Abstract
A large body of literature indicates that cannabinoids suppress behavioral responses to acute and persistent noxious stimulation in animals. This review exax mines neuroanatomical, behavioral, and neurophysiological evidence supporting a role for cannabinoids in suppressing pain at spinal, supraspinal, and peripheral levels. Localization studies employing receptor binding and quantitative autoradiography, immunocytochemistry, and in situ hybridization are reviewed to examine the distribution of cannabinoid receptors at these levels and provide a neuroanatomical framework with which to understand the roles of endogenous cannabinoids in sensory processing. Pharmacological and transgenic approaches that have been used to study cannabinoid antinociceptive mechanisms are described. These studies provide insight into the functional roles of cannabinoid CB1 (CB1R) and CB2 (CB2R) receptor subtypes in cannabinoid antinociceptive mechanisms, as revealed in animal models of acute and persistent pain. The role of endocannabinoids and related fatty acid amides that are implicated in endogenous mechanisms for pain suppression are discussed. Human studies evaluating therapeutic potential of cannabinoid pharmacotherapies in experimental and clinical pain syndromes are evaluated. The potential of exploiting cannabinoid antinociceptive mechanisms in novel pharmacotherapies for pain is discussed.
Access provided by Autonomous University of Puebla. Download to read the full chapter text
Chapter PDF
Similar content being viewed by others
Keywords
References
Abrams DI, Hilton JF, Leiser RJ, Shade SB, Elbeik TA, Aweeka FT, Benowitz NL, Bredt BM, Kosel B, Aberg JA, Deeks SG, Mitchell TF, Mulligan K, Bacchetti P, McCune JM, Schambeln M (2003) Short-term effects of cannabinoids in patients with HIV-1 infection: a randomized, placebo-controlled clinical trial. Ann Intern Med 139:258–266
Adams IB, Compton DR, Martin BR (1998) Assessment of anandamide interaction with the cannabinoid brain receptor: SR 141716A antagonism studies in mice and autoradiographic analysis of receptor binding in rat brain. J Pharmacol Exp Ther 284:1209–1217
Ahluwalia J, Urban L, Capogna M, Bevan S, Nagy I (2000) Cannabinoid 1 receptors are expressed in nociceptive primary sensory neurons. Neuroscience 100:685–688
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 110:747–753
Akil H, Mayer DJ, Liebeskind JC (1976) Antagonism of stimulation-produced analgesia by naloxone, a narcotic antagonist. Science 191:961–962
Arner S, Meyerson BA (1988) Lack of analgesic effect of opioids on neuropathic and idiopathic forms of pain [see comments]. Pain 33:11–23
Averill S, McMahon SB, Clary DO, Reichardt LF, Priestley JV (1995) Immunocytochemical localization of trkA receptors in chemically identified subgroups of adult rat sensory neurons. Eur J Neurosci 7:1484–1494
Baumann TK, Simone DA, Shain CN, LaMotte RH (1991) Neurogenic hyperalgesia: the search for the primary cutaneous afferent fibers that contribute to capsaicin-induced pain and hyperalgesia. J Neurophysiol 66:212–227
Beaulieu P, Bisogno T, Punwar S, Farquhar-Smith WP, Ambrosino G, Di Marzo V, Rice AS (2000) Role of the endogenous cannabinoid system in the formalin test of persistent pain in the rat. Eur J Pharmacol 396:85–92
Beecher HK (1959) The measurement of subjective responses: quantitative effects of drugs. Oxford University Press, New York, pp 164–166
Bellgowan PS, Helmstetter FJ (1996)Neural systems for the expression of hypoalgesia durin nonassociative fear. Behav Neurosci 110727–736
Beltramo M, Stella N, Calignano A, Lin SY, Makriyannis A, Piomell D (1997) Functional role of high-affinity anandamide transport, as revealed by selective inhibition. Science 277:1094–1097
Ben-Shabat S, Fride E, Sheskin T, Tamiri T, Rhee MH, Vogel Z, Bisogno T, De Petrocellis L, Di Marzo V, Mechoulam R (1998) An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. Eur J Pharmacol 353:23–31
Bereiter DA, Bereiter DF, Hirata H (2002) Topical cannabinoid agonist, WIN55,212-2, reduces cornea-evoked trigeminal brainstem activity in the rat. Pain 99:547–556
Berkley KJ, Hubscher CH (1995) Are there separate central nervous system pathways for touch and pain? Nat Med 1:766–773
Besse D, Lombard MC, Zajac JM, Roques BP, Besson JM (1990) Pre-and postsynaptic distribution of ;, δ and κ opioid receptors in the superficial layers of the cervical dorsal horn of the rat spinal cord. Brain Res 521:15–22
Bicher HI, Mechoulam R (1968) Pharmacological effects of two active constituents of marihuana. Arch Int Pharmacodyn Ther 172:24–31
Bisogno T, Melck D, Bobrov M, Gretskaya NM, Bezuglo VV, De Petrocellis L, D Marzo V (2000)N-Acyl-dopamines novel synthetic CB(1) cannabinoid-receptor ligands and inhibitors of anandamide inactivation with cannabimimetic activity in vitro and in vivo. Biochem J 351:817–824
Bloom AS, Dewey WL, Harris LS, Brosius KK (1977) 9-nor-9beta-hydroxyhexahydrocannabinol, a cannabinoid with potent antinociceptive activity: comparisons with morphine. J Pharmacol Exp Ther 200:263–270
Breyer RM, Bagdassarian CK, Myers SA, Breyer MD (2001) Prostanoid receptors: subtypes and signaling Annu Rev Pharmacol Toxicol 41:661–690
Bridges D, Ahmad K, Rice AS (2001) The synthetic cannabinoid WIN55,212-2 attenuates hyperalgesia and allodynia in a rat model of neuropathic pain. Br J Pharmacol 133:586–594
Bridges D, Rice AS, Egertová 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 119:803–812
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 63:161–168
Burstein SH, Karst M, Schneider U, Zurier RB (2004) Ajulemic acid: a novel cannabinoid produces analgesia without a “high”. Life Sci 75:1513–1522
Buxbaum DM (1972) Analgesic activity of Δ 9-tetrahydrocannabinol in the rat and mouse. Psychopharmacologia 25:275–280
Calignano A, La Rana G, Giuffrida A, Piomelli D (1998) Control of pain initiation by endogenous cannabinoids. Nature 394:277–281
Calza L, Pozza M, Zanni M, Manzini CU, Manzini E, Hokfelt T (1998) Peptide plasticity in primary sensory neurons and spinal cord during adjuvant-induced arthritis in the rat: an immunocytochemical and in situ hybridization study. Neuroscience 82:575–589
Chapman V (1999) The cannabinoid CB1 receptor antagonist, SR141716A, selectively facilitates nociceptive responses of dorsal horn neurones in the rat. Br J Pharmacol 127:1765–1767
Clark WC Janal MN Zeidenberg P Nahas G (1981) Effects of moderate and high doses of marihuana on thermal pain: a sensory decision theory analysis. J Clin Pharmacol 21:299S–310S
Clayton N, Marshall FH, Bountra C, O’shaughnessy CT (2002) CB1 and CB2 cannabinoid receptors are implicated in inflammatory pain. Pain 96:253–260
Coderre TJ, Melzack R (1992) The contribution of excitatory amino acids to central sensitization and persistent nociception after formalin-induced tissue injury. J Neurosci 12:3665–3670
Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB (1996) Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 384:83–87
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 U S A 98:9371–9376
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 U S A 101:10821–10826
Davis M, Whalen PJ (2001) The amygdala: vigilance and emotion. Mol Psychiatry 6:13–34
De Petrocellis L, Bisogno T, Davis JB, Pertwee RG, Di Marzo V (2000) Overlap between the ligand recognition properties of the anandamide transporter and the VR1 vanilloid receptor: inhibitors of anandamide uptake with negligible capsaicin-like activity. FEBS Lett 483:52–56
DeLeo JA, Tanga FY, Tawfik VL (2004) Neuroimmune activation and neuroinflammation in chronic pain and opioid tolerance/hyperalgesia. Neuroscientist 10:40–52
Deutsch DG, Chin SA (1993) Enzymatic synthesis and degradation of anandamide, a cannabinoid receptor agonist. Biochem Pharmacol 46:791–796
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 258:1946–1949
Di Marzo V, Bisogno T, Sugiura T, Melck D, De Petrocellis L (1998) The novel endogenous cannabinoid 2-arachidonoylglycerol is inactivated by neuronal-and basophil-like cells: connections with anandamide. Biochem J 331:15–19
Dixon WE (1899) The pharmacology of cannabis. Indica Br Med J 2:1354–1357
Dogrul A, Gul H, Akar A, Yildiz O, Bilgin F, Guzeldemir E (2003) Topical cannabinoid antinociception: synergy with spinal sites. Pain 105:11–16
Donaldson LF, McQueen DS, Seckl JR (1994) Local anaesthesia prevents acute inflammatory changes in neuropeptide messenger RNA expression in rat dorsal root ganglia neurons. Neurosci Lett 175:111–113
Dray A (1995) Inflammatory mediators of pain. Br J Anaesth 75:125–131
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 12:2079–2086
Egertová M, Giang DK, Cravatt BF, Elphick MR (1998) A new perspective on cannabinoid signalling: complementary localization of fatty acid amide hydrolase and the CB1 receptor in rat brain. Proc R Soc Lond B Biol Sci 265:2081–2085
Egertová M, Cravatt BF, Elphick MR (2003) Comparative analysis of fatty acid amide hydrolase and CB(1) cannabinoid receptor expression in the mouse brain: evidence of a widespread role for fatty acid amide of endocannabinoid signaling. Neuroscience 119:481–496
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 42966–975
Farquhar-Smith WP, Egertova M, Bradbury EJ, McMahon SB, Rice AS, Elphick MR (2000) Cannabinoid CB(1) receptor expression in rat spinal cord. Mol Cell Neurosci 15:510–521
Farquhar-Smith WP, Jaggar SI, Rice AS (2002) Attenuation of nerve growth factor-induced visceral hyperalgesia via cannabinoid CB(1) and CB(2)-like receptors. Pain 97:11–21
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 90:7656–7660
Fezza F, Bisogno T, Minassi A, Appendino G, Mechoulam R, Di Marzo V (2002) Noladin ether, a putative novel endocannabinoid: inactivation mechanisms and a sensitive method for its quantification in rat tissues. FEBS Lett 513:294–298
Fields HL, Heinricher MM, Mason P (1991) Neurotransmitters in nociceptive modulatory circuits. Annu Rev Neurosci 14:219–245
Fox A, Kesingland A, Gentry C, McNair K, Patel S, Urban L, James I (2001) The role of central and peripheral cannabinoid1 receptors in the antihyperalgesic activity of cannabinoids in a model of neuropathic pain. Pain 92:91–100
Fride E (1995) Anandamides: tolerance and cross-tolerance to delta 9-tetrahydrocannabinol. Brain Res 697:83–90
Fride E, Mechoulam R (1993) Pharmacological activity of the cannabinoid receptor agonist, anandamide, a brain constituent. Eur J Pharmacol 231:313–314
Galeazza MT, Garry MG, Yost HJ, Strait KA, Hargreaves KM, Seybold VS (1995) Plasticity in the synthesis and storage of substance P and calcitonin gene-related peptide in primary afferent neurons during peripheral inflammation. Neuroscience 66:443–458
Gilbert PE (1981) A comparison of THC, nantradol, nabilone, and morphine in the chronic spinal dog. J Clin Pharmacol 21:311S–319S
Gong LW, Ding YQ, Wang D, Zheng HX, Qin BZ, Li JS, Kaneko T, Mizuno N (1997) GABAergic synapses on mu-opioid receptor-expressing neurons in the superficial dorsal horn: an electron microscope study in the cat spinal cord. Neurosci Lett 227:33–36
Grant G (1995) Primary afferent projections to the spinal cord. In: Paxinos G (ed) The Rat Nervous System, 2nd edn. Academic Press, San Diego, 61–65
Griffin G, Fernando SR, Ross RA, McKay NG, Ashford ML, Shire D, Huffman JW, Yu S, Lainton JA, Pertwee RG (1997) Evidence for the presence of CB2-like cannabinoid receptors on peripheral nerve terminals. Eur J Pharmacol 339:53–61
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 454:153–163
Gutierrez T, Nackley AG, Neely MH, Freeman KG, Edwards GL, Hohmann AG (2003) Effects of neurotoxic destruction of descending noradrenergic pathways on cannabinoid antinocicepetion in models of acute and tonic nociception. Brain Res 987:176–185
Hanani M, Huang TY, Cherkas PS, Ledda M, Pannese E (2002) Glial cell plasticity in sensory ganglia induced by nerve damage. Neuroscience 114:279–283
Hanesch U, Blecher F, Stiller RU, Emson PC, Schaible HG, Heppelmann B (1995) The effect of a unilateral inflammation at the rats ankle joint on the expression of preprotachykinin-A mRNA and preprosomatostatin mRNA in dorsal root ganglion cells—a study using non-radioactive in situ hybridization. Brain Res 700:279–284
Hanus L, Gopher A, Almog S, Mechoulam R (1993) Two new unsaturated fatty acid ethanolamides in brain that bind to the cannabinoid receptor. J Med Chem 36:3032–3034
Hanus L, Breuer A, Tchilibon S, Shiloah S, Goldenberg 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 96:14228–14233
Hanus L, Abu-Lafi S, Fride E, Breuer A, Vogel Z, Shalev DE, Kustanovich I, Mechoulam R (2001) 2-Arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor. Proc Natl Acad Sci U S A 98:3662–3665
Harris J, Drew LJ, Chapman V (2000) Spinal anandamide inhibits nociceptive transmission via cannabinoid receptor activation in vivo. Neuroreport 11:2817–2819
Helmstetter FJ (1992) The amygdala is essential for the expression of conditional hypoalgesia. Behav Neurosci 106:518–528
Helmstetter FJ, Bellgowan PS (1993) Lesions of the amygdala block conditional hypoalgesia on the tail flick test. Brain Res 612:253–257
Helmstetter FJ, Bellgowan PS, Tershner SA (1993) Modulation of spinal nociceptive reflexes by the microinjection of morphine into the amygdala. NeuroReport 4:471–474
Helmstetter FJ, Bellgowan PS, Poore LH (1995) Microinfusion of mu, but not delta or kappa opioid agonists into the basolateral amygdala results in inhibition of the tail flick reflex in pentobarbital-anesthetized rats. J Pharmacol Exp Ther 275:381–388
Helyes Z, Nemeth J Than M, Bolcskei K, Pinter E, Szolcsanyi J (2003) Inhibitory effect of anandamide on resiniferatoxin-induced sensory neuropeptide release in vivo and neuropathic hyperalgesia in the rat. Life Sci 73:2345–2353
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 11:563–583
Herzberg U, Eliav E, Bennett GJ, Kopin IJ (1997) The analgesic effects of R(+)-WIN 55,212-2 mesylate, a high affinity cannabinoid agonist, in a rat model of neuropathic pain. Neurosci Lett 221:157–160
Hill SY, Schwin R, Goodwin DW, Powell BJ (1974) Marihuana and pain. J Pharmacol Exp Ther 188:415–418
Hohmann AG (2002) Spinal and peripheral mechanisms of cannabinoid antinociception: behavioral, neurophysiological and neuroanatomical perspectives. Chem Phys Lipids 121173–190
Hohmann AG, Herkenham M (1998) Regulation of cannabinoid and mu opioid receptor binding sites following neonatal capsaicin treatment. Neurosci Lett 252:13–16
Hohmann AG, Herkenham M (1999a) Cannabinoid receptors undergo axonal flow in sensory nerves. Neuroscience 92:1171–1175
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 90:923–931
Hohmann AG, Martin WJ, Tsou K, Walker JM (1995) Inhibition of noxious stimulus-evoked activity of spinal cord dorsal horn neurons by the cannabinoid WIN 55,212-2. Life Sci 56:2111–2118
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 WIN55,212-2 Neurosci Lett 257:119–122
Hohmann A Briley EM, Herkenham M (1999a) Pre-and postsynaptic distribution of cannabinoid and mu opioid receptors in rat spinal cord. Brain Res 822:17–25
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 81:575–583
Hohmann AG, Tsou K, Walker JM (1999c) Intrathecal cannabinoid administration suppresses noxious-stimulus evoked Fos protein-like immunoreactivity in rat spinal cord: comparison with morphine Acta Pharmacol Sin 20:1132–1136
Hohmann AG, Neely MH, Suplita RL, Nackley AG, Holmes PV, Crystal JD (2001) Endocannabinoid mechanisms of stress-induced analgesia. Soc Neurosci Abstr 27:716–719
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 308:446–453
Huang SM, Bisogno T, Trevisan M, Al-Hayani A, De Petrocellis L, Fezza F, Tognetto M, Petros TJ, Krey JF, Chu CJ, Miller JD, Davies SN, Geppetti P, Walker JM, Di Marzo V (2002) An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors Proc Natl Acad Sci U S A 99:8400–8405
Hunt SP, Pini A, Evan G (1987) Induction of c-fos-like protein in spinal cord neurons following sensory stimulation Nature 328:632–634
Ibrahim MM, Deng H, Zvonok A, Cockayne DA, Kwan J, Mata HP, Vanderah TW, Lai J, Porreca F, Makriyannis A, Malan TP (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 100:10529–10533
Jennings EA, Vaughan CW, Christie MJ (2001) Cannabinoid actions on rat superficial medullary dorsal horn neurons in vitro J Physiol 534:805–812
Ji RR, Zhang X, Wiesenfeld-Hallin Z, Hokfel T (1994) Expression of neuropeptide Y and neuropeptide Y (Y1) receptormRNA in rat spinal cord and dorsal root ganglia following peripheral tissue inflammation. J Neurosci 14:6423–6434
Ji RR, Zhang X, Zhang Q, Dagerlind A, Nilsson S, Wiesenfeld-Hallin Z, Hokfelt T (1995) Central and peripheral expression of galanin in response to inflammation Neuroscience 6:563–576
Johanek LM, Simone DA (2004) Activation of peripheral cannabinoid receptors attenuates cutaneous hyperalgesia produced by a heat injury Pain 109:432–442
Johanek LM, Heitmiller DR, Turner M, Nader N, Hodges J, Simone DA (2001) Cannabinoids attenuate capsaicin-evoked hyperalgesia through spinal and peripheral mechanisms. Pain 93:303–315
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 290:1757–1762
Kelly S, Chapman V (2001) Selective cannabinoid CB1 receptor activation inhibits spinal nociceptive transmission in vivo. J Neurophysiol 86:3061–3064
Kemp T, Spike RC, Watt C, Todd AJ (1996) The mu-opioid receptor (MOR1) is mainly restricted to neurons that do not contain GABA or glycine in the superficial dorsal horn of the rat spinal cord. Neuroscience751231–1238
Kenins P (1982)Responses of single nerve fibres to capsaicin applied to the skin. Neurosci Lett 29:83–88
Khasabova IA, Simone DA, Seybold VS (2002) Cannabinoids attenuate depolarizationdependent Ca2+ influx in intermediate-size primary afferent neurons of adult rats. Neuroscience 115:613–625
Klegeris A, Bissonnette CJ, McGeer PL (2003)Reduction of human monocytic cell neurotoxicity and cytokine secretion by ligands of the cannabinoid-type CB2 receptor. Br J Pharmacol 139:775–786
Ko MC, Woods JH (1999) Local administration of delta9-tetrahydrocannabinol attenuates capsaicin-induced thermal nociception in rhesus monkeys: a peripheral cannabinoid] action. Psychopharmacology (Berl) 143:322–326
Koga D, Santa T, Fukushima T, Homma H, Imai K (1997) Liquid chromatographic-atmospheric pressure chemical ionizationmass spectrometric determination of anandamide and its analogs in rat brain and peripheral tissues. J Chromatogr B Biomed Sci Appl 690:7–13
Kosersky DS, Dewey WL, Harris LS (1973) Antipyretic, analgesic and anti-inflammatory effects of delta 9-tetra hydrocannabinol in the rat. Eur J Pharmacol 24:1–7
Kozak KR, Rowlinson SW, Marnett LJ (2000) Oxygenation of the endocannabinoid, 2-arachidonylglycerol, to glyceryl prostaglandins by cyclooxygenase-2. J Biol Chem275: 33744–33749
Kozak KR, Crews BC, Morrow JD, Wang LH, Ma YH, Weinander R, Jakobsson PJ, Marnett LJ (2002) Metabolism of the endocannabinoids, 2-arachidonylglycerol and anandamide, into prostaglandin,thromboxane, and prostacyclin glycerol esters and ethanolamides Biol Chem 277:44877–44885
Kruger L, Light AR, Schweizer FE (2003)Axonal terminals of sensory neurons and their morphological diversity. J Neurocytol 3:205–216
LaMotte R, Shain CN, Simone DA, Tsai EF (1991)Neurogenic hyperalgesia: psychophysical studies of underlying mechanisms. J Neurophysiol 66:190–211
LaMotte RH, Lundberg LE, Torebjörk HE (1992) Pain, hyperalgesia and activity in nociceptive C units in humans after intradermal injection of capsaicinJ Physiol 448:749–764
Landsman RS, Burkey TH, Consroe P, Roeske WR, Yamamura HI (1997) SR141716A is an inverse agonist at the human cannabinoid CB1 receptor Eur J Pharmaco 334R1–R2
Ledent C, Valverd 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 283:401–404
Leslie TA, Emson PC, Dowd PM, Woolf CJ (1995) Nerve growth factor contributes to the upregulation of growth-associated protein 43 and preprotachykinin A messenger RNAs in primary sensory neurons following peripheral inflammation Neuroscience 67:753–761
Li J, Daughters RS, Bullis C, Bengiamin R, Stucky7 MW, Brennan J, Simone DA (1999) The cannabinoid receptor agonist WIN55,212-2 atmesylate blocks the development of hyperalgesia produced by capsaicin in rats. Pain8:25–33
Li L, Zhou XF (2001) PericellularGriffonia simplicifolia I isolectin B4-binding ring structures in the dorsal root ganglia following peripheral nerve injury in rats J Comp Neurol 439:259–274
Lichtman AH, Martin BR (1991a) Cannabinoid-induced antinociception is mediated by a spinal a2-noradrenergic mechanism Brain Res 559:309–314
Lichtman AH, Martin BR (1991b) Spinal and supraspinal components of cannabinoidinduced antinociception. J Pharmacol Exp Ther 258:517–523
Lichtman AH, Shelton CC, Advani T, Cravatt BF (2004) Mice lacking fatty acid amide hydrolase exhibit a cannabinoid receptor-mediated phenotypic hypoalgesia. Pain 109:319–327
Lim G, Sung B, JiRR, Mao J (2003) Upregulation of spinal cannabinoid-1-receptors following nerve injury enhances the effects of Win55,212-2 tion neuropathic pain behaviors in rats Pain 105:275–283
Luo C, Kumamoto E, Furue H, Chen J, Yoshimura M (2002) Anandamide inhibits excitatory transmission to rat substantia gelatinosa neurones in a manner different from that of capsaicin Neurosci Lett 321:17–20
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 48:655–668
Malan TP, Ibrahim MM, Makriyannis A, Porreca F (2004) CB2 cannabinoid receptors may produce peripheral analgesia by stimulating local release of endogenous opioids. 2004 Symposium on the Cannabinoids. International Cannabinoid Research Society,p 52
Malan TPJr, Ibrahim MM, Deng H, Liu Q, Mata HP, Vanderah T, Porreca F, Makriyannis A (2001) CB2cannabinoid receptor-mediated peripheral antinociception Pain 9:239–245
Malmberg AB, Chen C, Tonegawa S, Basbaum AI (1997) Preserved acute pain and reduced neuropathic pain in mice lacking PKCgamma Science 278279–283
Manning BH, Mayer DJ (1995) The central nucleus of the amygdala contributes to the production of morphine antinociception in the formalin test. Pain 63:141–152
Manning BH, Merin NM, Meng ID, Amaral DG (2001)Reductioninopioid-andcannabinoidinduced antinociception in rhesus monkeys after bilateral lesions of the amygdaloid complex J Neurosci 21:8238–8246
Manning BH, Martin WJ, Meng ID (2003) Therodent amygdala contributes totheproduction of cannabinoid-induced antinociception Neuroscience 120:1157–1170
Mao J, Price DD, Lu J, Keniston L, Mayer DJ (2000) Two distinctive antinociceptive systems in rats with pathological pain Neurosci Lett 28:13–16
Marsicano G, Wotjak CT, Azad SC, Bisogno T, Rammes G, Cascio MG, Hermann H, Tang J, Hofmann C, Zieglgansberger W, Di Marzo V, Lutz B (2002) The endogenous cannabinoid system controls extinction of aversive memories Nature 418:530–534
Martin BR, Compton DR, Thomas BF, Prescott WR, Little PJ, Razdan RK, Johnson MR, Melvin LS, Mechoulam R, Ward SJ (1991) Behavioral, biochemical, and molecularmodeling evaluations of cannabinoid analogs Pharmacol Biochem Behav 40:47–478
Martin WJ, Lai NK, Patrick SL, Tsou K, Walker JM (1993) Antinociceptive actions of cannabinoids following intraventricular administration in rats Brain Res 629:300–304
Martin WJ, Patrick SL, Cof.n PO, Tsou K, Walker JM (1995) An examination of the central sites of action of cannabinoid-induced antinociception in the rat Life Sci 56:2103–2109
Martin WJ, Hohmann AG, Walker JM (1996) Suppression of noxious stimulus-evoked activity in the ventral posterolateral nucleus of the thalamus by a cannabinoid agonist: correlation between electrophysiological and antinociceptive effects JNeurosci 16:6601–6611
Martin WJ, Tsou K, Walker JM (1998) Cannabinoid receptor-mediated inhibition of the rat tail-flick reflex aftermicroinjection into the rostral ventromedialmedulla Neurosci Lett 242:33–36
Martin WJ, Cof.n PO, Attias E, Balinsky M, Tsou K, Walker JM (1999a) Anatomical basis for cannabinoid-induced antinociception as revealed by intracerebral microinjections Brain Res 822:237–242
Martin WJ, Loo CM, Basbaum AI (1999b) Spinal cannabinoids are anti-allodynic in rats with persistent inflammation Pain 82:199–205
Mazzari S, Canella R, Petrell iL, Marcolongo G, Leon A(1996) N-(2-hydroxyethyl) hexadecanamide is orally active in reducing edema formation and inflammatory hyperalgesia by down-modulating mast cell activation Eur J Pharmacol 300:227–236
McCall WD, Tanner KD, Levine JD (1996) Formalin induces biphasic activity in C-fibers in the rat. Neurosci Lett 208:45–48
McMahon SB (1996) NGF as a mediator of inflammatory pain. Philos Trans R Soc Lond B Biol Sci 351431–440
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 50:83–90
Medina JF, Repa CJ, Mauk MD, LeDoux JE (2002) Parallels between cerebellum-and amygdala-dependent conditioning. Nature Rev Neuroscience 3:122–131
Meng ID, Manning BH, Martin WJ, Fields HL (1998) An analgesia circuit activated by cannabinoids Nature 395:381–384
Millan MJ (1999) The induction of pain: an integrative review Prog Neurobiol 57:1–164
Molander C, Grant G (1995) Spinal cord cytoarchitecture. In: Paxinos G (ed) The rat nervous system. Academic Press, San Diego, 39–45
Molliver DC, Radeke MJ, Feinstein SC, Snider WD(1995) Presence or absence ofTrkAprotein distinguishes subsets of small sensory neuronswith unique cytochemical characteristics and dorsal horn projections. J Comp Neurol 36:404–416
Monhemius R, Azami J, Green DL, Roberts MH (2001) CB1 receptor mediated analgesia fromthe nucleus reticularis gigantocellularis pars alpha is activated in an animal model of neuropathic pain Brain Res 908:67–74
Moreau JL, Fields HL (1986) Evidence for GABA involvement in midbrain control of medullary neurons that modulate nociceptive transmission Brain Res 397:37–46
Morisset V, Ahluwalia J, Nagy I, Urban L (2001)Possible mechanisms of cannabinoidinduced antinociception in the spinal cord Eur J Pharmacol 429:93–100
Munro S, Thomas KL, Abu-Shaar M (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365:61–65
Nackley AG, Makriyannis A, Hohmann AG (2003) Selective activation of cannabinoid CB2 receptors suppresses spinal Fos protein expression and pain behavior in a rat model of inflammation Neuroscience 119:747–757
Nackley AG, Suplita RL 2nd, Hohmann AG (2003)A peripheral cannabinoid mechanism suppresses spinal fos protein expression and pain behavior in a rat model of inflammation Neuroscience 117:659–670
Nackley AG, Zvonok A, 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 92:3562–3574
Nagy JI, Hunt SP (1982) Fluoride-resistant acid phosphatase-containing neurones in dorsal root ganglia are separate from those containing substance P or somatostatin. Neuroscience 7:89–97
Nag JI, Vincent SR, Staines WA, Fibiger HC, Reisine TD, Yamamura HI (1980) Neurotoxic action of capsaicin on spinal substance P neurons. Brain Res 186:435–444
Neumann S, Doubell TP, Leslie T, Woolf CJ (1996) Inflammatory pain hypersensitivity mediatedby phenotypicswitch inmyelinatedprimary sensory neurons Nature 384:360–364
Nirodi CS, Crews BC, Kozak KR, Morrow JD, Marnett LJ (2004) The glyceryl ester of prostaglandin E2 mobilizes calcium and activates signal transduction in RAW264.7 cells. Proc Natl Acad Sci U S A 101:1840–1845
Noyes R Jr, Brunk SF, Avery DA, Canter AC (1975a) The analgesic properties of delta-9-tetrahydrocannabinol and codeine. Clin Pharmacol Ther 18:84–89
Noyes R Jr, Brunk SF, Baram DA, Canter A (1975b) Analgesic effect of delta-9-tetrahydrocannabinol. J Clin Pharmacol 15:139–143
Oka S, Tsuchie A, Tokumura A, Muramatsu M, Suhara Y, Takayama H, Waku K, Sugiura T (2003)Ether-linked analogue of 2-arachidonoylglycerol (noladin ether) wasnot detected in the brains of various mammalian species. J Neurochem 85:1374–1381
Palazzo E, Marabese I, de Novellis V, Oliva P, Rossi F, Berrino L, Maione S (2001)Metabotropic and NMDA glutamate receptors participate in the cannabinoid-induced antinociception. Neuropharmacology 40:319–326
Patel HJ, Birrell MA, Crispino N, Hele DJ, Venkatesan P, Barnes PJ, Yacoub MH, Belvisi MG (2003) Inhibition of guinea-pig and human sensory nerve activity and the cough reflex in guinea-pigs by cannabinoid (CB2) receptor activation. Br J Pharmacol 140:261–268
Pertovaara A, Wei H, Hamalainen MM (1996) Lidocaine in the rostroventromedial medulla and the periaqueductal gray attenuates allodynia in neuropathic rats. Neurosci Lett 218:127–130
Pertwee R, Griffin G, Hanus L, Mechoulam R (1994) Effects of two endogenous fatty acid ethanolamides on mouse vasa deferentia. Eur J Pharmacol 259:115–120
Piomelli D, Beltramo M, Glasnapp S, Lin SY, Goutopoulos A, Xie XQ, Makriyannis A (1999) Structural determinants for recognition and translocation by the anandamide transporter. Proc Natl Acad Sci U S A 9:5802–5807
Porreca F, Ossipov MH, Gebhart GF (2002) Chronic pain and medullary descending facilitation. Trends Neurosci 25:319–325
Porter AC, Sauer JM, Knierman MD, Becker GW, Berna MJ, Bao J, Nomikos GG, Carter P, Bymaster FP, Leese AB, Felder CC (2002) Characterization of a novel endocannabinoid, virodhamine, with antagonist activity at the CB1 receptor. J Pharmacol Exp Ther 301:1020–1024
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 120:155–162
Prusakiewicz JJ, Kingsley PJ, Kozak KR, Marnett LJ (2002) Selective oxygenation of Narachidonylglycine by cyclooxygenase-2. Biochem Biophys Res Commun 29:612–617
Puffenbarger RA, Boothe AC, Cabral GA (2000) Cannabinoids inhibit LPS-inducible cytokine mRNA expression in rat microglial cells. Glia 29:58–69
Puig S, Sorkin LS (1996) Formalin-evoked activity in identified primary afferent fibers systemic lidocaine suppresses phase-2 activity. Pain 64:345–355
Quartilho A, Mata HP, Ibrahim MM, Vanderah TW, Porreca F, Makriyannis A, Malan TP Jr (2003) Inhibition of inflammatory hyperalgesia by activation of peripheral CB2 cannabinoid receptors. Anesthesiology 99:955–960
Raft D, Gregg J, Ghia J, Harris L (1977) Effects of intravenous tetrahydrocannabinol on experimental and surgical pain. Psychological correlates of the analgesic response. lin Pharmacol Ther 21:26–33
Reynolds DV (1969) Surgery in the rat during electrical analgesia induced by focal brain stimulation. Science 164:444–445
Rice AS, Farquhar-Smith WP, Nagy I (2002) Endocannabinoids and pain: spinal and peripheral analgesia in inflammation and neuropathy. Prostaglandins Leukot Essent Fatty Acids 66:243–256
Richardson JD, Aanonsen L, Hargreaves KM (1997) SR 141716A, cannabinoid receptor antagonist, produces hyperalgesia in untreated mice. Eur J Pharmacol 319:R3–R4
Richardso JD, Aanonsen L, Hargreaves KM (1998a) Antihyperalgesic effects of spinal cannabinoids. Eur J Pharmacol 345:145–153
Richardson JD Aanonsen L Hargreaves KM (1998b) Hypoactivity of the spinal cannabinoid system results in NMDA-dependent hyperalgesia. J Neurosci 18:457
Richardson JD, Kilo S, Hargreaves KM (1998c) Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors. Pain 75:111–119
Ross RA, Coutts AA, McFarlane SM, Anavi-Goffer, Irving AJ, Pertwee RG, MacEwan DJ, Scott RH (2001a) Actions of cannabinoid receptor ligands on rat cultured sensory neurones: implications for antinociception. Neuropharmacolo gy 4:221
Ross RA, Gibson M, Brockie HC Leslie M, Pashmi G, Craib S Di Marzo V, Pertwee RG (2001b) Structure-activity relationship for the endogenous cannabinoid, anandamide, and certain of its analogues at vanilloid receptors in transfected cells and vas deferens. Br J Pharmacol 132:631–640
Ross RA, Craib SJ, Stevenson LA, Pertwee RG, Henderson A, Toole J, Ellington HC (2002) Pharmacological characterization of the anandamide cyclooxygenase metabolite: prostaglandin E2 ethanolamide. J Pharmacol Exp Ther 30:900–907
Raukwied R, Watkinson A, McGlone F, Dvorak M (2003) Cannabinoid agonists attenuate capsaicin-induced responses in human skin. Pain102:283–288
Sagar DR, Smith PA, Millns PJ, Smart D, Kendall DA, Chapman V (2004) TRPV1 and CB(1) receptor-mediated effects of the endovanilloid/endocannabinoid N-arachidonoyl-dopamine on primary afferent fibre and spinal cord neuronal responses in the rat. Eur J Neurosci 20:1750184
Salio C, Fischer J, Franzoni MF, Mackie K, Kaneko T, Conrath M (2001) CB1-cannabinoid and mu-opioid receptor co-localization on postsynaptic target in the rat dorsal horn. Neurorepor 12:3689–3692
Salio C, Doly S, Fischer J, Franzoni M, Conrath M (2002a) Neuronal and astrocytic localization of the cannabinoid receptor-1 in the dorsal horn of the rat spinal cord. Neurosci Lett 329:13
Salio C, Fischer J, Franzoni MF, Conrath M (2002b) Pre-and postsynaptic localizations of the CB1 cannabinoid receptor in the dorsal horn of the rat spinal cord. Neuroscience 11:755–764
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 20:1115–1120
Shire D, Carillon C, Kaghad M, Calandra B, inaldi-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 270:3726–3731
Silverman JD, Kruger L (1990) Selective neuronal glycoconjugate expression in sensory and autonomic ganglia: relation of lectin reactivity to peptide and enzyme markers. J Neurocytol 19:789–801
Simone DA, Ngeow JY, Putterman GJ, LaMotte RH (1987) Hyperalgesia to heat after intradermal injection of capsaicin. Brain Res 41:201–203
Simone DA, Baumann TK, LaMotte RH (1989) Dose-dependent pain and mechanical hyperalgesia in humans after intradermal injection of capsaicin. Pain 38:99–107
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 129:227–230
Smith PB, Martin BR (1992) Spinal mechanisms of.9-tetrahydrocannabinol-induced analgesia. Brain Res 578:8–12
Sokal DM, Elmes SJR, Kendall DA, Chapman V (2003) Intraplantar injection of anandamide inhibits mechanically-evokedresponsesof spinal neurons via activationofCB2receptors in anesthetized rats. Neuropharmacology 45:404–411
Strangman NM, Walker JM (1999) The cannabinoid WIN 55,212-2 inhibits the activitydependent facilitation of spinal nociceptive responses. J Neurophysiol 81:472–477
Strangman NM, Patrick SL, Hohmann AG, Tsou K, Walker JM (1998) Evidence for a role of endogenous cannabinoids in the modulation of acute and tonic pain sensitivity. Brain Res 13:323–328
Sugiura T, Kondo S, Sukagawa A, Nakane S, Shinoda A, Itoh K, Yamashita A, Waku K (1995) 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun 215:89–97
Sumariwalla PF, Gallily R, Tchilibon S, Fride E, Mechoulam R, Feldmann M (2004) A novel synthetic, nonpsychoactive cannabinoid acid (HU-320) with anti inflammatory properties in murine collagen-induced arthritis. Arthritis Rheum 50:985–998
Svendsen KB, Jensen TS, Bach FW (2004) Does the cannabinoid dronabinol reduce central pain inmultiple sclerosis? Randomised double blind placebo controlled crossover trial. BMJ 329:253
Szolcsanyi J, Anton F, Reeh PW, Handwerker HO (1988) Selective excitation by capsaicin of mechano-heat sensitive nociceptors in rat skin. Brain Res 446:262–268
Torebjork HE, Lundberg LE, LaMotte RH (1992) Central changes in processing of mechanoreceptive input in capsaicin-inducedsecondaryhyperalgesia inhumans. JPhysiol 448:765–780
Tracey DJ Walker JS (1995) Pain due to nerve damage: are inflammatory mediators involved? Inflamm Res 44:407–411
Tsou K, Jang CS (1964) Studies on the site of analgesic action of morphine by intracerebral micro-injection. Sci Sin 13:1099–1109
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 70:791–798
Tsou K, Brown S, Sanudo-Pena MC, Mackie K, Walker JM (1998a) Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system. Neuroscience 83:393–411
Tsou K, Nogueron MI, Muthian S, Sanudo-Pena MC, Hillard CJ, Deutsch DG, Walker JM (1998b) Fatty acid amide hydrolase is located preferentially in large neurons in the rat central nervous system as revealed by immunohistochemistry. Neurosci Lett 254:137–140
Vaugha CW, McGregor IS, Christie MJ (1999)Cannabinoid receptor activation inhibits GABAergic neurotransmission in rostral ventromedial medulla neurons in vitro. Br J Pharmacol 127:935–940
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 57:288–295
Vivian JA, Kishioka S, Butelman ER, Broadbear J, Lee KO, Woods JH (1998) Analgesic, respiratory andheart rate effects of cannabinoidandopioidagonists in rhesus monkeys: antagonist effects of SR 141716A. J Pharmacol Exp Ther 286:697–703
Vogel Z, Bayewitch M, Levy R, Matus-Leibovitch N, Hanus L, Ben-Shabat S, Mechoulam R, Avidor-Reiss T, Barg J (1994) Binding and functional studies with the peripheral and neuronal cannabinoid receptors. Regul Pept 54:313–314
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 U S A 96:12198–12203
Walker JM, Huang SM, Sanudo-Pena (2000) Identification of the role of endogenous cannabinoids in pain modulation: strategies and pitfalls J Pain 1:20–32
Walker JM, Strangman NM, Huang SM (2001)Cannabinoids and pain. Pain Res Manag 6:74–79
Walter L, Franklin A, Witting A, Moller T, Stella N (2002) Astrocytes in culture produce anandamide and other acylethanolamides. J Biol Chem 27:20869–20876
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 23:1398–1405
Welch SP, Thomas C, Patrick GS (1995) Modulation of cannabinoid-induced antinociception after intracerebroventricular versus intrathecal administration to mice: possible mechanisms for interaction with morphine.J Pharmacol Exp Ther 272:310–321
Willis WD, Westlund KN, Carlton SM (1995) Pain. In: Paxinos G (ed) The Rat Nervous System, 2nd edn. Academic Press New York, 725–750
Yaks TL (1981) The antinociceptive effects of intrathecally administered levonantradol and desacetyllevonantradol in the rat. J Clin Pharmacol 21:334S–340S
Yesilyurt O, Dogrul A, Gul H, Seyrek M, Kusmez O, Ozkan Y, Yildiz O (2003) Topical cannabinoid enhances topical morphine antinociception. Pain 105:303–308
Young WSd, Wamsley JK, Zarbin MA, Kuhar MJ (1980)Opioid receptors undergo axonal flow. Scienc 210:76–78
Yu M, Ives D, Ramesha CS (1997)Synthesis of prostaglandin E2 ethanolamide from anandamide by cyclooxygenase-2. J Biol Chem 272:21181–21186
Zeidenberg P, Clark WC, Jaffe J, Anderson SW, Chin S, Malitz S (1973) Effect of oral administration of delta9 tetrahydrocannabinol onmemory, speech, and perception of thermal stimulation: results with four normal human volunteer subjects. Preliminary report. Compr Psychiatry 14:549–556
Zhang J, Hoffert C, Vu HK, Groblewski T, Ahmad S, öDonnell D (2003) Induction of CB2 receptor expression in the rat spinal cord of neuropathic but not inflammatory chronic pain models. Eur J Neurosci 17:2750–2754
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 U S A 96:5780–5785
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 400:452–457
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2005 Springer-Verlag
About this chapter
Cite this chapter
Walker, J.M., Hohmann, A.G. (2005). Cannabinoid Mechanisms of Pain Suppression. In: Pertwee, R.G. (eds) Cannabinoids. Handbook of Experimental Pharmacology, vol 168. Springer, Berlin, Heidelberg. https://doi.org/10.1007/3-540-26573-2_17
Download citation
DOI: https://doi.org/10.1007/3-540-26573-2_17
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-540-22565-2
Online ISBN: 978-3-540-26573-3
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)