Cannabinoid Receptor Signaling

  • A. C. Howlett
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 168)


The cannabinoid receptor family currently includes twotypes:CB1, characterized in neuronal cells and brain, and CB2, characterized in immune cells and tissues. CB1 and CB2 receptors are members of the superfamily of seven-transmembrane-spanning (7-TM) receptors, having a protein structure defined by an array of seven membrane-spanning helices with intervening intracellular loops and a C-terminal domain that can associate with G proteins. Cannabinoid receptors are associated with G proteins of the Gi/o family (Gi1,2 and 3, and Go1 and 2). Signal transduction via Gi inhibits adenylyl cyclase in most tissues and cells, although signaling via Gs stimulates adenylyl cyclase in some experimental models. Evidence exists for cannabinoid receptor-mediated Ca2+ fluxes and stimulation of phospholipases A and C. Stimulation of CB1 and CB2 cannabinoid receptors leads to phosphorylation and activation of p42/p44 mitogen-activated protein kinase (MAPK), p38 MAPK and Jun N-terminal kinase (JNK) as signaling pathways to regulate nuclear transcription factors. The CB1 receptor regulates K+ and Ca2+ ion channels, probably via Go. Ion channel regulation serves as an important component of neurotransmission modulation by endogenous cannabinoid compounds released in response to neuronal depolarization. Cannabinoid receptor signaling via G proteins results from interactions with the second, third and fourth intracellular loops of the receptor. Desensitization of signal transduction pathways that couple through the G proteins probably entails phosphorylation of critical amino acid residues on these intracellular surfaces.


Adenylyl cyclase Aminoalkylindole Anandamide Ca2+ Cannabinoid Cyclic AMP Depolarization suppression of inhibition or excitation Desensitization Endocannabinoid G proteins Ion channels Mitogen activated protein kinases Neurotransmission Nitric oxide Serine/threonine kinases Seven-transmembrane spanning receptors Synaptic plasticity Tyrosine kinases 


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  1. Abadji V, Lucas-Lenard JM, Chin C, Kendall DA (1999) Involvement of the carboxyl terminus of the third intracellular loop of the cannabinoid CB1 receptor in constitutive activation of Gs. J Neurochem 72:2032–2038PubMedCrossRefGoogle Scholar
  2. Abood ME, Sauss C, Fan F, Tilton CL, Martin BR (1993) Development of behavioral tolerance to delta 9-THC without alteration of cannabinoid receptor binding or mRNA levels in whole brain. Pharmacol Biochem Behav 46:575–579PubMedCrossRefGoogle Scholar
  3. Alger BE (2002) Retrograde signaling in the regulation of synaptic transmission: focus on endocannabinoids. Prog Neurobiol 68:247–286PubMedGoogle Scholar
  4. Alger BE, Pitler TA, Wagner JJ, Martin LA, Morishita W, Kirov SA, Lenz RA (1996) Retrograde signalling in depolarization-induced suppression of inhibition in rat hippocampal CA1 cells. J Physiol 496:197–209PubMedGoogle Scholar
  5. Azad SC, Marsicano G, Eberlein I, Putzke J, Zieglgansberger W, Spanagel R, Lutz B (2001) Differential role of the nitric oxide pathway on delta(9)-THC-induced central nervous system effects in the mouse. Eur J Neurosci 13:561–568PubMedCrossRefGoogle Scholar
  6. Barth F, Rinaldi-Carmona M (1999) The development of cannabinoid antagonists. Curr Med Chem 6:745–755PubMedGoogle Scholar
  7. Bash R, Rubovitch V, Gafni M, Sarne Y (2003) The stimulatory effect of cannabinoids on calcium uptake is mediated by Gs GTP-binding proteins and cAMP formation. Neurosignals 12:39–44PubMedCrossRefGoogle Scholar
  8. Beau FE, Alger BE (1998) Transient suppression of GABA-A-receptor-mediated IPSPs after epileptiform burst discharges in CB1 pyramidal cells. J Neurophysiol 79:659–669PubMedGoogle Scholar
  9. Bidaut-Russell M, Howlett AC (1991) Cannabinoid receptor-regulated cyclic AMP accumulation in the rat striatum. J Neurochem 57:1769–1773PubMedGoogle Scholar
  10. Bisogno T, Maccarrone M, De Petrocellis L, Jarrahian A, Finazzi-Agro A, Hillard C, Di Marzo, V (2001) The uptake by cells of 2-arachidonoylglycerol, an endogenous agonist of cannabinoid receptors. Eur J Biochem 268:1982–1989PubMedCrossRefGoogle Scholar
  11. Bonhaus DW, Chang LK, Kwan J, Martin GR (1998) Dual activation and inhibition of adenylyl cyclase by cannabinoid receptor agonists: evidence for agonist-specific trafficking of intracellular responses. J Pharmacol Exp Ther 287:884–888PubMedGoogle Scholar
  12. Bouaboula M, Bourrie B, Rinaldi-Carmona M, Shire D, Le Fur G, Casellas P (1995a) Stimulation of cannabinoid receptor CB1 induces krox-24 expression in human astrocytoma cells. J Biol Chem 270:13973–13980PubMedGoogle Scholar
  13. Bouaboula M, Poinot-Chazel C, Bourrie B, Canat X, Calandra B, Rinaldi-Carmona M, Le Fur G, Casellas P (1995b) Activation of mitogen-activated protein kinases by stimulation of the central cannabinoid receptor CB1. Biochem J 312:637–641PubMedGoogle Scholar
  14. Bouaboula M, Poinot-Chazel C, Marchand J, Canat X, Bourrie B, Rinaldi-Carmona M, Calandra B, Le Fur G, Casellas P (1996) Signaling pathway associated with stimulation of CB2 peripheral cannabinoid receptor. Involvement of both mitogen-activated protein kinase and induction of Krox-24 expression. Eur J Biochem 237:704–711PubMedCrossRefGoogle Scholar
  15. Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, Vogt LJ, Sim-Selley LJ (1999) Chronic delta9-tetrahydrocannabinol treatment produces a time-dependent loss of cannabinoid receptors and cannabinoid receptor-activated G proteins in rat brain. J Neurochem 73:2447–2459PubMedCrossRefGoogle Scholar
  16. Breivogel CS, Walker JM, Huang SM, Roy MB, Childers SR (2004) Cannabinoid signaling in rat cerebellar granule cells: G-protein activation, inhibition of glutamate release and endogenous cannabinoids. Neuropharmacology 47:81–91PubMedCrossRefGoogle Scholar
  17. Brenowitz SD, Regehr WG (2003) Calcium dependence of retrograde inhibition by endocannabinoids at synapses onto Purkinje cells. J Neurosci 23:6373–6384PubMedGoogle Scholar
  18. Burstein S (1991) Cannabinoid induced changes in eicosanoid synthesis by mouse peritoneal cells. Adv Exp Med Biol 288:107–112PubMedGoogle Scholar
  19. Burstein S, Hunter SA, Latham V, Mechoulam R, Melchior DL, Renzulli L, Tefft RE Jr (1986) Prostaglandins and cannabis XV. Comparison of enantiomeric cannabinoids in stimulating prostaglandin synthesis in fibroblasts. Life Sci 39:1813–1823PubMedCrossRefGoogle Scholar
  20. Burstein S, Budrow J, Debatis M, Hunter SA, Subramanian A (1994) Phospholipase participation in cannabinoid-induced release of free arachidonic acid. Biochem Pharmacol 48:1253–1264PubMedCrossRefGoogle Scholar
  21. Cabral GA, Harmon KN, Carlisle SJ (2001) Cannabinoid-mediated inhibition of inducible nitric oxide production by rat microglial cells: evidence for CB1 receptor participation. Adv Exp Med Biol 493:207–214PubMedGoogle Scholar
  22. Carrier EJ, Kearn CS, Barkmeier AJ, Breese NM, Yang W, Nithipatikom K, Pfister SL, Campbell WB, Hillard CJ (2004) Cultured rat microglial cells synthesize the endocannabinoid 2-arachidonylglycerol, which increases proliferation via a CB2 receptor-dependent mechanism. Mol Pharmacol 65:999–1007PubMedCrossRefGoogle Scholar
  23. Caulfield MP, Brown DA (1992) Cannabinoid receptor agonists inhibit Ca current in NG108-15 neuroblastoma cells via a pertussis toxin-sensitive mechanism. Br J Pharmacol 106:231–232PubMedGoogle Scholar
  24. Childers SR, Deadwyler SA (1996) Role of cyclic AMP in the actions of cannabinoid receptors. Biochem Pharmacol 52:819–827PubMedCrossRefGoogle Scholar
  25. Childers SR, Sexton T, Roy MB (1994) Effects of anandamide on cannabinoid receptors in rat brain membranes. Biochem Pharmacol 47:711–715PubMedCrossRefGoogle Scholar
  26. Compton DR, Gold LH, Ward SJ, Balster RL, Martin BR (1992) Aminoalkylindole analogs: cannabimimetic activity of a class of compounds structurally distinct from delta 9-tetrahydrocannabinol. J Pharmacol Exp Ther 263:1118–1126PubMedGoogle Scholar
  27. Daniel H, Rancillac A, Crepel F (2004) Mechanisms underlying cannabinoid inhibition of presynaptic Ca2+ influx at parallel fibre synapses of the rat cerebellum. J Physiol 557:159–174PubMedCrossRefGoogle Scholar
  28. Davis MI, Ronesi J, Lovinger DM (2003) A predominant role for inhibition of the adenylate cyclase/protein kinase A pathway in ERK activation by cannabinoid receptor 1 in N1E-115 neuroblastoma cells. J Biol Chem 278:48973–48980PubMedGoogle Scholar
  29. De Petrocellis L, Bisogno T, Maccarrone M, Davis JB, Finazzi-Agro A, Di Marzo V (2001) The activity of anandamide at vanilloid VR1 receptors requires facilitated transport across the cell membrane and is limited by intracellular metabolism. J Biol Chem 276:12856–12863PubMedGoogle Scholar
  30. Deadwyler SA, Hampson RE, Mu J, Whyte A, Childers S (1995) Cannabinoids modulate voltage sensitive potassium A-current in hippocampal neurons via a cAMP-dependent process. J Pharmacol Exp Ther 273:734–743PubMedGoogle Scholar
  31. Derkinderen P, Toutant M, Burgaya F, Le Bert M, Siciliano JC, de F, V, Gelman M, Girault JA (1996) Regulation of a neuronal form of focal adhesion kinase by anandamide. Science 273:1719–1722PubMedGoogle Scholar
  32. Derkinderen P, Ledent C, Parmentier M, Girault JA (2001a) Cannabinoids activate p38 mitogen-activated protein kinases through CB1 receptors in hippocampus. J Neurochem 77:957–960PubMedCrossRefGoogle Scholar
  33. Derkinderen P, Toutant M, Kadare G, Ledent C, Parmentier M, Girault JA (2001b) Dual role of Fyn in the regulation of FAK+6,7 by cannabinoids in hippocampus. J Biol Chem 276:38289–38296PubMedGoogle Scholar
  34. Derkinderen P, Valjent E, Toutant M, Corvol JC, Enslen H, Ledent C, Trzaskos J, Caboche J, Girault JA (2003) Regulation of extracellular signal-regulated kinase by cannabinoids in hippocampus. J Neurosci 23:2371–2382PubMedGoogle Scholar
  35. Derocq JM, Jbilo O, Bouaboula M, Segui M, Clere C, Casellas P (2000) Genomic and functional changes induced by the activation of the peripheral cannabinoid receptor CB2 in the promyelocytic cells HL-60. Possible involvement of the CB2 receptor in cell differentiation. J Biol Chem 275:15621–15628PubMedCrossRefGoogle Scholar
  36. Devane WA, Dysarz FA, III, Johnson MR, Melvin LS, Howlett AC (1988) Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol 34:605–613PubMedGoogle Scholar
  37. Di Marzo V, Bisogno T, De Petrocellis L, Melck D, Martin BR (1999) Cannabimimetic fatty acid derivatives: the anandamide family and other endocannabinoids. Curr Med Chem 6:721–744PubMedGoogle Scholar
  38. Dill JA, Howlett AC (1988) Regulation of adenylate cyclase by chronic exposure to cannabimimetic drugs. J Pharmacol Exp Ther 244:1157–1163PubMedGoogle Scholar
  39. Eisinger DA, Ammer H, Schulz R (2002) Chronic morphine treatment inhibits opioid receptor desensitization and internalization. J Neurosci 22:10192–10200PubMedGoogle Scholar
  40. Esposito G, Ligresti A, Izzo AA, Bisogno T, Ruvo M, Di Rosa M, Di Marzo V, Iuvone T (2002) The endocannabinoid system protects rat glioma cells against HIV-1 Tat protein-induced cytotoxicity. Mechanism and regulation. J Biol Chem 277:50348–50354PubMedCrossRefGoogle Scholar
  41. Fan F, Tao Q, Abood M, Martin BR (1996) Cannabinoid receptor down-regulation without alteration of the inhibitory effect of CP 55,940 on adenylyl cyclase in the cerebellum of CP 55,940-tolerant mice. Brain Res 706:13–20PubMedCrossRefGoogle Scholar
  42. Faubert Kaplan BL, Kaminski NE (2003) Cannabinoids inhibit the activation of ERK MAPK in PMA/Io-stimulated mouse splenocytes. Int Immunopharmacol 3:1503–1510PubMedGoogle Scholar
  43. Felder CC, Veluz JS, Williams HL, Briley EM, Matsuda LA (1992) Cannabinoid agonists stimulate both receptor-and non-receptor-mediated signal transduction pathways in cells transfected with and expressing cannabinoid receptor clones. Mol Pharmacol 42:838–845PubMedGoogle Scholar
  44. Felder CC, Briley EM, Axelrod J, Simpson JT, Mackie K, Devane WA (1993) Anandamide, an endogenous cannabimimetic eicosanoid, binds to the cloned human cannabinoid receptor and stimulates receptor-mediated signal transduction. Proc Natl Acad Sci U S A 90:7656–7660PubMedGoogle Scholar
  45. Felder CC, Joyce KE, Briley EM, Mansouri J, Mackie K, Blond O, Lai Y, Ma AL, Mitchell RL (1995) Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors. Mol Pharmacol 48:443–450PubMedGoogle Scholar
  46. Felder CC, Joyce KE, Briley EM, Glass M, Mackie KP, Fahey KJ, Cullinan GJ, Hunden DC, Johnson DW, Chaney MO, Koppel GA, Brownstein M (1998) LY320135, a novel cannabinoid CB1 receptor antagonist, unmasks coupling of the CB1 receptor to stimulation of cAMP accumulation. J Pharmacol Exp Ther 284:291–297PubMedGoogle Scholar
  47. Fimiani C, Liberty T, Aquirre AJ, Amin I, Ali N, Stefano GB (1999a) Opiate, cannabinoid, and eicosanoid signaling converges on common intracellular pathways nitric oxide coupling. Prostaglandins Other Lipid Mediat 57:23–34PubMedGoogle Scholar
  48. Fimiani C, Mattocks D, Cavani F, Salzet M, Deutsch DG, Pryor S, Bilfinger TV, Stefano GB (1999b) Morphine and anandamide stimulate intracellular calcium transients in human arterial endothelial cells: coupling to nitric oxide release. Cell Signal 11:189–193PubMedCrossRefGoogle Scholar
  49. Freund TF, Katona I, Piomelli D (2003) Role of endogenous cannabinoids in synaptic signaling. Physiol Rev 83:1017–1066PubMedGoogle Scholar
  50. Galante M, Diana MA (2004) Group I metabotropic glutamate receptors inhibit GABA release at interneuron-Purkinje cell synapses through endocannabinoid production. J Neurosci 24:4865–4874PubMedCrossRefGoogle Scholar
  51. Galve-Roperh I, Rueda D, Gomez dP, Velasco G, Guzman M (2002) Mechanism of extracellular signal-regulated kinase activation by the CB(1) cannabinoid receptor. Mol Pharmacol 62:1385–1392PubMedCrossRefGoogle Scholar
  52. Garcia DE, Brown S, Hille B, Mackie K (1998) Protein kinase C disrupts cannabinoid actions by phosphorylation of the CB1 cannabinoid receptor. J Neurosci 18:2834–2841PubMedGoogle Scholar
  53. Gebremedhin D, Lange AR, Campbell WB, Hillard CJ, Harder DR (1999) Cannabinoid CB1 receptor of cat cerebral arterial muscle functions to inhibit L-type Ca2+ channel current. Am J Physiol 276:H2085–H2093PubMedGoogle Scholar
  54. Gerard C, Mollereau C, Vassart G, Parmentier M (1990) Nucleotide sequence of a human cannabinoid receptor cDNA. Nucleic Acids Res 18:7142PubMedGoogle Scholar
  55. Gerdeman GL, Ronesi J, Lovinger DM (2002) Postsynaptic endocannabinoid release is critical to long-term depression in the striatum. Nat Neurosci 5:446–451PubMedGoogle Scholar
  56. Giuffrida A, Beltramo M, Piomelli D (2001) Mechanisms of endocannabinoid inactivation: biochemistry and pharmacology. J Pharmacol Exp Ther 298:7–14PubMedGoogle Scholar
  57. Glass M, Felder CC (1997) Concurrent stimulation of cannabinoid CB1 and dopamine D2 receptors augments cAMP accumulation in striatal neurons: evidence for a Gs linkage to the CB1 receptor. J Neurosci 17:5327–5333PubMedGoogle Scholar
  58. Gomez del Pulgar T, Velasco G, Guzman M (2000) The CB1 cannabinoid receptor is coupled to the activation of protein kinase B/Akt.. Biochem J 347:369–373Google Scholar
  59. Gonsiorek W, Lunn C, Fan X, Narula S, Lundell D, Hipkin RW (2000) Endocannabinoid 2-arachidonyl glycerol is a full agonist through human type 2 cannabinoid receptor: antagonism by anandamide. Mol Pharmacol 57:1045–1050PubMedGoogle Scholar
  60. Guhring H, Hamza M, Sergejeva M, Ates M, Kotalla CE, Ledent C, Brune K (2002) A role for endocannabinoids in indomethacin-induced spinal antinociception. Eur J Pharmacol 454:153–163PubMedGoogle Scholar
  61. Guo J, Ikeda SR (2004) Endocannabinoids modulate N-type calcium channels and G-protein-coupled inwardly rectifying potassium channels via CB1 cannabinoid receptors heterologously expressed in mammalian neurons. Mol Pharmacol 65:665–674PubMedCrossRefGoogle Scholar
  62. Guzman M, Sanchez C (1999) Effects of cannabinoids on energy metabolism. Life Sci 65:657–664PubMedCrossRefGoogle Scholar
  63. Hampson AJ, Bornheim LM, Scanziani M, Yost CS, Gray AT, Hansen BM, Leonoudakis DJ, Bickler PE (1998) Dual effects of anandamide on NMDA receptor-mediated responses and neurotransmission. J Neurochem 70:671–676PubMedGoogle Scholar
  64. Hampson RE, Evans GJ, Mu J, Zhuang SY, King VC, Childers SR, Deadwyler SA (1995) Role of cyclic AMP dependent protein kinase in cannabinoid receptor modulation of potassium “A-current” in cultured rat hippocampal neurons. Life Sci 56:2081–2088PubMedCrossRefGoogle Scholar
  65. Hampson RE, Zhuang SY, Weiner JL, Deadwyler SA (2003) Functional significance of cannabinoid-mediated, depolarization-induced suppression of inhibition (DSI) in the hippocampus. J Neurophysiol 90:55–64PubMedGoogle Scholar
  66. Harkany T, Hartig W, Berghuis P, Dobszay MB, Zilberter Y, Edwards RH, Mackie K, Ernfors P (2003) Complementary distribution of type 1 cannabinoid receptors and vesicular glutamate transporter 3 in basal forebrain suggests input-specific retrograde signalling by cholinergic neurons. Eur J Neurosci 18:1979–1992PubMedCrossRefGoogle Scholar
  67. Henry DJ, Chavkin C (1995) Activation of inwardly rectifying potassium channels (GIRK1) by co-expressed rat brain cannabinoid receptors in Xenopus oocytes. Neurosci Lett 186:91–94PubMedCrossRefGoogle Scholar
  68. Herkenham M, Lynn AB, Little MD, Johnson MR, Melvin LS, De Costa BR, Rice KC (1990) Cannabinoid receptor localization in brain. Proc Natl Acad Sci U S A 87:1932–1936PubMedGoogle Scholar
  69. Herkenham M, Lynn AB, Johnson MR, Melvin LS, De Costa BR, Rice KC (1991) Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J Neurosci 11:563–583PubMedGoogle Scholar
  70. Hillard CJ, Bloom AS (1983) Possible role of prostaglandins in the effects of the cannabinoids on adenylate cyclase activity. Eur J Pharmacol 91:21–27PubMedCrossRefGoogle Scholar
  71. Hillard CJ, Harris RA, Bloom AS (1985) Effects of the cannabinoids on physical properties of brain membranes and phospholipid vesicles: fluorescence studies. J Pharmacol Exp Ther 232:579–588PubMedGoogle Scholar
  72. Hoffman AF, Riegel AC, Lupica CR (2003) Functional localization of cannabinoid receptors and endogenous cannabinoid production in distinct neuron populations of the hippocampus. Eur J Neurosci 18:524–534PubMedCrossRefGoogle Scholar
  73. Houston DB, Howlett AC (1998) Differential receptor-G-protein coupling evoked by dissimilar cannabinoid receptor agonists. Cell Signal 10:667–674PubMedCrossRefGoogle Scholar
  74. Howlett AC (1984) Inhibition of neuroblastoma adenylate cyclase by cannabinoid and nantradol compounds. Life Sci 35:1803–1810PubMedCrossRefGoogle Scholar
  75. Howlett AC (1985) Cannabinoid inhibition of adenylate cyclase. Biochemistry of the response in neuroblastoma cell membranes. Mol Pharmacol 27:429–436PubMedGoogle Scholar
  76. Howlett AC (1987) Cannabinoid inhibition of adenylate cyclase: relative activity of constituents and metabolites of marihuana. Neuropharmacology 26:507–512PubMedCrossRefGoogle Scholar
  77. Howlett AC (1995) Pharmacology of cannabinoid receptors. Annu Rev Pharmacol Toxicol 35:607–634PubMedCrossRefGoogle Scholar
  78. Howlett AC, Fleming RM (1984) Cannabinoid inhibition of adenylate cyclase. Pharmacology of the response in neuroblastoma cell membranes. Mol Pharmacol 26:532–538PubMedGoogle Scholar
  79. Howlett AC, Mukhopadhyay S (2000) Cellular signal transduction by anandamide and 2-arachidonoylglycerol. Chem Phys Lipids 108:53–70PubMedGoogle Scholar
  80. Howlett AC, Qualy JM, Khachatrian LL (1986) Involvement of Gi in the inhibition of adenylate cyclase by cannabimimetic drugs. Mol Pharmacol 29:307–313PubMedGoogle Scholar
  81. Howlett AC, Johnson MR, Melvin LS, Milne GM (1988) Nonclassical cannabinoid analgetics inhibit adenylate cyclase: development of a cannabinoid receptor model. Mol Pharmacol 33:297–302PubMedGoogle Scholar
  82. Howlett AC, Scott DK, Wilken GH (1989) Regulation of adenylate cyclase by cannabinoid drugs. Insights based on thermodynamic studies. Biochem Pharmacol 38:3297–3304PubMedCrossRefGoogle Scholar
  83. Howlett AC, Champion TM, Wilken GH, Mechoulam R (1990) Stereochemical effects of 11-OH-delta 8-tetrahydrocannabinol-dimethylheptyl to inhibit adenylate cyclase and bind to the cannabinoid receptor. Neuropharmacology 29:161–165PubMedCrossRefGoogle Scholar
  84. Howlett AC, Song C, Berglund BA, Wilken GH, Pigg JJ (1998) Characterization of CB1 cannabinoid receptors using receptor peptide fragments and site-directed antibodies. Mol Pharmacol 53:504–510PubMedGoogle Scholar
  85. Howlett AC, Mukhopadhyay S, Shim JY, Welsh WJ (1999) Signal transduction of eicosanoid CB1 receptor ligands. Life Sci 65:617–625PubMedCrossRefGoogle Scholar
  86. Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG (2002) International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev 54:161–202PubMedCrossRefGoogle Scholar
  87. Huang CC, Chan SH, Hsu KS (2004) 3-Morpholinylsydnonimine inhibits glutamatergic transmission in rat rostral ventrolateral medulla via peroxynitrite formation and adenosine release. Mol Pharmacol 66:492–501PubMedGoogle Scholar
  88. Jarrahian A, Watts VJ, Barker EL (2004) D2 dopamine receptors modulate Galpha-subunit coupling of the CB1 cannabinoid receptor. J Pharmacol Exp Ther 308:880–886PubMedGoogle Scholar
  89. Jeon YJ, Yang KH, Pulaski JT, Kaminski NE (1996) Attenuation of inducible nitric oxide synthase gene expression by delta 9-tetrahydrocannabinol is mediated through the inhibition of nuclear factor-kappa B/Rel activation. Mol Pharmacol 50:334–341PubMedGoogle Scholar
  90. Jin W, Brown S, Roche JP, Hsieh C, Celver JP, Kovoor A, Chavkin C, Mackie K (1999) Distinct domains of the CB1 cannabinoid receptor mediate desensitization and internalization. J Neurosci 19:3773–3780PubMedGoogle Scholar
  91. Johnson MR, Melvin LS, Althuis TH, Bindra JS, Harbert CA, Milne GM, Weissman A (1981) Selective and potent analgetics derived from cannabinoids. J Clin Pharmacol 21:271S–282SPubMedGoogle Scholar
  92. Karler R, Turkanis SA (1981) The cannabinoids as potential antiepileptics. J Clin Pharmacol 21:437S–448SPubMedGoogle Scholar
  93. Kim J, Isokawa M, Ledent C, Alger BE (2002) Activation of muscarinic acetylcholine receptors enhances the release of endogenous cannabinoids in the hippocampus. J Neurosci 22:10182–10191PubMedGoogle Scholar
  94. Kobayashi Y, Arai S, Waku K, Sugiura T (2001) Activation by 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand, of p42/44 mitogen-activated protein kinase in HL-60 cells. J Biochem (Tokyo) 129:665–669PubMedGoogle Scholar
  95. Kreitzer AC, Carter AG, Regehr WG (2002) Inhibition of interneuron firing extends the spread of endocannabinoid signaling in the cerebellum. Neuron 34:787–796PubMedCrossRefGoogle Scholar
  96. Lee MC, Smith FL, Stevens DL, Welch SP (2003) The role of several kinases in mice tolerant to delta 9-tetrahydrocannabinol. J Pharmacol Exp Ther 305:593–599PubMedGoogle Scholar
  97. Little PJ, Compton DR, Johnson MR, Melvin LS, Martin BR (1988) Pharmacology and stereoselectivity of structurally novel cannabinoids in mice. J Pharmacol Exp Ther 247:1046–1051PubMedGoogle Scholar
  98. Liu J, Gao B, Mirshahi F, Sanyal AJ, Khanolkar AD, Makriyannis A, Kunos G (2000) Functional CB1 cannabinoid receptors in human vascular endothelial cells. Biochem J 346:835–840PubMedGoogle Scholar
  99. Maccarrone M, Bari M, Lorenzon T, Bisogno T, Di Marzo V, Finazzi-Agro A (2000) Anandamide uptake by human endothelial cells and its regulation by nitric oxide. J Biol Chem 275:13484–13492PubMedGoogle Scholar
  100. Mackie K, Hille B (1992) Cannabinoids inhibit N-type calcium channels in neuroblastomaglioma cells. Proc Natl Acad Sci U S A 89:3825–3829PubMedGoogle Scholar
  101. Mackie K, Devane WA, Hille B (1993) Anandamide, an endogenous cannabinoid, inhibits calcium currents as a partial agonist in N18 neuroblastoma cells. Mol Pharmacol 44:498–503PubMedGoogle Scholar
  102. Mackie K, Lai Y, Westenbroek R, Mitchell R (1995) Cannabinoids activate an inwardly rectifying potassium conductance and inhibit Q-type calcium currents in AtT20 cells transfected with rat brain cannabinoid receptor. J Neurosci 15:6552–6561PubMedGoogle Scholar
  103. Maejima T, Hashimoto K, Yoshida T, Aiba A, Kano M (2001a) Presynaptic inhibition caused by retrograde signal from metabotropic glutamate to cannabinoid receptors. Neuron 31:463–475PubMedCrossRefGoogle Scholar
  104. Maejima T, Ohno-Shosaku T, Kano M (2001b) Endogenous cannabinoid as a retrograde messenger from depolarized postsynaptic neurons to presynaptic terminals. Neurosci Res 40:205–210PubMedCrossRefGoogle Scholar
  105. Maneuf YP, Brotchie JM (1997) Paradoxical action of the cannabinoid WIN 55,212-2 in stimulated and basal cyclic AMP accumulation in rat globus pallidus slices. Br J Pharmacol 120:1397–1398PubMedGoogle Scholar
  106. Martin BR (1986) Cellular effects of cannabinoids. Pharmacol Rev 38:45–74PubMedGoogle Scholar
  107. Martin BR, Mechoulam R, Razdan RK (1999) Discovery and characterization of endogenous cannabinoids. Life Sci 65:573–595PubMedCrossRefGoogle Scholar
  108. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346:561–564PubMedCrossRefGoogle Scholar
  109. McAllister SD, Griffin G, Satin LS, Abood ME (1999) Cannabinoid receptors can activate and inhibit G protein-coupled inwardly rectifying potassium channels in a xenopus oocyte expression system. J Pharmacol Exp Ther 291:618–626PubMedGoogle Scholar
  110. Melvin LS, Johnson MR (1987) Structure-activity relationships of tricyclic and nonclassical bicyclic cannabinoids. NIDA Res Monogr 79:31–47PubMedGoogle Scholar
  111. Melvin LS, Milne GM, Johnson MR, Subramaniam B, Wilken GH, Howlett AC (1993) Structure-activity relationships for cannabinoid receptor-binding and analgesic activity: studies of bicyclic cannabinoid analogs. Mol Pharmacol 44:1008–1015PubMedGoogle Scholar
  112. Melvin LS, Milne GM, Johnson MR, Wilken GH, Howlett AC (1995) Structure-activity relationships defining the ACD-tricyclic cannabinoids: cannabinoid receptor binding and analgesic activity. Drug Des Discov 13:155–166PubMedGoogle Scholar
  113. Misner DL, Sullivan JM (1999) Mechanism of cannabinoid effects on long-term potentiation and depression in hippocampal CA1 neurons. J Neurosci 19:6795–6805PubMedGoogle Scholar
  114. Molina-Holgado F, Lledo A, Guaza C (1997) Anandamide suppresses nitric oxide and TNF-alpha responses to Theiler’s virus or endotoxin in astrocytes. Neuroreport 8:1929–1933PubMedGoogle Scholar
  115. Molina-Holgado F, Molina-Holgado E, Guaza C, Rothwell NJ (2002) Role of CB1 and CB2 receptors in the inhibitory effects of cannabinoids on lipopolysaccharide-induced nitric oxide release in astrocyte cultures. J Neurosci Res 67:829–836PubMedCrossRefGoogle Scholar
  116. Molina-Holgado F, Pinteaux E, Moore JD, Molina-Holgado E, Guaza C, Gibson RM, Rothwell NJ (2003) Endogenous interleukin-1 receptor antagonist mediates anti-inflammatory and neuroprotective actions of cannabinoids in neurons and glia. J Neurosci 23:6470–6474PubMedGoogle Scholar
  117. Mombouli JV, Schaeffer G, Holzmann S, Kostner GM, Graier WF (1999) Anandamide-induced mobilization of cytosolic Ca2+ in endothelial cells. Br J Pharmacol 126:1593–1600PubMedCrossRefGoogle Scholar
  118. Morishita W, Kirov SA, Alger BE (1998) Evidence for metabotropic glutamate receptor activation in the induction of depolarization-induced suppression of inhibition in hippocampal CA1. J Neurosci 18:4870–4882PubMedGoogle Scholar
  119. Mukhopadhyay S, Howlett AC (2001) CB1 receptor-G protein association. Subtype selectivity is determined by distinct intracellular domains. Eur J Biochem 268:499–505PubMedCrossRefGoogle Scholar
  120. Mukhopadhyay S, Cowsik SM, Lynn AM, Welsh WJ, Howlett AC (1999) Regulation of Gi by the CB1 cannabinoid receptor C-terminal juxtamembrane region: structural requirements determined by peptide analysis. Biochemistry 38:3447–3455PubMedCrossRefGoogle Scholar
  121. Mukhopadhyay S, McIntosh HH, Houston DB, Howlett AC (2000) The CB1 cannabinoid receptor juxtamembrane C-terminal peptide confers activation to specific G proteins in brain. Mol Pharmacol 57:162–170PubMedGoogle Scholar
  122. Mukhopadhyay S, Sandiford S, Howlett AC (2002a) Palmitoylation regulates CB1 cannabinoid receptor-G protein interaction. Proc XIV World Congress PharmacolGoogle Scholar
  123. Mukhopadhyay S, Shim JY, Assi AA, Norford D, Howlett AC (2002b) CB1 cannabinoid receptor-G protein association: a possible mechanism for differential signaling. Chem Phys Lipids 121:91–109PubMedGoogle Scholar
  124. Munro S, Thomas KL, Abu-Shaar M (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365:61–65PubMedCrossRefGoogle Scholar
  125. Nah SY, Saya D, Vogel Z (1993) Cannabinoids inhibit agonist-stimulated formation of inositol phosphates in rat hippocampal cultures. Eur J Pharmacol 246:19–24PubMedGoogle Scholar
  126. Netzeband JG, Conroy SM, Parsons KL, Gruol DL (1999) Cannabinoids enhance NMDA-elicited Ca2+ signals in cerebellar granule neurons in culture. J Neurosci 19:8765–8777PubMedGoogle Scholar
  127. Nie J, Lewis DL (2001) The proximal and distal C-terminal tail domains of the CB1 cannabinoid receptor mediate G protein coupling. Neuroscience 107:161–167PubMedCrossRefGoogle Scholar
  128. Norford DC, Newton D, Jones J, Carney S, Howlett AC (2002) Detection of cannabinoidinduced nitric oxide production in neuronal and glial cells. J Cell BiolGoogle Scholar
  129. Ohno-Shosaku T, Shosaku J, Tsubokawa H, Kano M (2002a) Cooperative endocannabinoid production by neuronal depolarization and group I metabotropic glutamate receptor activation. Eur J Neurosci 15:953–961PubMedCrossRefGoogle Scholar
  130. Ohno-Shosaku T, Tsubokawa H, Mizushima I, Yoneda N, Zimmer A, Kano M (2002b) Presynaptic cannabinoid sensitivity is a major determinant of depolarization-induced retrograde suppression at hippocampal synapses. J Neurosci 22:3864–3872PubMedGoogle Scholar
  131. Oviedo A, Glowa J, Herkenham M (1993) Chronic cannabinoid administration alters cannabinoid receptor binding in rat brain: a quantitative autoradiographic study. Brain Res 616:293–302PubMedCrossRefGoogle Scholar
  132. Pacheco M, Childers SR, Arnold R, Casiano F, Ward SJ (1991) Aminoalkylindoles: actions on specific G-protein-linked receptors. J Pharmacol Exp Ther 257:170–183PubMedGoogle Scholar
  133. Pacheco MA, Ward SJ, Childers SR (1993) Identification of cannabinoid receptors in cultures of rat cerebellar granule cells. Brain Res 603:102–110PubMedCrossRefGoogle Scholar
  134. Pan X, Ikeda SR, Lewis DL (1996) Rat brain cannabinoid receptor modulates N-type Ca2+ channels in a neuronal expression system. Mol Pharmacol 49:707–714PubMedGoogle Scholar
  135. Pan X, Ikeda SR, Lewis DL (1998) SR 141716A acts as an inverse agonist to increase neuronal voltage-dependent Ca2+ currents by reversal of tonic CB1 cannabinoid receptor activity. Mol Pharmacol 54:1064–1072PubMedGoogle Scholar
  136. Pertwee RG (1988) The central neuropharmacology of psychotropic cannabinoids. Pharmacol Ther 36:189–261PubMedCrossRefGoogle Scholar
  137. Pertwee RG (1997) Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther 74:129–180PubMedCrossRefGoogle Scholar
  138. Pertwee RG (1999) Pharmacology of cannabinoid receptor ligands. Curr Med Chem 6:635–664PubMedGoogle Scholar
  139. Peterson LJ, McIntosh HH, Howlett AC (2004) Tyrosine phosphorylation of the CB1 receptor. Int Cannab Res Soc 14:127Google Scholar
  140. Pinto JC, Potie F, Rice KC, Boring D, Johnson MR, Evans DM, Wilken GH, Cantrell CH, Howlett AC (1994) Cannabinoid receptor binding and agonist activity of amides and esters of arachidonic acid. Mol Pharmacol 46:516–522PubMedGoogle Scholar
  141. Piomelli D (2003) The molecular logic of endocannabinoid signalling. Nat Rev Neurosci 4:873–884PubMedCrossRefGoogle Scholar
  142. Prevot V, Rialas CM, Croix D, Salzet M, Dupouy JP, Poulain P, Beauvillain JC, Stefano GB (1998) Morphine and anandamide coupling to nitric oxide stimulates GnRH and CRF release from rat median eminence: neurovascular regulation. Brain Res 790:236–244PubMedCrossRefGoogle Scholar
  143. Priller J, Briley EM, Mansouri J, Devane WA, Mackie K, Felder CC (1995) Mead ethanolamide, a novel eicosanoid, is an agonist for the central (CB1) and peripheral (CB2) cannabinoid receptors. Mol Pharmacol 48:288–292PubMedGoogle Scholar
  144. Reggio PH, Traore H (2000) Conformational requirements for endocannabinoid interaction with the cannabinoid receptors, the anandamide transporter and fatty acid amidohydrolase. Chem Phys Lipids 108:15–35PubMedGoogle Scholar
  145. Rhee MH, Bayewitch M, Avidor-Reiss T, Levy R, Vogel Z (1998) Cannabinoid receptor activation differentially regulates the various adenylyl cyclase isozymes. J Neurochem 71:1525–1534PubMedGoogle Scholar
  146. Rinaldi-Carmona M, Barth F, Heaulme M, Shire D, Calandra B, Congy C, Martinez S, Maruani J, Neliat G, Caput D (1994) SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett 350:240–244PubMedCrossRefGoogle Scholar
  147. Rinaldi-Carmona M, Barth F, Millan J, Derocq JM, Casellas P, Congy C, Oustric D, Sarran M, Bouaboula M, Calandra B, Portier M, Shire D, Breliere JC, Le Fur GL (1998) SR 144528, the first potent and selective antagonist of the CB2 cannabinoid receptor. J Pharmacol Exp Ther 284:644–650PubMedGoogle Scholar
  148. Rodriguez de Fonseca F, Gorriti MA, Fernandez-Ruiz JJ, Palomo T, Ramos JA (1994) Down-regulation of rat brain cannabinoid binding sites after chronic delta 9-tetrahydrocannabinol treatment. Pharmacol Biochem Behav 47:33–40Google Scholar
  149. Romero J, Garcia L, Fernandez-Ruiz JJ, Cebeira M, Ramos JA (1995) Changes in rat brain cannabinoid binding sites after acute or chronic exposure to their endogenous agonist, anandamide, or to delta 9-tetrahydrocannabinol. Pharmacol Biochem Behav 51:731–737PubMedCrossRefGoogle Scholar
  150. Romero J, Garcia-Palomero E, Castro JG, Garcia-Gil L, Ramos JA, Fernandez-Ruiz JJ (1997) Effects of chronic exposure to delta9-tetrahydrocannabinol on cannabinoid receptor binding and mRNA levels in several rat brain regions. Brain Res Mol Brain Res 46:100–108PubMedGoogle Scholar
  151. Ronesi J, Gerdeman GL, Lovinger DM (2004) Disruption of endocannabinoid release and striatal long-term depression by postsynaptic blockade of endocannabinoid membrane transport. J Neurosci 24:1673–1679PubMedCrossRefGoogle Scholar
  152. Roth SH, Williams PJ (1979) The non-specific membrane binding properties of delta9-tetrahydrocannabinol and the effects of various solubilizers. J Pharm Pharmacol 31:224–230PubMedGoogle Scholar
  153. Rubino T, Forlani G, Vigano D, Zippel R, Parolaro D (2004) Modulation of extracellular signal-regulated kinases cascade by chronic delta 9-tetrahydrocannabinol treatment. Mol Cell Neurosci 25:355–362PubMedCrossRefGoogle Scholar
  154. Rubovitch V, Gafni M, Sarne Y (2004) The involvement of VEGF receptors and MAPK in the cannabinoid potentiation of Ca2+ flux into N18TG2 neuroblastoma cells. Brain Res Mol Brain Res 120:138–144PubMedGoogle Scholar
  155. Rueda D, Galve-Roperh I, Haro A, Guzman M (2000) The CB(1) cannabinoid receptor is coupled to the activation of c-Jun N-terminal kinase. Mol Pharmacol 58:814–820PubMedGoogle Scholar
  156. Rueda D, Navarro B, Martinez-Serrano A, Guzman M, Galve-Roperh I (2002) The endocannabinoid anandamide inhibits neuronal progenitor cell differentiation through attenuation of the Rap1/B-Raf/ERK pathway. J Biol Chem 277:46645–46650PubMedCrossRefGoogle Scholar
  157. Sanchez C, Galve-Roperh I, Rueda D, Guzman M (1998) Involvement of sphingomyelin hydrolysis and the mitogen-activated protein kinase cascade in the Delta9-tetrahydrocannabinol-induced stimulation of glucose metabolism in primary astrocytes. Mol Pharmacol 54:834–843PubMedGoogle Scholar
  158. Sarker KP, Maruyama I (2003) Anandamide induces cell death independently of cannabinoid receptors or vanilloid receptor 1: possible involvement of lipid rafts. Cell Mol Life Sci 60:1200–1208PubMedGoogle Scholar
  159. Sarker KP, Biswas KK, Yamakuchi M, Lee KY, Hahiguchi T, Kracht M, Kitajima I, Maruyama I (2003) ASK1-p38 MAPK/JNK signaling cascade mediates anandamide-induced PC12 cell death. J Neurochem 85:50–61PubMedCrossRefGoogle Scholar
  160. Schmid HH (2000) Pathways and mechanisms of N-acylethanolamine biosynthesis: can anandamide be generated selectively? Chem Phys Lipids 108:71–87PubMedGoogle Scholar
  161. Seeman P, Chau-Wong M, Moyyen S (1972) Themembrane binding of morphine, diphenylhydantoin, and tetrahydrocannabinol. Can J Physiol Pharmacol 50:1193–1200PubMedGoogle Scholar
  162. Shapira M, Gafni M, Sarne Y (1998) Independence of, and interactions between, cannabinoid and opioid signal transduction pathways in N18TG2 cells. Brain Res 806:26–35PubMedCrossRefGoogle Scholar
  163. Shen M, Thayer SA (1998) The cannabinoid agonist Win55,212-2 inhibits calcium channels by receptor-mediated and direct pathways in cultured rat hippocampal neurons. Brain Res 783:77–84PubMedCrossRefGoogle Scholar
  164. Shim, JY, Howlett AC (2004) Steric trigger as a mechanism for CB1 cannabinoid receptor activation. J Chem Inf Comp Sci 44:1466–1476CrossRefGoogle Scholar
  165. Shim JY, Welsh WJ, Howlett AC (2003) Homology model of the CB1 cannabinoid receptor: sites critical for non-classical cannabinoid agonist interaction. Biopolymers 71:169–189PubMedCrossRefGoogle Scholar
  166. Shivachar AC, Martin BR, Ellis EF (1996) Anandamide-and delta9-tetrahydrocannabinol-evoked arachidonic acid mobilization and blockade by SR141716A [N-(Piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride]. Biochem Pharmacol 51:669–676PubMedCrossRefGoogle Scholar
  167. Sim LJ, Hampson RE, Deadwyler SA, Childers SR (1996) Effects of chronic treatment with delta9-tetrahydrocannabinol on cannabinoid-stimulated [35S]GTPgammaS autoradiography in rat brain. J Neurosci 16:8057–8066PubMedGoogle Scholar
  168. Sim-Selley LJ (2003) Regulation of cannabinoid CB1 receptors in the central nervous system by chronic cannabinoids. Crit Rev Neurobiol 15:91–119PubMedCrossRefGoogle Scholar
  169. Simmons ML, Murphy S (1992) Induction of nitric oxide synthase in glial cells. J Neurochem 59:897–905PubMedGoogle Scholar
  170. Singh R, Hurst DP, Barnett-Norris J, Lynch DL, Reggio PH, Guarnieri F (2002) Activation of the cannabinoid CB1 receptor may involve a W6.48/F3.36 rotamer toggle switch. J Pept Res 60:357–370PubMedCrossRefGoogle Scholar
  171. Slipetz DM, O’Neill GP, Favreau L, Dufresne C, Gallant M, Gareau Y, Guay D, Labelle M, Metters KM (1995) Activation of the human peripheral cannabinoid receptor results in inhibition of adenylyl cyclase. Mol Pharmacol 48:352–361PubMedGoogle Scholar
  172. Stefano GB, Liu Y, Goligorsky MS (1996) Cannabinoid receptors are coupled to nitric oxide release in invertebrate immunocytes, microglia, and human monocytes. J Biol Chem 271:19238–19242PubMedGoogle Scholar
  173. Stefano GB, Salzet B, Rialas CM, Pope M, Kustka A, Neenan K, Pryor S, Salzet M (1997a) Morphine-and anandamide-stimulated nitric oxide production inhibits presynaptic dopamine release. Brain Res 763:63–68PubMedCrossRefGoogle Scholar
  174. Stefano GB, Salzet B, Salzet M (1997b) Identification and characterization of the leech CNS cannabinoid receptor: coupling to nitric oxide release. Brain Res 753:219–224PubMedCrossRefGoogle Scholar
  175. Stefano GB, Salzet M, Magazine HI, Bilfinger TV (1998) Antagonism of LPS and IFN-gamma induction of iNOS in human saphenous vein endothelium by morphine and anandamide by nitric oxide inhibition of adenylate cyclase. J Cardiovasc Pharmacol 31:813–820PubMedGoogle Scholar
  176. Steffens M, Szabo B, Klar M, Rominger A, Zentner J, Feuerstein TJ (2003) Modulation of electrically evoked acetylcholine release through cannabinoid CB1 receptors: evidence for an endocannabinoid tone in the human neocortex. Neuroscience 120:455–465PubMedCrossRefGoogle Scholar
  177. Sugiura T, Waku K (2000) 2-Arachidonoylglycerol and the cannabinoid receptors. Chem Phys Lipids 108:89–106PubMedCrossRefGoogle Scholar
  178. Sugiura T, Kodaka T, Kondo S, Tonegawa T, Nakane S, Kishimoto S, Yamashita A, Waku K (1996) 2-Arachidonoylglycerol, a putative endogenous cannabinoid receptor ligand, induces rapid, transient elevation of intracellular free Ca2+ in neuroblastoma x glioma hybrid NG108-15 cells. Biochem Biophys Res Commun 229:58–64PubMedCrossRefGoogle Scholar
  179. Sugiura T, Kodaka T, Kondo S, Nakane S, Kondo H, Waku K, Ishima Y, Watanabe K, Yamamoto I (1997a) Is the cannabinoid CB1 receptor a 2-arachidonoylglycerol receptor? Structural requirements for triggering a Ca2+ transient in NG108-15 cells. J Biochem (Tokyo) 122:890–895PubMedGoogle Scholar
  180. Sugiura T, Kodaka T, Kondo S, Tonegawa T, Nakane S, Kishimoto S, Yamashita A, Waku K (1997b) Inhibition by 2-arachidonoylglycerol, a novel type of possible neuromodulator, of the depolarization-induced increase in intracellular free calcium in neuroblastoma x glioma hybrid NG108-15 cells. Biochem Biophys Res Commun 233:207–210PubMedCrossRefGoogle Scholar
  181. Sugiura T, Kodaka T, Nakane S, Miyashita T, Kondo S, Suhara Y, Takayama H, Waku K, Seki C, Baba N, Ishima Y (1999) Evidence that the cannabinoid CB1 receptor is a 2-arachidonoylglycerol receptor. Structure-activity relationship of 2-arachidonoylglycerol, ether-linked analogues, and related compounds. J Biol Chem 274:2794–2801PubMedCrossRefGoogle Scholar
  182. Thomas BF, Compton DR, Martin BR (1990) Characterization of the lipophilicity of natural and synthetic analogs of delta 9-tetrahydrocannabinol and its relationship to pharmacological potency. J Pharmacol Exp Ther 255:624–630PubMedGoogle Scholar
  183. Turkanis SA, Karler R (1981) Electrophysiologic properties of the cannabinoids. J Clin Pharmacol 21:449S–463SPubMedGoogle Scholar
  184. Turkanis SA, Karler R (1983) Effects of delta 9-tetrahydrocannabinol on cat spinal motoneurons. Brain Res 288:283–287PubMedCrossRefGoogle Scholar
  185. Turkanis SA, Karler R (1986) Cannabidiol-caused depression of spinal motoneuron responses in cats. Pharmacol Biochem Behav 25:89–94PubMedCrossRefGoogle Scholar
  186. Turkanis SA, Karler R, Partlow LM (1991) Differential effects of delta-9-tetrahydrocannabinol and its 11-hydroxy metabolite on sodium current in neuroblastoma cells. Brain Res 560:245–250PubMedCrossRefGoogle Scholar
  187. Ulfers AL, McMurry JL, Kendall DA, Mierke DF (2002a) Structure of the third intracellular loop of the human cannabinoid 1 receptor. Biochemistry 41:11344–11350PubMedCrossRefGoogle Scholar
  188. Ulfers AL, McMurry JL, Miller A, Wang L, Kendall DA, Mierke DF (2002b) Cannabinoid receptor-G protein interactions: G(alphai1)-bound structures of IC3 and a mutant with altered G protein specificity. Protein Sci 11:2526–2531PubMedCrossRefGoogle Scholar
  189. Upham BL, Rummel AM, Carbone JM, Trosko JE, Ouyang Y, Crawford RB, Kaminski NE (2003) Cannabinoids inhibit gap junctional intercellular communication and activate ERK in a rat liver epithelial cell line. Int J Cancer 104:12–18PubMedCrossRefGoogle Scholar
  190. Valjent E, Pages C, Herve D, Girault JA, Caboche J (2004) Addictive and non-addictive drugs induce distinct and specific patterns of ERK activation in mouse brain. Eur J Neurosci 19:1826–1836PubMedCrossRefGoogle Scholar
  191. Varma N, Carlson GC, Ledent C, Alger BE (2001) Metabotropic glutamate receptors drive the endocannabinoid system in hippocampus. J Neurosci 21:RC188PubMedGoogle Scholar
  192. Vasquez C, Lewis DL (1999) The CB1 cannabinoid receptor can sequester G-proteins, making them unavailable to couple to other receptors. J Neurosci 19:9271–9280PubMedGoogle Scholar
  193. Vogel Z, Barg J, Levy R, Saya D, Heldman E, Mechoulam R (1993) Anandamide, a brain endogenous compound, interacts specifically with cannabinoid receptors and inhibits adenylate cyclase. J Neurochem 61:352–355PubMedGoogle Scholar
  194. Wartmann M, Campbell D, Subramanian A, Burstein SH, Davis RJ (1995) The MAP kinase signal transduction pathway is activated by the endogenous cannabinoid anandamide. FEBS Lett 359:133–136PubMedCrossRefGoogle Scholar
  195. Wilson RI, Nicoll RA (2001) Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature 410:588–592PubMedCrossRefGoogle Scholar
  196. Wilson RI, Nicoll RA (2002) Endocannabinoid signaling in the brain. Science 296:678–682PubMedCrossRefGoogle Scholar
  197. Wilson RI, Kunos G, Nicoll RA (2001) Presynaptic specificity of endocannabinoid signaling in the hippocampus. Neuron 31:453–462PubMedCrossRefGoogle Scholar
  198. Yamaji K, Sarker KP, Kawahara K, Iino S, Yamakuchi M, Abeyama K, Hashiguchi T, Maruyama I (2003) Anandamide induces apoptosis in human endothelial cells: its regulation system and clinical implications. Thromb Haemost 89:875–884PubMedGoogle Scholar
  199. Zhou D, Song HZ (2001) CB1 cannabinoid receptor-mediated neurite remodeling in mouse neuroblastoma N1E-115 cells. J Neurosci Res 65:346–353PubMedGoogle Scholar
  200. Zhou D, Song ZH (2002) CB1 cannabinoid receptor-mediated tyrosine phosphorylation of focal adhesion kinase-related non-kinase. FEBS Lett 525:164–168PubMedCrossRefGoogle Scholar
  201. Zhuang SY, Chen Y, Weiner JL, Hampson RE, Deadwyler SA (2003) Lack of functional presynaptic, but putative postsynaptic actions of cannabinoids in hippocampal neurons. Soc Neurosci Abstracts 29:462.1Google Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • A. C. Howlett
    • 1
  1. 1.Neuroscience/Drug Abuse Research ProgramDurhamUSA

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