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Analgesia pp 265-306 | Cite as

Cannabinoids and Pain

  • I. J. Lever
  • A. S. C. Rice
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 177)

Abstract

Convincing evidence frompreclinical studies demonstrates that cannabinoids can reducepain responses ina rangeof inflammatory and neuropathicpain models. The anatomical and functional data reveal cannabinoid receptor-mediated analgesic actions operating at sites concerned with the transmission and processing of nociceptive signals in brain, spinal cord and the periphery. The precise signalling mechanisms by which cannabinoids produce analgesic effects at these sites remain unclear; however, significant clues point to cannabinoid modulation of the functions of neurone and immune cells that mediate nociceptive and inflammatory responses. Intracellular signalling mechanisms engaged by cannabinoid receptors—like the inhibition of calciumtransients and adenylate cyclase, and pre-synaptic modulation of transmitter release—have been demonstrated in some of these cell types and are predicted to play a role in the analgesic effects of cannabinoids. In contrast, the clinical effectiveness of cannabinoids as analgesics is less clear. Progress in this area requires the development of cannabinoids with a more favourable therapeutic index than those currently available for human use, and the testing of their efficacy and side-effects in high-quality clinical trials.

Keywords

CB1 CB2 Endocannabinoid Spinal cord Sensory neurone G protein-coupled receptor 

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References

  1. Ahluwalia J, Urban L, Capogna M, Bevan S, Nagy I (2000) Cannabinoid 1 receptors are expressed in nociceptive primary sensory neurones. Neuroscience 100:685–688PubMedGoogle Scholar
  2. Ahluwalia J, Urban L, Bevan S, Capogna M, Nagy I (2002) Cannabinoid 1 receptors are expressed by nerve growth factor-and glial cell-derived neurotrophic factor-responsive primary sensory neurones. Neuroscience 110:747–753PubMedGoogle Scholar
  3. Ahluwalia J, Urban L, Bevan S, Nagy I (2003a) Anandamide regulates neuropeptide release from capsaicin-sensitive primary sensory neurones by activating both the cannabinoid 1 receptor and the vanilloid receptor 1 in vitro. Eur J Neurosci 17:2611–2618PubMedGoogle Scholar
  4. Ahluwalia J, Yacoob M, Urban L, Bevan S, Nagy I (2003b) Activation of capsaicin-sensitive primary sensory neurones induces anandamide production and release. J Neurochem 84:585–591PubMedGoogle Scholar
  5. Arseneault L, Cannon M, Poulton R, Murray R, Caspi A, Moffitt TE (2002) Cannabis use in adolescence and risk for adult psychosis: longitudinal prospective study. Br Med J 325:1212–1213Google Scholar
  6. Ates M, Hamza M, Seidel K, Kotalla CE, Ledent C, Guhring H (2003) Intrathecally applied flurbiprofen produces an endocannabinoid-dependent antinociception in the rat formalin test. Eur J Neurosci 17:597–604PubMedGoogle Scholar
  7. Bandell M, Story GM, Hwang SW, Viswanath V, Eid SR, Petrus MJ, Earley TJ, Patapoutian A (2004) Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin. Neuron 41:849–857PubMedGoogle Scholar
  8. Bayewitch M, Avidor Reiss T, Levy R, Barg J, Mechoulam R, Vogel Z (1995) The peripheral cannabinoid receptor: adenylate cyclase inhibition and G protein coupling. FEBS Lett 375:143–147PubMedGoogle Scholar
  9. Begg M, Pacher P, Batkai S, Osei-Hyiaman D, Offertaler L, Mo FM, Liu J, Kunos G (2005) Evidence of for novel cannabinoid receptors. Pharmacol Ther 106:133–145PubMedGoogle Scholar
  10. Bell MR, D’Ambra TE, Kumar V, Eissenstat MA, Herrmann JL Jr, Wetzel JR, Rosi D, Philion RE, Daum SJ, Hlasta DJ (1991) Antinociceptive (aminoalkyl)indoles. J Med Chem 34:1099–1110PubMedGoogle Scholar
  11. Beltramo M, Stella N, Calignano A, Lin SY, Makriyannis A, Piomelli D (1997) Functional role of high-affinity anandamide transport, as revealed by selective inhibition. Science 277:1094–1097PubMedGoogle Scholar
  12. Berman JS, Symonds C, Birch R (2004) Efficacy of two cannabis basedmedicinal extracts for relief of central neuropathic pain frombrachial plexus avulsion: results of a randomised controlled trial. Pain 112:299–306PubMedGoogle Scholar
  13. Bisogno T, Maurelli S, Melck D, De Petrocellis L, Di Marzo V (1997) Biosynthesis, uptake, and degradation of anandamide and palmitoylethanolamide in leukocytes. J Biol Chem 272:3315–3323PubMedGoogle Scholar
  14. Bisogno T, Hanus L, De Petrocellis L, Tchilibon S, Ponde DE, Brandi I, Schiano Moriello A, Davis JB, Mechoulam R, Di Marzo V (2001) Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol 134:845–852PubMedGoogle Scholar
  15. Bouaboula M, Perrachon S, Milligan L, Canat X, Rinaldi-Carmona M, Portier M, Barth F, Calandra B, Pecceu F, Lupker J, Maffrand JP, Le Fur G, Casellas P (1997) A selective inverse agonist for central cannabinoid receptor inhibits mitogen-activated protein kinase activation stimulated by insulin or insulin-like growth factor 1. Evidence for a new model of receptor/ligand interactions. J Biol Chem 272:22330–22339PubMedGoogle Scholar
  16. Bouaboula M, Desnoyer N, Carayon P, Combes T, Casellas P (1999) Gi protein modulation induced by a selective inverse agonist for the peripheral cannabinoid receptor CB2: implication for intracellular signalization cross-regulation. Mol Pharmacol 55:473–480PubMedGoogle Scholar
  17. Bracey MH, Hanson MA, Masuda KR, Stevens RC, Cravatt BF (2002) Structural adaptations in a membrane enzyme that terminates endocannabinoid signaling. Science 298:1793–1796PubMedGoogle Scholar
  18. Bradshaw HB, Walker JM (2005) The expanding field of cannabimimetic and related lipid mediators. Br J Pharmacol 144:459–465PubMedGoogle Scholar
  19. Breivogel CS, Selley DE, Childers SR (1998) Cannabinoid receptor agonist efficacy for stimulating [35S]GTPgammaS binding to rat cerebellar membranes correlates with agonistinduced decreases in GDP affinity. J Biol Chem 273:16865–16873PubMedGoogle Scholar
  20. Breivogel CS, Griffin G, DiMarzo V, Martin BR (2001) Evidence for a new G-protein coupled cannabinoid receptor in mouse brain. Mol Pharmacol 60:155–163PubMedGoogle Scholar
  21. Bridges D, Ahmad KS, Rice ASC (2001a) The synthetic cannabinoidWIN55,212-2 attenuates hyperalgesia and allodynia in a rat model of neuropathic pain. Br J Pharmacol 133:586–594PubMedGoogle Scholar
  22. Bridges D, Thompson SWN, Rice ASC (2001b) Mechanisms ofneuropathicpain. Br J Anaesth 87:12–26PubMedGoogle Scholar
  23. Bridges D, Rice ASC, Egertova M, Elphick MR, Winter J (2002) The distribution of cannabinoid CB1 receptor within the dorsal root ganglion following peripheral nerve injury. 10th World Congress of Pain, Abstr 371-P5Google Scholar
  24. Bridges D, Rice ASC, Egertova M, Elphick MR, Winter J, Michael GJ (2003) Localisation of cannabinoid receptor 1 in rat dorsal root ganglion using in situ hybridisation and immunohistochemistry. Neuroscience 119:803–812PubMedGoogle Scholar
  25. Brooks JW, Thompson SW, Rice AS, Malcangio M (2004) (S)-AMPA inhibits electrically evoked calcitonin gene-related peptide (CGRP) release fromthe rat dorsal horn: reversal by cannabinoid receptor antagonist SR141716A. Neurosci Lett 372:85–88PubMedGoogle Scholar
  26. Brown SM, Wager-Miller J, Mackie K (2002) Cloning and molecular characterization of the rat CB2 cannabinoid receptor. Biochim Biophys Acta 1576:255–264PubMedGoogle Scholar
  27. Buckley NE, McCoy KL, Mezey E, Bonner T, Zimmer A, Felder CC, Glass M (2000) Immunomodulation by cannabinoids is absent in mice deficient for the cannabinoid CB(2) receptor. Eur J Pharmacol 396:141–149PubMedGoogle Scholar
  28. Burdyga G, Lal S, Varro A, Dimaline R, Thompson DG, Dockray GJ (2004) Expression of CB1 receptors in vagal afferent neurons in inhibited by cholecystokinin. J Neurosci 24:2708–2715PubMedGoogle Scholar
  29. Burstein SH, Friderichs E, Kogel B, Schneider J, Selve N (1998) Analgesic effects of 1′,1′ dimethylheptyl-delta8-THC-11-oic acid (CT3) in mice. Life Sci 63:161–168PubMedGoogle Scholar
  30. Calignano A, La Rana G, Beltramo M, Makriyannis A, Piomelli D (1997) Potentiation of anandamide hypotension by the transport inhibitor, AM404. Eur J Pharmacol 337:R1–2PubMedGoogle Scholar
  31. Calignano A, La Rana G, Giuffrida A, Piomelli D (1998) Control of pain initiation by endogenous cannabinoids. Nature 394:277–281PubMedGoogle Scholar
  32. Calignano A, La Rana G, Piomelli D (2001) Antinociceptive activity of the endogenous fatty acid amide, palmitylethanolamide. Eur J Pharmacol 419:191–198PubMedGoogle Scholar
  33. Campbell F, Tramer M, Carroll D, Reynolds DJM, Moore RA, McQuay HJ (2001) Are cannabinoids an effective and safe option in the management of pain? A qualitative systematic review. Br Med J 323:13–16Google Scholar
  34. Carlisle SJ, Marciano-carbral F, Staab A, Ludwick C, Cabral GA (2002)Differential expression of the CB2 cannabinoid receptor by rodent macrophages and macrophage-like cells in relation to cell activation. Int Immunopharmacol 2:69–82PubMedGoogle Scholar
  35. Caspi A, Moffitt TE, Cannon M, McClay J, Murray R, Harrington H, Taylor A, Arseneault L, Williams B, Braithwaite A (2005) Moderation of the effect of adolescentonset cannabis use on adult psychosis by a functional polymorphism in the catechol-omethyltransferase gene: longitudinal evidence of a gene X environment interaction. Biol Psychiatry 57:1117–1127PubMedGoogle Scholar
  36. Chakrabarti A, Onaivi ES, Chaudhuri G (1995) Cloning and sequencing of a cDNA encoding the mouse brain-type cannabinoid receptor protein. DNA Seq 5:385–388PubMedGoogle Scholar
  37. Chapman V (1999) The cannabinoid CB1 receptor antagonist, SR141716A, selectively facilitates nociceptive responses of dorsal horn neurones in the rat. Br J Pharmacol 127:1765–1767PubMedGoogle Scholar
  38. Chemin J, Monteil A, Perez-Reyes E, Nargot J, Lory P (2001) Direct inhibition of T-type calcium channels by the endogenous cannabinoid anandamide. EMBO J 20:7033–7040PubMedGoogle Scholar
  39. Clayton N, Marshall FH, Bountra C, O’Shaughnessy CT (2002) CB1 and CB2 cannabinoid receptors are implicated in inflammatory pain. Pain 96:253–260PubMedGoogle Scholar
  40. Costa B, Colleoni M, Conti S, Parolaro D, Trovato AE, Franke CM, Giagnoni G (2004) Oral anti-inflammatory activity of cannabidiol, a non-psychoactive constituent of cannabis, in acute carrageenan-induced inflammation in the rat paw. Naunyn Schmiedebergs Arch Pharmacol 369:294–299PubMedGoogle Scholar
  41. Costa B, Giagnoni G, Franke CM, Trovato AE, Colleoni M (2004b) Vanilloid TRPV1 receptor mediated the antihyperalgesic effect of the nonpsychoactive cannabinoid, cannabidiol, in a rat model of acute inflammation. Br J Pharmacol 143:247–250PubMedGoogle Scholar
  42. Costa B, Colleoni M, Conti S, Trovato AE, Bianchi M, Sotgiu ML, Giagnoni G (2004c) Repeated treatment with the synthetic cannabinoid WIN55,212-2 reduces both hyperalgesia and production of pronociceptive mediators in a rat model of neuropathic pain. Br J Pharmacol 141:4–8PubMedGoogle Scholar
  43. Costigan M, Befort K, Karchewski L, Griffin R, D’Urso D, Allchorne A, Sitarski J, Mannion J, Pratt R, Woolf C (2002) Replicate high-density rat genome oligonucleotide microarrays reveal hundreds of regulated genes in the dorsal root ganglion after peripheral nerve injury. BMC Neurosci 3:16PubMedGoogle Scholar
  44. Coutts AA, Anavi-Goffer S, Ross RA, MacEwan DJ, Mackie K, Pertwee RG, Irving AJ (2001) Agonist-induced internalisation and trafficking of cannabinoid CB1 receptors in hippocampal neurons. J Neurosci 21:2425–2433PubMedGoogle Scholar
  45. Cox ML, Welch SP (2004) The antinociceptive effect of Delta9-tetrahydrocannabinol in the arthritic rat. Eur J Pharmacol 493:65–74PubMedGoogle Scholar
  46. Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB (1996) Molecular characterization of an enzymethat degrades neuromodulatory fatty-acid amides. Nature 384:83–87PubMedGoogle Scholar
  47. Cravatt BF, Demarest K, Patricelli MP, Bracey MH, Giang DK, Martin BR, Lichtman AH (2001) Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc Natl Acad Sci USA 98:9371–9376PubMedGoogle Scholar
  48. Cravatt BF, Saghatelian A, Hawkins EG, Clement AB, Bracey MH, Lichtman AH(2004) Functional disassociation of the central and peripheral fatty acid amide signaling systems. Proc Natl Acad Sci USA 101:10821–10826PubMedGoogle Scholar
  49. D’Souza DC, Perry E, MacDougall L, Yola Ammerman Y, Thomas Cooper T, Wu T, Braley G, Gueorguieva R, Krystal JH (2004) The psychotomimetic effects of intravenous delta-9-tetrahydrocannabinol in healthy individuals: implications for psychosis. Neuropsychopharmacology 29:1558–1572PubMedGoogle Scholar
  50. De Petrocellis L, Cascio MG, Di Marzo V (2004) The endocannabinoid system: a general view and latest editions. Br J Pharmacol 141:765–774PubMedGoogle Scholar
  51. 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
  52. DeLeo JA, Yezierski RP (2001) The role of neuroinflammation and neuroimmune activation in persistent pain. Pain 90:1–6PubMedGoogle Scholar
  53. Derkinderen P, Ledent C, Parmentier M, Girault JA (2001) Cannabinoids activate p38 mitogen-activated protein kinases through CB1 receptors in hippocampus. J Neurochem 77:957–960PubMedGoogle Scholar
  54. Deutsch DG, Chin SA (1993) Enzymatic synthesis and degradation of anandamide, a cannabinoid receptor agonist. Biochem Pharmacol 46:791–796PubMedGoogle Scholar
  55. Deutsch DG, Ueda N, Yamamoto S (2002) The fatty acid amide hydrolase (FAAH). Prostaglandins Leukot Essent Fatty Acids 66:201–210PubMedGoogle Scholar
  56. Devane WA, Dysarz FA3, Johnson MR, Melvin LS, Howlett AC (1988) Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol 34:605–613PubMedGoogle Scholar
  57. Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A, Mechoulam R (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258:1946–1949PubMedGoogle Scholar
  58. Di Marzo V, Deutsch DG (1998) Biochemistry of the endogenous ligands of cannabinoid receptors. Neurobiol Dis 5:386–404PubMedGoogle Scholar
  59. Di Marzo V, Fontana A, Cadas H, Schinelli S, Cimino G, Schwartz JC, Piomelli D (1994) Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature 372:686–691PubMedGoogle Scholar
  60. 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
  61. Di Marzo V, Bifulco M, De Petrocellis L (2004) The endocannabinoid system and its therapeutic exploitation. Nat Rev Drug Discov 9:771–784Google Scholar
  62. Dinh TP, Carpenter D, Leslie FM, Freund TF, Katona I, Sensi SL, Kathuria S, Piomelli D (2002) Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc Natl Acad Sci USA 99:10819–10824PubMedGoogle Scholar
  63. Dinis P, Charrua A, Avelino A, Yaqoob M, Bevan S, Nagy I, Cruz F (2004) Anandamide-evoked activation of vanilloid receptor 1 contributes to the development of bladder hyperreflexia and nociceptive transmission to spinal dorsal horn neurons in cystitis. J Neurosci 24:11253–11263PubMedGoogle Scholar
  64. Dogrul A, Gul H, Akar A, Yildiz O, Bilgin F, Guzeldemir E (2003) Topical cannabinoid antinociception: synergy with spinal sites. Pain 105:11–16PubMedGoogle Scholar
  65. Dovrak M, Watkinson A, McGlone F, Rukwied R (2003) Histamine induced responses are attenuated by a cannabinoid receptor in human skin. Inflamm Res 52:238–245Google Scholar
  66. Drew LJ, Harris J, Millns PJ, Kendall DA, Chapman V (2000) Activation of spinal cannabinoid 1 receptors inhibits C-fibre driven hyperexcitable neuronal responses and increases [35S]GTPgammaS binding in the dorsal horn of the spinal cord of noninflamed and inflamed rats. Eur J Neurosci 12:2079–2086PubMedGoogle Scholar
  67. Egertova M, Elphick MR (2000) Localisation of cannabinoid receptors in the rat brain using antibodies to the intracellular C-terminal of CB1. J Comp Neurol 422:159–171PubMedGoogle Scholar
  68. Egertova M, Giang DK, Cravatt BF, Elphick MR (1998) A new perspective on cannabinoid signalling: complementary localization of fatty acid amide hydrolase and CB1 receptor in brain. Proc R Soc Lond B Biol Sci 265:2081–2085Google Scholar
  69. Egertova M, Cravatt BF, Elphick MR (2003) Comparative analysis of fatty acid amide hydrolase and cb1 cannabinoid receptor expression in the mouse brain: evidence of a widespread role for fatty acid amide hydrolase in regulation of endocannabinoid signaling. Neuroscience 119:481–496PubMedGoogle Scholar
  70. Ellington HC, Cotter MA, Cameron NE, Ross RA (2002) The effect of cannabinoids on capsaicin-evoked calcitonin gene-related peptide (CGRP) release from the isolated paw skin of diabetic and non-diabetic rats. Neuropharmacology 42:966–975PubMedGoogle Scholar
  71. Elmes SJR, Jhaveri MD, Smart D, Kendall DA, Chapman V (2004) Cannabinoid CB2 receptor activation inhibits mechanically evoked responses of wide dynamic range dorsal horn neurons in naive rats and in rat models of inflammatory and neuropathic pain. Eur J Pharmacol 20:2311–2320Google Scholar
  72. Evans RM, Scott RH, Ross RA (2004) Multiple actions of anandamide on neonatal rat cultured sensory neurones. Br J Pharmacol 141:1223–1233PubMedGoogle Scholar
  73. Farquhar-Smith WP, Rice AS (2003) A novel neuroimmune mechanism in cannabinoid-mediated attenuation of nerve growth factor-induced hyperalgesia. Anesthesiology 99:1391–1401PubMedGoogle Scholar
  74. Farquhar-Smith WP, Rice ASC (2001) Administration of endocannabinoids prevents a referred hyperalgesia associated with inflammation of the urinary bladder. Anesthesiology 94:507–513PubMedGoogle Scholar
  75. Farquhar-Smith WP, Egertova M, Bradbury EJ, McMahon SB, Rice ASC, Elphick MR (2000) Cannabinoid CB1 receptor expression in rat spinal cord. Mol Cell Neurosci 15:510–521PubMedGoogle Scholar
  76. Farquhar-Smith WP, Jaggar SI, Rice ASC (2002) Attenuation of nerve growth factor-induced visceral hyperalgesia via cannabinoid CB1 and CB2-like receptors. Pain 97:11–21PubMedGoogle Scholar
  77. 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
  78. Finn DP, Jhaveri MD, Beckett SRG, Roe CH, Kendall DA, Marsden CA, Chapman V (2003) Effects of direct periaqueductal grey administration of a cannabinoid receptor agonist on nociceptive and aversive responses in rats. Neuropharmacology 45:594–604PubMedGoogle Scholar
  79. Fowler CJ, Jacobsson SOP (2002) Cellular transport of anandamide, 2-arachidonoylglycerol and palmitoylethanolamide—target for drug development? Prostaglandins Leukot Essent Fatty Acids 66:193–200PubMedGoogle Scholar
  80. Fox A, Kesingland A, Gentry C, McNair K, Patel S, Urban L, James IF (2001) The role of central and peripheral cannabinoid1 receptors in the antihyperalgesic activity of cannabinoids in a model of neuropathic pain. Pain 92:91–100PubMedGoogle Scholar
  81. Fride E, Feigin C, Ponde DE, Breuer A, Hanus L, Arshavsky N, Mechoulam R (2004) (+)-Cannabidiol analogues which bind cannabinoid receptors but exert peripheral activity only. Eur J Pharmacol 506:179–188PubMedGoogle Scholar
  82. Galiègue S, Mary S, Marchand J, Dussossoy D, Carriere D, Carayon P, Bouaboula M, Shire D, Le Fur G, Casellas P (1995) Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Pharmacol 232:54–61Google Scholar
  83. Gaoni Y, Mechoulam R (1964) Isolation, structure and partial synthesis of an active constituent of hashish. J Am Chem Soc 86:1646–1647Google Scholar
  84. 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
  85. Gerard CM, Mollereau C, Vassart G, Parmentier M (1991) Molecular cloning of a human cannabinoid receptor which is also expressed in testis. Biochem J 279:129–134PubMedGoogle Scholar
  86. Giuffrida A, Parsons LH, Kerr TM, Rodriguez de Fonseca F, Navarro M, Piomelli D (1999) Dopamine activation of endogenous cannabinoid signalling in dorsal striatum. Nat Neurosci 2:358–363PubMedGoogle Scholar
  87. Glass M, Dragunow M, Faull RL (1997) Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain. Neuroscience 77:299–318PubMedGoogle Scholar
  88. Greenwald MK, Stitzer ML (2000) Antinociceptive, subjective and behavioral effects of smoked marijuana in humans. Drug Alcohol Depend 59:261–275PubMedGoogle Scholar
  89. Griffin G, Tao Q, Abood ME (2000) Cloning and pharmacological characterization of the rat CB2 cannabinoid receptor. J Pharmacol Exp Ther 292:886–894PubMedGoogle Scholar
  90. Guhring H, Schuster J, Hamza M, Ates M, Kotalla CE, Brune K (2001) HU210 shows higher efficacy and potency than morphine after intrathecal administration in the mouse formalin test. Eur J Pharmacol 429:127–134PubMedGoogle Scholar
  91. Gutierrez T, Nackley AG, Neely MH, Freeman KG, Edwards GL, Hohmann AG (2003) Effects of neurotoxic destruction of descending noradrenergic pathways on cannabinoid antinociception in models of acute and tonic nociception. Brain Res 987:176–185PubMedGoogle Scholar
  92. Guylas AI, Cravatt BF, Bracey MH, Dinh TP, Piomelli D, Boscia F, Freund TF (2004) Segregation of two endocannabinoid-hydrolysing enzymes into pre-and postsynaptic compartments in the rat hippocampus, cerebellum and amygdala. Eur J Neurosci 20:441–458Google Scholar
  93. Hájos N, Freund TF (2002) Distinct cannabinoid sensitive receptors regulate hippocampal excitation and inhibition. Chem Phys Lipids 121:73–82PubMedGoogle Scholar
  94. Hájos N, Katona I, Naiem SS, Mackie K, Ledent C, Mody I, Freund TF (2000) Cannabinoids inhibit hippocampal GABAergic transmission and network oscillations. Eur J Neurosci 12:3239–3249PubMedGoogle Scholar
  95. Hanus L, Breuer A, Tchilibon S, Shiloah S, Goldenburg D, Horowitz M, Pertwee RG, Ross RA, Mechoulam R, Fride E (1999) HU 308: a specific agonist for CB(2), a peripheral cannabinoid receptor. Proc Natl Acad Sci U S A 96:14228–14233PubMedGoogle Scholar
  96. Harris J, Drew LJ, Chapman V (2000) Spinal anandamide inhibits nociceptive transmission via cannabinoid receptor activation in vivo. Neuroreport 12:2817–2818Google Scholar
  97. Henquet C, Krabbendam L, Spauwen J, Kaplan C, Lieb R, Wittchen HU, van Os J (2005) Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people. Br Med J 330:11Google Scholar
  98. 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
  99. 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
  100. Herzberg U, Eliav E, Bennett GJ, Kopin IJ (1997) The analgesic effects of R(+)-WIN55,212-2 mesylate, a high affinity cannabinoid agonist, in a rat model of neuropathic pain. Neurosci Lett 221:157–160PubMedGoogle Scholar
  101. Hillard CJ (2000) Biochemistry and pharmacology of the endocannabinoids arachidonylethanolamide and 2-arachidonylglycerol. Prostaglandins Other Lipid Mediat 61:3e18Google Scholar
  102. Hohmann AG, Herkenham M (1998) Regulation of cannabinoid and mu opioid receptors in rat lumbar spinal cord following neonatal capsaicin treatment. Neurosci Lett 252:13–16PubMedGoogle Scholar
  103. Hohmann AG, Herkenham M (1999a) Cannabinoid receptors undergo axonal flow in sensory nerves. Neuroscience 92:1171–1175PubMedGoogle Scholar
  104. Hohmann AG, Herkenham M (1999b) Localization of central cannabinoid CB1 receptor messenger RNA in neuronal subpopulations of rat dorsal root ganglia: a double-label in situ hybridization study. Neuroscience 90:923–931PubMedGoogle Scholar
  105. Hohmann AG, Martin WJ, Tsou K, Walker JM (1995) Inhibition of noxious stimulus-evoked activity of spinal cord dorsal horn neurons by the cannabinoid WIN55,212-2. Life Sci 56:2111–2118PubMedGoogle Scholar
  106. Hohmann AG, Tsou K, Walker JM (1998) Cannabinoid modulation of wide dynamic range neurons in the lumbar dorsal horn of the rat by spinally administered WIN55,212. Neurosci Lett 257:119–122PubMedGoogle Scholar
  107. Hohmann AG, Briley EM, Herkenham M (1999a) Pre-and postsynaptic distribution of cannabinoid and mu opioid receptors in rat spinal cord. Brain Res 822:17–25PubMedGoogle Scholar
  108. Hohmann AG, Tsou K, Walker JM (1999b) Cannabinoid suppression of noxious heat-evoked activity in wide dynamic range neurons in the lumbar dorsal horn of the rat. J Neurophysiol 81:575–583PubMedGoogle Scholar
  109. Hohmann AG, Farthing JN, Zvonok AM, Makriyannis A (2004) Selective activation of cannabinoid CB2 receptors suppresses hyperalgesia evoked by intradermal capsaicin. J Pharmacol Exp Ther 308:446–453PubMedGoogle Scholar
  110. Hohmann AG, Suplita II RL, Bolton NM, Neely MH, Fegley D, Mangieri R, Krey JF, Walker JM, Holmes PV, Crystal JD, Duranti A, Tontini M, Tarzia G, Piomelli D (2005) An endocannabinoid mechanism for stress-induced analgesia. Nature 435:1108–1112PubMedGoogle Scholar
  111. Howlett AC (1988) The CB1 cannabinoid receptor in the brain. Neurobiol Dis 5:405–416Google Scholar
  112. 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 54:161–202PubMedGoogle Scholar
  113. Ibrahim MM, Deng H, Zvonok A, Cockayne DA, Kwan J, Mata HP, Vanderah TW, Lai J, Porreca F, Makriyannis A, Malan TP Jr (2003) Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: pain inhibition by receptors not present in the CNS. Proc Natl Acad Sci USA 100:10529–10533PubMedGoogle Scholar
  114. Ibrahim MM, Porreca F, Lai J, Albrecht PJ, Rice FL, Khodortova A, Davar G, Makriyannnis A, Vanderah TW, Mata HP, Malan TP Jr (2005) CB-2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Proc Natl Acad Sci USA 102:3039–3098Google Scholar
  115. Ishac EJN, Jiang L, Lake KD, Varga K, Abood ME, Kunos G (1996) Inhibition of exocytotic noradrenaline release by presynaptic cannabinoid CB1 receptors on peripheral sympathetic nerves. Br J Pharmacol 118:2023–2028PubMedGoogle Scholar
  116. Jaggar SI, Hasnie FS, Sellaturay S, Rice ASC (1998) The anti-hyperalgesic actions of the cannabinoid anandamide and the putative CB2 agonist palmitoylethanolamide investigated in models of visceral and somatic inflammatory pain. Pain 76:189–199PubMedGoogle Scholar
  117. Járai Z, Wagner JA, Varga K, Lake KD, Compton DR, Martin BR, Zimmer AM, Bonner TI, Buckley NE, Mezey E, Razdan RK, Zimmer A, Kunos G (1999) Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors. Proc Natl Acad Sci U S A 96:14136–14141PubMedGoogle Scholar
  118. Johanek LM, Simone DA (2004) Activation of peripheral cannabinoid receptors attenuates cutaneous hyperalgesia produced by a heat injury. Pain 109:432–442PubMedGoogle Scholar
  119. Johanek LM, Simone DA (2005) Cannabinoid agonist, CP55,940, prevents capsaicin-induced sensitization of spinal cord dorsal horn neurons. J Neurophysiol 93:989–997PubMedGoogle Scholar
  120. Johanek LM, Heitmiller DR, Turner M, Nader N, Hodges J, Simone DA (2001) Cannabinoids attenuate capsaicin-evoked hyperalgesia through spinal and peripheral mechanisms. Pain 93:303–315PubMedGoogle Scholar
  121. Jordt SE, Bautista DM, Chuang HH, McKemy DD, Zygmunt PM, Hogestatt ED, Mend ID, Julius D (2004) Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature 427:260–265PubMedGoogle Scholar
  122. Karst M, Salim K, Burstein S, Conrad I, Hoy L, Schneider U (2003) Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: a randomized controlled trial. JAMA 290:1757–1762PubMedGoogle Scholar
  123. Katona I, Sperlagh B, Sik A, Kafalvi A, Vizi ES, Mackie K, Freund TF (1999) Presynaptically located CB1 cannabinoid receptors regulate GABA release from axon terminals of specific hippocampal interneurons. J Neurosci 19:4544–4558PubMedGoogle Scholar
  124. Katona I, Rancz EA, Acsady L, Ledent C, Mackie K, Hajos N, Freund TF (2001)Distribution of CB1cannabinoid receptors in the amygdala and their control of GABAergic transmission. J Neurosci 23:9506–9518Google Scholar
  125. Kearn CS, Greenberg MJ, DiCamelli R, Kurzawa K, Hillard CJ (1999) Relationships between ligand affinities for the cerebellar cannabinoid receptor CB1 and the induction of GDP/GTP exchange. J Neurochem 72:2379–2387PubMedGoogle Scholar
  126. Kehl LJ, Hamamoto DT, Wacnik PW, Croft DL, Norsted BD, Wilcox GL, Simone DA (2003) A cannabinoid agonist differentially attenuates deep tissue hyperalgesia in animal models of cancer and inflammatory muscle pain. Pain 103:175–186PubMedGoogle Scholar
  127. Kelly S, Jhaveri DM, Sagar DR, Kendall DA, Chapman V (2003) Activation of peripheral cannabinoid CB1 receptors inhibits mechanically evoked responses of spinal neurons in non-inflamed rats and rats with hindpaw inflammation. Eur J Neurosci 18:2239–2243PubMedGoogle Scholar
  128. Kemp T, Spike RC, Watt C, Todd AJ (1996) The mu opioid receptor (MOR1) is mainly restricted to neurones that do not contain GABA or glycine in the superficial dorsal horn of the rat spinal cord. Neuroscience 75:1231–1238PubMedGoogle Scholar
  129. Khasabova IA, Simone DA, Seybold VS (2002) Cannabinoids attenuate depolarization-dependent Ca2+ influx in intermediate-size primary afferent neurons of adult rats. Neuroscience 115:613–625PubMedGoogle Scholar
  130. Khasabova IA, Harding-Rose C, Simone DA, Seybold VS (2004) Differential effects of CB1 and opioid agonists on two populations of adult rat dorsal root ganglion neurons. J Neurosci 24:1744–1753PubMedGoogle Scholar
  131. Ko MC, Woods JH (1999) Local administration of delta9-tetrahydrocannabinol attenuates capsaicin-induced thermal nociception in rhesus monkeys: a peripheral cannabinoid action. Psychopharmacology (Berl) 143:322–326PubMedGoogle Scholar
  132. Kouznetsova M, Kelley B, Shen M, Thayer SA (2002) Desensitization of cannabinoid-mediated presynaptic inhibition of neurotransmission between rat hippocampal neurons in culture. Mol Pharmacol 61:477–485PubMedGoogle Scholar
  133. Ledent C, Valverde O, Cossu G, Petitet F, Aubert JF, Beslot F, Bohme GA, Imperato A, Pedrazzini T, Roques BP, Vassart G, Fratta W, Parmentier M (1999) Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice. Science 283:401–404PubMedGoogle Scholar
  134. Lever IJ, Malcangio M (2002) CB1 receptor antagonist SR141716A increases capsaicin-evoked release of Substance P from the adult mouse spinal cord. Br J Pharmacol 135:21–24PubMedGoogle Scholar
  135. Li J, Daughters RS, Bullis C, Bengiamin R, Stucky MW, Brennan J, Simone DA (1999) The cannabinoid receptor agonist WIN55,212-2 blocks the development of hyperalgesia produced by capsaicin in rats. Pain 81:25–34PubMedGoogle Scholar
  136. Liang CY, Huang CC, Hsu KS, Takahashi T (2004) Cannabinoid-induced presynaptic inhibition at the primary afferent trigeminal synapse of juvenile rat brainstem slices. J Physiol 555:85–96PubMedGoogle Scholar
  137. Lichtman AH, Martin BR (1991) Spinal and supraspinal components of cannabinoid-induced antinociception. J Pharmacol Exp Ther 258:517–523PubMedGoogle Scholar
  138. Lichtman AH, Hawkins EG, Griffin G, Cravatt BF (2002) Pharmacological activity of fatty acid amides is regulated, but not mediated, by fatty acid amide hydrolase in vivo. J Pharmacol Exp Ther 302:73–79PubMedGoogle Scholar
  139. Lichtman AH, Shelton CC, Advani T, Cravatt BF (2004a) Mice lacking fatty acid amide hydrolase exhibit a cannabinoid receptor-mediated phenotypic hypoalgesia. Pain 109:319–327PubMedGoogle Scholar
  140. Lichtman AH, Leung D, Shelton C, Saghatelian A, Hardouin C, Boger D, Cravatt BF (2004b) Reversible inhibitors of fatty acid amide hydrolase that promote analgesia: evidence for an unprecedented combination of potency and selectivity. J Pharmacol Exp Ther 311:441–448PubMedGoogle Scholar
  141. Lim G, Sung B, Ji RR, Mao J (2003) Upregulation of spinal cannabinoid-1-receptors following nerve injury enhances the effects of Win 55,212-2 on neuropathic pain behaviors in rats. Pain 105:275–283PubMedGoogle Scholar
  142. Lo VJ, Fu J, Astarita G, La Rana G, Russo R, Calignano A, Piomelli D (2005) The nuclear receptor peroxisome proliferator-activated receptor-alpha mediates the anti-inflammatory actions of palmitoylethanolamide. Mol Pharmacol 67:15–19Google Scholar
  143. Lodzki M, Godin B, Rakou L, Mechoulam R, Gallily R, Touitou E (2003) Cannabidiol-transdermal delivery and anti-inflammatory effect in a murine model. J Control Release 93:377–387PubMedGoogle Scholar
  144. Mackie K, Hille B (1992) Cannabinoids inhibit N-type calcium channels in neuroblastoma-glioma cells. Proc Natl Acad Sci USA 89:3825–3829PubMedGoogle Scholar
  145. 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
  146. 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
  147. Mailleux P, Vanderhaeghen JJ (1992) Distribution of neuronal cannabinoid receptor in the adult rat brain: a comparative receptor binding radioautography and in situ hybridization histochemistry. Neuroscience 48:655–668PubMedGoogle Scholar
  148. Malan TP, Ibrahim MM, Deng H, Liu Q, Mata HP, Vanderah T, Porreca F, Makriyannis A (2001) CB2 cannabinoid receptor-mediated peripheral antinociception. Pain 93:239–245PubMedGoogle Scholar
  149. Malan TP Jr, Ibrahim MM, Vanderah TW, Makriyannis A, Porreca F (2002) Inhibition of pain responses by activation of CB(2) cannabinoid receptors. Chem Phys Lipids 121:191–200PubMedGoogle Scholar
  150. Malan TP, Ibrahim MM, Lai J, Vanderah T, Makriyannis A, Porreca F (2003) CB2 cannabinoid receptor agonists: pain relief without the psychoactive effects? Curr Opin Pharmacol 3:62–67PubMedGoogle Scholar
  151. Malfait AM, Gallily R, Sumariwalla PF, Malik AS, Andreakos E, Mechoulam R, Feldmann M (2000) The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis. Proc Natl Acad Sci USA 97:9561–9566PubMedGoogle Scholar
  152. Manning BH, Merin NM, Meng ID, Amaral DG (2001) Reduction in opioid-and cannabinoid-induced antinociception in Rhesus monkeys after bilateral lesions of the amygdaloid complex. J Neurosci 21:8238–8246PubMedGoogle Scholar
  153. Manning BH, Martin WJ, Meng ID (2003) The rodent amygdala contributes totheproduction of cannabinoid-induced antinociception. Neuroscience 120:1157–1170PubMedGoogle Scholar
  154. Manzanares J, Corchero J, Romero J, Fernandez-Ruiz JJ, Ramos JA, Fuentes JA (1999) Pharmacological and biochemical interactions between opioids and cannabinoids. Trends Pharmacol Sci 20:287–294PubMedGoogle Scholar
  155. Mao J, Price DD, Lu J, Keniston L, Mayer DJ (2000) Two distinctive antinociceptive systems in rats with pathological pain. Neurosci Lett 280:13–16PubMedGoogle Scholar
  156. Marsicano G, Wotjak CT, Azad SC, Bisogno T, Rammes G, Cascio MG, Hermann H, Tang J, Hofmann C (2002) The endogenous cannabinoid system controls extinction of aversive memories. Nature 418:530–534PubMedGoogle Scholar
  157. Martin BR, Compton DR, Thomas BF, Prescott WR, Little PJ, Razdan RK, Johnson MR, Melvin LS, Mechoulam R, Ward SJ (1991) Behavioral, biochemical, and molecular modeling evaluations of cannabinoid analogs. Pharmacol Biochem Behav 40:471–478PubMedGoogle Scholar
  158. Martin WJ, Tsou K, Walker JM (1998) Cannabinoid receptor-mediated inhibition of the rat tail-flick reflex after micro injection into the rostral ventromedial medulla. Neurosci Lett 242:33–36PubMedGoogle Scholar
  159. Martin WJ, Gupta CM, Loo DS, Rohde DS, Basbaum AI (1999a) Differential effects of neurotoxic destruction of descending noradrenergic pathways on acute and persistent nociceptive processing. Pain 80:57–65PubMedGoogle Scholar
  160. Martin WJ, Coffin PO, Attias E, Balinsky M, Tsou K, Walker JM (1999b) Anatomical basis for cannabinoid-induced antinociception as revealed by intracerebral microinjections. Brain Res 822:237–242PubMedGoogle Scholar
  161. Martin WJ, Loo CM, Basbaum AI (1999c) Spinal cannabinoids are anti-allodynic in rats with persistent inflammation. Pain 82:199–205PubMedGoogle Scholar
  162. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346:561–564PubMedGoogle Scholar
  163. Matsuda LA, Bonner TI, Lolait SJ (1993) Localization of cannabinoid receptor mRNA in rat brain. J Comp Neurol 327:535–550PubMedGoogle Scholar
  164. Mazzari S, Canella R, Petrelli L, Marcolongo G, Leon A(1996) N-(2-Hydroxyethyl) hexadecanamide is orally active in reducing edema formation and inflammatory hyperalgesia by down-regulating mast cell activation. Eur J Pharmacol 300:227–236PubMedGoogle Scholar
  165. McAllister SD, Glass M (2002) CB(1) and CB(2) receptor-mediated signalling: a focus on endocannabinoids. Prostaglandins Leukot Essent Fatty Acids 66:161–171PubMedGoogle Scholar
  166. Mechoulam R (2000) Looking back at cannabis research. Curr Pharm Des 6:1313–1322PubMedGoogle Scholar
  167. Mechoulam R, Ben Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, Gopher A, Almog S, Martin BR, Compton DR, et al (1995) Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol 50:83–90PubMedGoogle Scholar
  168. Mechoulam R, Fride E, Ben-Shabat S, Meiri U, Horowitz M (1998) Endocannabinoids. Eur J Pharmacol 359:1–18PubMedGoogle Scholar
  169. 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
  170. Meng ID, Johansen JP (2004) Antinociception and modulation of rostral ventromedial medulla neuronal activity by local microinfusion of a cannabinoid receptor agonist. Neuroscience 124:685–693PubMedGoogle Scholar
  171. Meng ID, Manning BH, Martin WJ, Fields HL (1998) An analgesic circuit activated by cannabinoids. Nature 395:381–383PubMedGoogle Scholar
  172. Millns PJ, Chapman V, Kendall DA (2001) Cannabinoid inhibition of the capsaicin-induced calcium response in rat dorsal root ganglion neurones. Br J Pharmacol 132:969–971PubMedGoogle Scholar
  173. Molina-Holgado F (2002) Cannabinoids promote oligodendrocyte progenitor survival: involvement of cannabinoid receptors and phosphatidylinositol-3 Kinase/Akt signalling. J Neurosci 22:9742–9753PubMedGoogle Scholar
  174. 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
  175. Monhemius R, Azami J, Green DL, Roberts MHT (2001) CB1 receptor mediated analgesia from the nucleus reticularis gigantocellularis pars alpha is activated in an animal model of neuropathic pain. Brain Res 908:67–74PubMedGoogle Scholar
  176. Morisset V, Urban L (2001) Cannabinoid-induced presynaptic inhibition of glutamatinergic EPSCs in sustantia gelatinosa neurons of the rat spinal cord. J Neurophysiol 86:40–48PubMedGoogle Scholar
  177. Moss DE, Johnson RL (1980) Tonic analgesic effects of delta 9 THC as measured with the formalin test. Eur J Pharmacol 61:313–315PubMedGoogle Scholar
  178. Munro S, Thomas KL, Abu Shaar M (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365:61–65PubMedGoogle Scholar
  179. Nackley AG, Makriyannis A, Hohmann AG (2003a) Selective activation of cannabinoid CB2 receptors suppresses spinal fos protein expression and pain behavior in a rat model of inflammation. Neuroscience 119:747–757PubMedGoogle Scholar
  180. Nackley AG, Suplita II, Hohmann AG (2003b) A peripheral cannabinoid mechanism suppresses spinal fos protein expression and pain behavior in a rat model of inflammation. Neuroscience 117:659–670PubMedGoogle Scholar
  181. Nackley AG, Zvonok AM, Makriyannis A, Hohmann AG (2004) Activation of cannabinoid CB2 receptors suppresses C-fiber responses and windup in spinal wide dynamic range neurons in the absence and presence of inflammation. J Neurophysiol 92:3562–3574PubMedGoogle Scholar
  182. Naderi N, Shafaghi B, Khodayar MJ, Zarindast MR (2005) Interaction between gamma-aminobutyric acid GABA-B and cannabinoid CB1 receptors in spinal pain pathways in rat. Eur J Pharmacol 514:159–164PubMedGoogle Scholar
  183. Naef M, Curatolo M, Petersen-Felix S, Arendt-Nielsen L, Zbinden A, Brenneisen R (2003) The analgesic effects of oral delta-nine-tetrahydrocannabinol (THC), morphine and THC-morphine combination in healthy subjects under experimental pain conditions. Pain 105:79–88PubMedGoogle Scholar
  184. Nie J, Lewis DL (2001a) The proximal and distal C-terminal tail domains of the CB1 receptor mediate G protein coupling. Neuroscience 107:161–167PubMedGoogle Scholar
  185. Nie J, Lewis DL (2001b) Structural domains of the CB1 cannabinoid receptor that contribute to constitutive activity and G-protein sequestration. J Neurosci 21:8758–8764PubMedGoogle Scholar
  186. Notcutt W, Price M, Miller R, Newport S, Phillips C, Simmons S, Sansom C (2004) Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 ′N of 1′ studies. Anaesthesia 59:440–452PubMedGoogle Scholar
  187. Noyes R, Brunk SF, Baram DA, Canter A (1975) The analgesic properties of delta-9-THC and codeine. Clin Pharmacol Ther 18:84–89PubMedGoogle Scholar
  188. Offertaler L, Mo FM, Batkai S, Liu J, Begg M, Razdan RK, Martin BR, Bukoski RD, Kunos G (2003) Selective ligands and cellular effectors of a G protein-coupled endothelial cannabinoid receptor. Mol Pharmacol 63:699–705PubMedGoogle Scholar
  189. Oka S, Yanagimoto S, Ikeda S, Gokoh M, Kishimoto S, Waku K, Ishima T, Sugiura T (2005) Evidence for the involvement of the cannabinoid CB2 receptor and its endogenous ligand 2-arachidonoylglycerol in 12-O-tetradecanoylphorbol-13-acetate-induced acute inflammation in mouse ear. J Biol Chem 280:18488–18497PubMedGoogle Scholar
  190. Okamoto Y, Morishita J, Tsuboi K, Tonai T, Ueda N (2004) Molecular characterization of a phospholipase D generating anandamide and its congeners. J Biol Chem 279:5298–5305PubMedGoogle Scholar
  191. Ong WY, Mackie K (1999) A light and electron microscopic study of the CB1 cannabinoid receptor in the primate spinal cord. J Neurocytol 28:39–45PubMedGoogle Scholar
  192. Oshita K, Inoue A, Tang HB, Nakata Y, Kawamoto M, Yuge O (2005) CB1 cannabinoid receptor stimulation modulates transient receptor potential vanilloid receptor 1 activities in calcium influx and substance P release in cultured rat dorsal root ganglion cells. J Pharmacol Sci 97:377–385PubMedGoogle Scholar
  193. Patton GC, Coffey C, Carlin JB, Degenhardt L, Lynskey M, Hall W (2002) Cannabis use and mental health in young people: cohort study. Br Med J 325:1195–1198Google Scholar
  194. Pertwee RG (1997) Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther 74:129–180PubMedGoogle Scholar
  195. Pertwee RG (2001) Cannabinoids and pain. Prog Neurobiol 63:569–611PubMedGoogle Scholar
  196. Pestojamasp VK, Burstein SH (1998) Anandamide synthesis is induced by arachidonate mobilizing agonists in cells of the immune system. Biochim Biophys Acta 1394:249–260Google Scholar
  197. Piomelli D, Beltramo M, Giuffrida A, Stella N (1998) Endogenous cannabinoid signaling. Neurobiol Dis 5:462–473PubMedGoogle Scholar
  198. Presley RW, Menetrey D, Levine JD, Basbaum AI (1990) Systemic morphine suppresses noxious stimulus evoked Fos protein-like immunoreactivity in the rat spinal cord. Jneurosci 110:323–335Google Scholar
  199. Price TJ, Helesic G, Parghi D, Hargreaves KM, Flores CM (2003) The neuronal distribution of cannabinoid receptor type 1 in the trigeminal ganglion of the rat. Neuroscience 120:155–162PubMedGoogle Scholar
  200. Price TJ, Patwardhan A, Akopian AN, Hargreaves KM (2004) Cannabinoid receptor-independent actions of the aminoalkylindole WIN55212-2 on trigeminal sensory neurons. Br J Pharmacol 142:257–266PubMedGoogle Scholar
  201. Puffenbarger R, Boothe AC, Cabral GA (2000) Cannabinoids inhibit LPS-inducible cytokine mRNA expression in rat microglial cells. Glia 29:58–69PubMedGoogle Scholar
  202. Quartilho A, Mata HP, Ibrahim MM, Vanderah TW, Porreca F, Makriyannis A, Malan TP (2003) Inhibition of inflammatory hyperalgesia by activation of peripheral CB2 cannabinoid receptors. Anesthesiology 99:955–960PubMedGoogle Scholar
  203. Raffa RB, Stone DJ, Hipp SJ (1999) Differential cholera-toxin sensitivity of supraspinal antinociception induced by the cannabinoid agonists delta9-THC, WIN 55, 212-2 and anandamide in mice. Neurosci Lett 263:29–32PubMedGoogle Scholar
  204. Randall MD, McCulloch AI, Kendall DA (1997) Comparative pharmacology of endothelium-derived hyperpolarizing factor and anandamide in rat isolated mesentery. Eur J Pharmacol 333:191–197PubMedGoogle Scholar
  205. Rice ASC (2005) Cannabinoids. In: Koltzenburg M, McMahon SB (eds) Melzack and Wall: textbook of pain. Elsevier, LondonGoogle Scholar
  206. Rice ASC, Brooks JW, Thompson SWN (2002) Spinal intrathecal administration of the cannabinoid WIN55,212-2 attenuates pain behaviour in the formalin model. 10th World Congress of Pain, Abstr 839:P109Google Scholar
  207. Richardson JD, Aanonsen L, Hargreaves KM (1997) SR 141716A, a cannabinoid receptor antagonist, produces hyperalgesia in untreated mice. Eur J Pharmacol 319:R3–R4PubMedGoogle Scholar
  208. Richardson JD, Aanonsen L, Hargreaves KM (1998a) Antihyperalgesic effects of spinal cannabinoids. Eur J Pharmacol 345:145–153PubMedGoogle Scholar
  209. Richardson JD, Kilo S, Hargreaves KM (1998b) Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors. Pain 75:111–119PubMedGoogle Scholar
  210. Roberts LA, Christie MJ, Conor M (2002) Anandamide is a partial agonist at native vanilloid receptors in acutely isolated trigeminal sensory neurones. Br J Pharmacol 137:421–428PubMedGoogle Scholar
  211. Rodella LF, Borsani E, Rezzani R, Ricci F, Buffoli B, Bianchi R (2005) AM404, an inhibitor of anandamide reuptake decreases Fos-immunoreactivity in the spinal cord of neuropathic rats after non-noxious stimulation. Eur J Pharmacol 508:139–146PubMedGoogle Scholar
  212. Romero J, Hillard CJ, Calero M, Rabano A (2002) Fatty acid amide hydrolase localization in the human central nervous system: an immunohistochemical study. Mol Brain Res 100:85–93PubMedGoogle Scholar
  213. Ross RA (2003) Anandamide and vanilloid TRPV1 receptors. Br J Pharmacol 140:790–801PubMedGoogle Scholar
  214. Ross RA, Coutts AA, McFarlane SM, Anavi-Goffer S, Irving AJ, Pertwee RG, MacEwan DJ, Scott RH (2001) Actions of cannabinoid receptor ligands on rat cultured sensory neurones: implications for antinociception. Neuropharmacology 40:221–232PubMedGoogle Scholar
  215. Ross RA, Evans RM, Scott RH (2004) Cannabinoids and sensory neurones. Curr Neuropharmacol 2:59–73Google Scholar
  216. Rukwied R, Watkinson A, McGlone F, Dvorak M (2003) Cannabinoid agonists attenuate capsaicin-induced responses in human skin. Pain 102:283–288PubMedGoogle Scholar
  217. Ryberg E, Vu HK, Larsson N, Groblewski T, Hjorth S, Elebring T, Sjogren S, Greasley PJ (2005) Identification and characterisation of a novel splice variant of the human CB1 receptor. FEBS Lett 579:259–264PubMedGoogle Scholar
  218. Salim K, Schneider U, Burstein S, Hoy L, Karst M (2005) Pain measurements and side effect profile of the novel cannabinoid ajulemic acid. Neuropharmacology 48:1164–1171PubMedGoogle Scholar
  219. Salio C, Fischer J, Franzoni MF, Mackie K, Kaneko T, Conrath M (2001) CB 1 cannabinoid and μ opioid receptor co-localization on postsynaptic targets in the rat dorsal horn. Neuroreport 12:3689–3692PubMedGoogle Scholar
  220. Salio C, Fischer J, Franzoni MF, Conrath M (2002a) Pre-and postsynaptic localizations of the CB1 cannabinoid receptor in the dorsal horn of the rat spinal cord. Neuroscience 110:755–764PubMedGoogle Scholar
  221. Salio C, Doly S, Fischer J, Franzoni MF, Conrath M (2002b) Neuronal and astrocytic localization of the cannabinoid receptor-1 in the dorsal horn of the rat spinal cord. Neurosci Lett 329:13–16PubMedGoogle Scholar
  222. Samson MT, Small-Howard A, Shimoda LMN, Koblan-Huberson M, Stokes AJ, Turner H (2003) Differential roles of CB1 and CB2 cannabinoid receptors in mast cells. J Immunol 170:4953–4962PubMedGoogle Scholar
  223. Sanudo-Pena MC, Strangman NM, Mackie K, Walker JM, Tsou K (1999) CB1 receptor localization in rat spinal cord and roots, dorsal root ganglion and peripheral nerve. Acta Pharmacol Sin 20:1115–1120Google Scholar
  224. Scott DA, Wright CE, Angus JA (2004) Evidence that CB-1 and CB-2 cannabinoid receptors mediate antinociception in neuropathic pain in the rat. Pain 109:124–131PubMedGoogle Scholar
  225. Seltzer Z, Dubner R, Yoram S (1990) A novel behavioural model of neuropathic pain disorders produced in rats by partial sciatic nerve injury. Pain 43:205–218PubMedGoogle Scholar
  226. Shen M, Piser TM, Seybold VS, Thayer SA (1996) Cannabinoid receptor agonists inhibit glutamatergic synaptic transmission in rat hippocampal cultures. J Neurosci 16:4322–4334PubMedGoogle Scholar
  227. Shire D, Carillon C, Kaghad M, Calandra B, Rinaldi Carmona M, Le Fur G, Caput D, Ferrara P (1995) An amino-terminal variant of the central cannabinoid receptor resulting from alternative splicing [published erratum appears in J Biol Chem 1996 Dec 27;271(52):33706]. J Biol Chem 270:3726–3731PubMedGoogle Scholar
  228. Shire D, Calandra B, Rinaldi-Carmona M, Oustric D, Pessegue B, Bonnin-Cabanne O, Le Fur G, Caput D, Ferrara P (1996) Molecular cloning, expression and function of the murine CB2 peripheral cannabinoid receptor. Biochim Biophys Acta 1307:132–136PubMedGoogle Scholar
  229. Siegling A, Hofmann HA, Denzer D, Mauler F, De Vry J (2001) Cannabinoid CB1 receptor upregulation in a rat model of chronic neuropathic pain. Eur J Pharmacol 415:R5–R7PubMedGoogle Scholar
  230. Smart D, Gunthorpe MJ, Jerman JC, Nasir S, Gray J, Muir AI, Chambers JK, Randall AD, Davis JB (2000) The endogenous lipid anandamide is a full agonist at the human vanilloid receptor (hVR1). Br J Pharmacol 129:227–230PubMedGoogle Scholar
  231. Smith FL, Fujimore K, Lowe J, Welch SP (1998) Characterisation of delta9 tetrahydrocannabinol and anandamide antinociception in nonarthritic and arthritic rats. Pharmacol Biochem Behav 60:183–191PubMedGoogle Scholar
  232. Smith PB, Martin BR (1992) Spinal mechanisms of delta 9-tetrahydrocannabinol-induced analgesia. Brain Res 578:8–12PubMedGoogle Scholar
  233. Sokal DM, Elmes SJR, Kendall DA, Chapman V (2003) Intraplantar injection of anandamide inhibits mechanically-evoked responses of spinal neurones via activation of CB2 receptors in anaesthetised rats. Neuropharmacology 45:404–411PubMedGoogle Scholar
  234. Solowij N, Stephens RS, Roffman RA, Babor T, Kadden R, Miller M, Christiansen K, McRee B, Vendetti J, et al (2002) Cognitive functioning of long-term cannabis users seeking treatment. JAMA 287:1123–1131PubMedGoogle Scholar
  235. Ständer S, Schmelz M, Metze D, Luger T, Rukwied R (2005) Distribution of cannabinoid receptor 1 (CB1) and 2 (CB2) on sensory nerve fibres and adnexal structures in human skin. J Dermatol 38:177–188Google Scholar
  236. Stella N, Piomelli D (2001) Receptor-dependent formation of endogenous cannabinoids in cortical neurones. Eur J Pharmacol 425:189–196PubMedGoogle Scholar
  237. Stella N, Schweitzer P, Piomelli D (1997) A second endogenous cannabinoid that modulates long-term potentiation. Nature 388:773–778PubMedGoogle Scholar
  238. Strangman NM, Walker JM (1999) Cannabinoid WIN 55,212-2 inhibits the activity-dependent facilitation of spinal nociceptive responses. J Neurophysiol 82:472–477PubMedGoogle Scholar
  239. Sugiura T, Kondo S, Kishimoto S, Miyashita T, Nakane S, Kodaka T, Suhara Y, Takayama H, Waku K (2000) Evidence that 2-arachidonoylglycerol but not N-palmitoylethanolamine or anandamide is the physiological ligand for the cannabinoid CB2 receptor. Comparison of the agonistic activities of various cannabinoid receptor ligands in HL-60 cells. J Biol Chem 275:605–612PubMedGoogle Scholar
  240. Sugiura T, Kobayashi S, Oka S, Waku K (2002) Biosynthesis and degradation of anandamide and 2-arachidonylglycerol and thieir possible physiological significance. Prostaglandins Leukot Essent Fatty Acids 66:173–192PubMedGoogle Scholar
  241. Sun H, Xu J, Della Penna KB, Benz RJ, Kinose F, Holder DJ, Koblan KS, Gerhold DL, Wang H (2002) Dorsal horn-enriched genes identified by DNA microarray, in situ hybridization and immunohistochemistry. BMC Neurosci 3:11PubMedGoogle Scholar
  242. Svendsen KB, Jensen TS, Bach FW (2004) Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial. BMJ 329:253PubMedGoogle Scholar
  243. Thomas EA, Cravatt BF, Danielson PE, Gilula NB, Sutcliffe JG (1997) Fatty acid amide hydrolase, the degradative enzyme for anandamide and oleamide, has selective distribution in neurons within the rat central nervous system. J Neurosci Res 50:1047–1052PubMedGoogle Scholar
  244. Thorat SN, Bhargava HN (1994) Evidence for a bidirectional cross-tolerance between morphine and delta 9-tetrahydrocannabinol in mice. Eur J Pharmacol 260:5–13PubMedGoogle Scholar
  245. Tognetto M, Amadesi S, Harrison S, Creminon C, Trevisani M, Carreras M, Matera M, Geppetti P, Bianchi A (2001) Anandamide excites central terminals of dorsal root ganglion neurons via vanilloid receptor-1 activation. J Neurosci 21:1104–1109PubMedGoogle Scholar
  246. Tsou K, Lowitz KA, Hohmann AG, Martin WJ, Hathaway CB, Bereiter DA, Walker JM (1996) Suppression of noxious stimulus-evoked expression of FOS protein-like immunoreactivity in rat spinal cord by a selective cannabinoid agonist. Neuroscience 70:791–798PubMedGoogle Scholar
  247. Tsou K, Brown S, Mackie K, Sanudo-Pena MC, Walker JM (1998) Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system. Neuroscience 83:393–411PubMedGoogle Scholar
  248. Tsuda M, Inoue K, Salter MW (2005) Neuropathic pain and spinal microglia: a big problem from molecules in’ small’ glia. Trends Neurosci 28:101–107PubMedGoogle Scholar
  249. Twitchell W, Brown S, Mackie K (1997) Cannabinoids inhibit N-and P/Q-type calcium channels in cultured rat hippocampal neurons. J Neurophysiol 78:43–50PubMedGoogle Scholar
  250. Ulugol A, Karadag HC, Ipci Y, Tarner M, Dokmeci I (2004) The effect of WIN 55,212-2, a cannabinoid agonist, on tactile allodynia in diabetic rats. Neurosci Lett 371:167–170PubMedGoogle Scholar
  251. Vaughan CW, McGregor IS, Christie MJ (1999) Cannabinoid receptor activation inhibits GABAergic neurotransmission in rostral ventromedial medulla neurons in vitro. Br J Pharmacol 127:935–940PubMedGoogle Scholar
  252. Vaughan CW, Connor M, Bagley EE, Christie MJ (2000) Actions of cannabinoids on membrane properties and synaptic transmission in rat periaqueductal gray neurons in vitro. Mol Pharmacol 57:288–295PubMedGoogle Scholar
  253. Wade DT, Robson P, House H, Makela P, Aram J (2003) A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Clin Rehabil 17:18–26Google Scholar
  254. Walker JM, Huang SM, Strangman NM, Tsou K, Sanudo Pena MC (1999) Pain modulation by release of the endogenous cannabinoid anandamide. Proc Natl Acad Sci USA 96:12198–12203PubMedGoogle Scholar
  255. Wallace VCJ, Cottrell DF, Brophy PJ, Fleetwood-Walker SM (2003) Focal lysolecithin-induced demyelination of peripheral afferents results in neuropathic pain behavior that is attenuated by cannabinoids. J Neurosci 23:3221–3233PubMedGoogle Scholar
  256. Walter L, Stella N (2004) Cannabinoids and neuroinflammation. Br J Pharmacol 141:775–785PubMedGoogle Scholar
  257. Walter L, Franklin A, Witting A, Wade C, Xie Y, Kunos G, Mackie K, Stella N (2003) Nonpsychotropic cannabinoid receptors regulate microglial cell migration. J Neurosci 23:1398–1405PubMedGoogle Scholar
  258. Ware MA, Doyle CR, Woods R, Lynch ME, Clark AJ (2003) Cannabis use for chronic noncancer pain: results of a prospective survey. Pain 102:211–216PubMedGoogle Scholar
  259. Ware MA, Adams H, Guy GW (2005) The medicinal use of cannabis in the UK: results of a nationwide survey. Int J Clin Pract 59:291–295PubMedGoogle Scholar
  260. Watkins LR, Milligan ED, Maier SF (2001) Spinal cord glia: new players in pain. Pain 93:201–205PubMedGoogle Scholar
  261. Watkins LR, Milligan ED, Maier SF (2003) Immune and glial involvement in physiological and pathological exaggerated pain states. Progress in Pain Research and Management, Proceedings of the 10th World Congress on Pain 24:369–385. IASP Press, SeattleGoogle Scholar
  262. Welch SP, Eads M (1999) Synergistic interactions of endogenous opioids and cannabinoid systems. Brain Res 848:183–190PubMedGoogle Scholar
  263. Woolridge E, Barton S, Samuel J, Osorio J, Dougherty A, Holdcroft A (2005) Cannabis use in HIV for pain and other medical symptoms. J Pain Symptom Manage 29:358–367PubMedGoogle Scholar
  264. Yesilyurt O, Dogrul A, Gul H, Seyrek M, Kusmes O, Ozkan Y, Yildiz O (2003) Topical cannabinoid enhances topical morphine antinociception. Pain 105:303–308PubMedGoogle Scholar
  265. Yu M, Ives D, Ramesha CS (1997) Synthesis of prostaglandin E2 ethanolamide from anandamide by cyclooxygenase-2. J Biol Chem 272:21181–21186PubMedGoogle Scholar
  266. Zajicek J, Fox P, Sanders H, Wright D, Vickery J, Nunn A, Thompson A (2003) Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. Lancet 362:1517–1526PubMedGoogle Scholar
  267. Zammit S, Allebeck P, Andreasson S, Lundberg I, Lewis G (2002) Self reported cannabis use as a risk factor for schizophrenia in Swedish conscripts of 1969: historical cohort study. Br Med J 325:1199Google Scholar
  268. Zhang J, Hoffert C, Khang V, Groblewski T, Ahmad S, O’Donnell D (2003) Induction of CB2 receptor expression in the rat spinal cord of neuropathic but not inflammatory chronic pain models. Eur J Pharmacol 17:2750–2754Google Scholar
  269. Zimmer A, Zimmer AM, Hohmann AG, Herkenham M, Bonner TI (1999) Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice. Proc Natl Acad Sci USA 96:5780–5785PubMedGoogle Scholar
  270. Zygmunt PM, Petersson J, Andersson DA, Chuang H, Sorgard M, Di Marzo V, Julius D, Hogestatt ED (1999) Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 400:452–457PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2006

Authors and Affiliations

  1. 1.Pain Research Group, Department of Anaesthetics, Intensive Care and Pain MedicineImperial College London, Chelsea and Westminster Hospital CampusLondonUK

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