21:179–185CrossRefPubMedGoogle Scholar
  78. Prasad HC, Zhu CB, McCauley JL, Samuvel DJ, Ramamoorthy S, Shelton RC, Hewlett WA, Sutcliffe JS, Blakely RD (2005) Human serotonin transporter variants display altered sensitivity to protein kinase G and p38 mitogen-activated protein kinase. Proc Natl Acad Sci U S A 102:11545–11550CrossRefPubMedGoogle Scholar
  79. Raman M, Chen W, Cobb MH (2007) Differential regulation and properties of MAPKs. Oncogene 26:3100–3112CrossRefPubMedGoogle Scholar
  80. Raynor K, Kong H, Hines J, Kong G, Benovic J, Yasuda K, Bell GI, Reisine T (1994) Molecular mechanisms of agonist-induced desensitization of the cloned mouse kappa opioid receptor. J Pharmacol Exp Ther 270:1381–1386PubMedGoogle Scholar
  81. Redila VA, Chavkin C (2008) Stress-induced reinstatement of cocaine seeking is mediated by the kappa opioid system. Psychopharmacology (Berl.) 200:59–70Google Scholar
  82. Rockman MV, Hahn MW, Soranzo N, Zimprich F, Goldstein DB, Wray G (2005) Ancient and recent positive selection transformed opioid cis-regulation in humans. PLoS Biol 3:e387CrossRefPubMedGoogle Scholar
  83. Roth BL, Baner K, Westkaemper R, Siebert D, Rice KC, Steinberg S, Ernsberger P, Rothman RB (2002) Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist. Proc Natl Acad Sci U S A 99:11934–11939CrossRefPubMedGoogle Scholar
  84. Rumbaugh G, Adams JP, Kim JH (2006) Huganir RL (2006) SynGAP regulates synaptic strength and mitogen-activated protein kinases in cultured neurons. Proc Natl Acad Sci U S A 103:4344–4351CrossRefPubMedGoogle Scholar
  85. Rusin KI, Giovannucci DR, Stuenkel EL, Moises HC (1997) Kappa-opioid receptor activation modulates Ca2+ currents and secretion in isolated neuroendocrine nerve terminals. J Neurosci 17:6565–6574PubMedGoogle Scholar
  86. Sadja R, Alagem N, Reuveny E (2003) Gating of GIRK channels: details of an intricate, membrane-delimited signaling complex. Neuron 39:9–12CrossRefPubMedGoogle Scholar
  87. Samuvel DJ, Jayanthi LD, Bhat NR, Ramamoorthy S (2005) A role for p38 mitogen-activated protein kinase in the regulation of the serotonin transporter: evidence for distinct cellular mechanisms involved in transporter surface expression. J Neurosci 25:29–41CrossRefPubMedGoogle Scholar
  88. Shahabi NA, McAllen K, Sharp BM (2006) delta opioid receptors stimulate Akt-dependent phosphorylation of c-jun in T cells. J Pharmacol Exp Ther 316:933–939CrossRefPubMedGoogle Scholar
  89. Smith C, Rahman T, Toohey N, Mazurkiewicz J, Herrick-Davis K, Teitler M (2006) Risperidone irreversibly binds to and inactivates the h5-HT7 serotonin receptor. Mol Pharmacol 70:1264–1270CrossRefPubMedGoogle Scholar
  90. Song X, Coffa S, Fu H, Gurevich VV (2009) How does arrestin assemble MAPKs into a signaling complex? J Biol Chem 284:685–695CrossRefPubMedGoogle Scholar
  91. Spencer RJ, Jin W, Thayer SA, Chakrabarti S, Law PY, Loh HH (1997) Mobilization of Ca2+ from intracellular stores in transfected neuro2a cells by activation of multiple opioid receptor subtypes. Biochem Pharmacol 7:809–818CrossRefGoogle Scholar
  92. Steiner JA, Carneiro AM, Blakely RD (2008) Going with the flow: trafficking-dependent and -independent regulation of serotonin transport. Traffic 9:1393–1402CrossRefPubMedGoogle Scholar
  93. Stephenson RP (1956) A modification of receptor theory. Br J Pharmacol 11:379–393Google Scholar
  94. Stiene-Martin A, Mattson MP, Hauser KF (1993) Opiates selectively increase intracellular calcium in developing type-1 astrocytes: role of calcium in morphine-induced morphologic differentiation. Brain Res Dev Brain Res 76:189–196CrossRefPubMedGoogle Scholar
  95. Sweatt JD (2004) Mitogen-activated protein kinases in synaptic plasticity and memory. Curr Opin Neurobiol 14:311–317CrossRefPubMedGoogle Scholar
  96. Taussig R, Iñiguez-Lluhi JA, Gilman AG (1993) Inhibition of adenylyl cyclase by Gi alpha. Science 261:218–221CrossRefPubMedGoogle Scholar
  97. Thomas GM, Huganir RL (2004) MAPK cascade signalling and synaptic plasticity. Nat Rev Neurosci 5:173–183CrossRefPubMedGoogle Scholar
  98. Tibbles LA, Woodgett JR (1999) The stress-activated protein kinase pathways. Trends Neurosci 28:436–445Google Scholar
  99. Urban JD, Clarke WP, von Zastrow M, Nichols DE, Kobilka B, Weinstein H, Javitch JA, Roth BL, Christopoulos A, Sexton PM, Miller KJ, Spedding M, Mailman RB (2007) Functional selectivity and classical concepts of quantitative pharmacology. J Pharmacol Exp Ther 320:1–13CrossRefPubMedGoogle Scholar
  100. Violin JD, Lefkowitz RJ (2007) Beta-arrestin-biased ligands at seven transmembrane receptors. Trends Pharmacol Sci 28:416–422CrossRefPubMedGoogle Scholar
  101. Walker BM, Koob GF (2008) Pharmacological evidence for a motivational role of kappa-opioid systems in ethanol dependence. Neuropsychopharmacology 33:643–652CrossRefPubMedGoogle Scholar
  102. Wang Y, Tang K, Inan S, Siebert D, Holzgrabe U, Lee DY, Huang P, Li JG, Cowan A, Liu-Chen LY (2005) Comparison of pharmacological activities of three distinct kappa ligands (Salvinorin A, TRK-820 and 3FLB) on kappa opioid receptors in vitro and their antipruritic and antinociceptive activities in vivo. J Pharmacol Exp Ther 312:220–230CrossRefPubMedGoogle Scholar
  103. Wang Y, Chen Y, Xu W, Lee DY, Ma Z, Rawls SM, Cowan A, Liu-Chen LY (2008) 2-Methoxymethyl-salvinorin B is a potent kappa opioid receptor agonist with longer lasting action in vivo than salvinorin A. J Pharmacol Exp Ther 324:1073–1083CrossRefPubMedGoogle Scholar
  104. Watkins LR, Milligan ED, Maier SF (2001) Glial activation: a driving force for pathological pain. Trends Neurosci 24:450–455CrossRefPubMedGoogle Scholar
  105. Wickman KD, Clapham DE (1995) G-protein regulation of ion channels. Curr Opin Neurobiol 5(3):278–285CrossRefPubMedGoogle Scholar
  106. Xu M, Bruchas MR, Ippolito DL, Gendron L, Chavkin C (2007) Sciatic nerve ligation-induced proliferation of spinal cord astrocytes is mediated by kappa opioid activation of p38 mitogen-activated protein kinase J Neurosci 27:2570–2581CrossRefPubMedGoogle Scholar
  107. Yan F, Bikbulatov RV, Mocanu V, Dicheva N, Parker CE, Wetsel WC, Mosier PD, Westkaemper RB, Allen JA, Zjawiony JK, Roth BL (2009) Structure-based design, synthesis, and biochemical and pharmacological characterization of novel salvinorin A analogues as active state probes of the kappa-opioid receptor. Biochemistry 48:6898–6908CrossRefPubMedGoogle Scholar
  108. Zhu CB, Carneiro AM, Dostmann WR, Hewlett WA, Blakely RD (2005) p38 MAPK activation elevates serotonin transport activity via a trafficking-independent, protein phosphatase 2A-dependent process. J Biol Chem 280:15649–15658CrossRefPubMedGoogle Scholar
  109. Zhuang ZY, Wen YR, Zhang DR, Borsello T, Bonny C, Strichartz GR, Decosterd I, Ji RR (2006) A peptide c-Jun N-terminal kinase (JNK) inhibitor blocks mechanical allodynia after spinal nerve ligation: respective roles of JNK activation in primary sensory neurons and spinal astrocytes for neuropathic pain development and maintenance. J Neurosci 26:3551–3560CrossRefPubMedGoogle Scholar

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© Springer-Verlag 2010

Authors and Affiliations

  1. 1.Department of PharmacologyUniversity of WashingtonSeattleUSA

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