Abstract
Cannabinoids are antinociceptive in animal models of acute, tissue injury—, and nerve injury—induced nociception. This review examines the biology of endogenous cannabinoids (endocannabinoids) and behavioral, neurophysiological, and neuroanatomical evidence supporting the notion that cannabinoids play a role in pain modulation. Behavioral pharmacological approaches, in conjunction with the identification and quantification of endocannabinoids through the use of liquid and gas chromatography mass spectrometry, have provided insight into the functional roles of endocannabinoids in pain modulation. Here we examine the distribution of cannabinoid receptors and endocannabinoid-hydrolyzing enzymes within pain modulatory circuits together with behavioral, neurochemical, and neurophysiological studies that suggest a role for endocannabinoid signaling in pain modulation. This review will provide a comprehensive evaluation of the roles of the endocannabinoids 2-arachidonoylglycerol and anandamide in stress-induced analgesia. These findings provide a functional framework with which to understand the roles of endocannabinoids in nociceptive processing at the supraspinal level.
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References
Gerard CM, Mollereau C, Vassart G, Parmentier M. Molecular cloning of a human cannabi-noid receptor which is also expressed in testis. Biochem J. 1991;279:129-134.
Herkenham M, Lynn AB, Johnson MR, Melvin LS, de Costa BR, Rice KC. Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J Neurosci. 1991;11:563-583.
Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature. 1990;346:561-564.
Devane WA, Hanus L, Breuer A, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 1992;258:1946-1949.
Mechoulam R, Ben-Shabat S, Hanus L, et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol. 1995;50:83-90.
Sugiura T, Kondo S, Sukagawa A, et al. 2-Arachidonoylglycerol: a possible endogenous can-nabinoid receptor ligand in brain. Biochem Biophys Res Commun. 1995;215:89-97.
Tsou K, Brown S, Sanudo-Peña MC, Mackie K, Walker JM. Immunohistochemical distribu-tion of cannabinoid CB1 receptors in the rat central nervous system. Neuroscience. 1997;83:393-411.
Buckley NE, McCoy KL, Mezey E, et al. Immunomodulation by cannabinoids is absent in mice deficient for the cannabinoid CB(2) receptor. Eur J Pharmacol. 2000;396:141-149.
Zimmer A, Zimmer AM, Hohmann AG, Herkenham M, Bonner TI. Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice. Proc Natl Acad Sci USA. 1999;96:5780-5785.
Galiegue S, Mary S, Marchand J, et al. Expression of central and peripheral cannabinoid recep-tors in human immune tissues and leukocyte subpopulations. Eur J Biochem. 1995;232:54-61.
Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature. 1993;365:61-65.
Schatz AR, Lee M, Condie RB, Pulaski JT, Kaminski NE. Cannabinoid receptors CB1 and CB2: a characterization of expression and adenylate cyclase modulation within the immune system. Toxicol Appl Pharmacol. 1997;142:278-287.
Zhang J, Hoffert C, Vu HK, Groblewski T, Ahmad S, O’Donnell D. Induction of CB2 receptor expression in the rat spinal cord of neuropathic but not inflammatory chronic pain models. Eur J Neurosci. 2003;17:2750-2754.
Felder CC, Joyce KE, Briley EM, et al. Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors. Mol Pharmacol. 1995;48:443-450.
Howlett AC, Qualy JM, Khachatrian LL. Involvement of Gi in the inhibition of adenylate cyclase by cannabimimetic drugs. Mol Pharmacol. 1986;29:307-313.
Caulfield MP, Brown DA. Cannabinoid receptor agonists inhibit Ca current in NG108-15 neuroblastoma cells via a pertussis toxin-sensitive mechanism. Br J Pharmacol. 1992;106: 231-232.
Mackie K, Hille B. Cannabinoids inhibit N-type calcium channels in neuroblastoma-glioma cells. Proc Natl Acad Sci USA. 1992;89:3825-3829.
Mackie K, Lai Y, Westenbroek R, Mitchell R. Cannabinoids activate an inwardly rectifying potassium conductance and inhibit Q-type calcium currents in AtT20 cells transfected with rat brain cannabinoid receptor. J Neurosci. 1995;15:6552-6561.
Deadwyler SA, Hampson RE, Mu J, Whyte A, Childers S. Cannabinoids modulate voltage sensitive potassium A-current in hippocampal neurons via a cAMP-dependent process. J Pharmacol Exp Ther. 1995;273:734-743.
Hohmann AG. Spinal and peripheral mechanisms of cannabinoid antinociception: behavioral, neurophysiological and neuroanatomical perspectives. Chem Phys Lipids. 2002;121:173-190.
Walker JM, Hohmann AG. Cannabinoid mechanisms of pain suppression. In: Pertwee R, ed. Cannabinoids—Handbook of Experimental Pharmacology. Berlin, Germany: Springer; 2005:509-554.
Malan TP, Jr, Ibrahim MM, Deng H, et al. CB2 cannabinoid receptor-mediated peripheral antinociception. Pain. 2001;93:239-245.
Calignano A, La Rana G, Giuffrida A, Piomelli D. Control of pain initiation by endogenous cannabinoids. Nature. 1998;394:277-281.
Clayton N, Marshall FH, Bountra C, O’Shaughnessy CT. CB1 and CB2 cannabinoid receptors are implicated in inflammatory pain. Pain. 2002;96:253-260.
Hanus L, Breuer A, Tchilibon S, et al. HU-308: a specific agonist for CB(2), a peripheral cannabinoid receptor. Proc Natl Acad Sci USA. 1999;96:14228-14233.
Hohmann AG, Farthing JN, Zvonok AM, Makriyannis A. Selective activation of cannabinoid CB2 receptors suppresses hyperalgesia evoked by intradermal capsaicin. J Pharmacol Exp Ther. 2003;308:446-453.
Nackley AG, Makriyannis A, Hohmann AG. Selective activation of cannabinoid CB2 recep-tors suppresses spinal fos protein expression and pain behavior in a rat model of inflammation. Neuroscience. 2003;119:747-757.
Nackley AG, 2nd, Suplita RL, 2nd, Hohmann AG. A peripheral cannabinoid mechanism sup-presses spinal fos protein expression and pain behavior in a rat model of inflammation. Neuroscience. 2003;117:659-670.
Quartilho A, Mata HP, Ibrahim MM, et al. Inhibition of inflammatory hyperalgesia by activa-tion of peripheral CB2 cannabinoid receptors. Anesthesiology. 2003;99:955-960.
Ibrahim MM, Deng H, Zvonok A, et al. 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. 2003;100:10529-10533.
Malan TP, Jr, Ibrahim MM, Vanderah TW, Makriyannis A, Porreca F. Inhibition of pain responses by activation of CB2 cannabinoid receptors. Chem Phys Lipids. 2002;121:191-200.
Rice AS, Farquhar-Smith WP, Nagy I. Endocannabinoids and pain: spinal and peripheral analgesia in inflammation and neuropathy. Prostaglandins Leukot Essent Fatty Acids. 2002;66:243-256.
Walker JM, Huang SM. Endocannabinoids in pain modulation. Prostaglandins Leukot Essent Fatty Acids. 2002;66:235-242.
Walker JM, Strangman NM, Huang SM. Cannabinoids and pain. Pain Res Manag. 2001;6:74-79.
Stella N, Schweitzer P, Piomelli D. A second endogenous cannabinoid that modulates long-term potentiation. Nature. 1997;388:773-778.
Piomelli D. The molecular logic of endocannabinoid signalling. Nat Rev Neurosci. 2003;4:873-884.
Gauldie SD, McQueen DS, Pertwee R, Chessell IP. Anandamide activates peripheral nocicep-tors in normal and arthritic rat knee joints. Br J Pharmacol. 2001;132:617-621.
Smart D, Gunthorpe MJ, Jerman JC, et al. The endogenous lipid anandamide is a full agonist at the human vanilloid receptor (hVR1). Br J Pharmacol. 2000;129:227-230.
Hogestatt ED, Zygmunt PM, Petersson J, et al. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature. 1999;400:452-457.
Adams IB, Compton DR, Martin BR. Assessment of anandamide interaction with the cannabi-noid brain receptor: SR 141716A antagonism studies in mice and autoradiographic analysis of receptor binding in rat brain. J Pharmacol Exp Ther. 1998;284:1209-1217.
Smith PB, Compton DR, Welch SP, Razdan RK, Mechoulam R, Martin BR. The pharmaco-logical activity of anandamide, a putative endogenous cannabinoid, in mice. J Pharmacol Exp Ther. 1994;270:219-227.
Stella N, Piomelli D. Receptor-dependent formation of endogenous cannabinoids in cortical neu-rons. Eur J Pharmacol. 2001;425:189-196.
Jung K-M, Mangieri R, Stapleton C, et al. Stimulation of endocannabinoid formation in brain slice cultures through activation of group I metabotropic glutamate receptors. Mol Pharmacol. 2005;68:1196-1202.
Sugiura T. Evidence that the cannabinoid CB1 receptor is a 2-arachidonoylglycerol receptor. Structure-activity relationship of 2-arachidonoylglycerol, ether-linked analogues, and related compounds. J Biol Chem. 1999;274:2794-2801.
Sugiura T. Evidence that 2-arachidonoylglycerol but not N-palmitoylethanolamine or anandamide is the physiological ligand for the cannabinoid CB2 receptor. J Biol Chem. 2000;275:605-612.
Ben-Shabat S, Fride E, Sheskin T, et al. An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. Eur J Pharmacol. 1998;353:23-31.
Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB. Molecular characteri-zation of an enzyme that degrades neuromodulatory fatty-acid amides. Nature. 1996;384: 83-87.
Deutsch DG, Chin SA. Enzymatic synthesis and degradation of anandamide, a cannabinoid receptor agonist. Biochem Pharmacol. 1993;46:791-796.
Di Marzo V, Bisogno T, Melck D, et al. Interactions between synthetic vanilloids and the endogenous cannabinoid system. FEBS Lett. 1998;436:449-454.
Huang SM, Bisogno T, Trevisani M, et al. An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors. Proc Natl Acad Sci USA. 2002;99:8400-8405.
Dinh TP, Carpenter D, Leslie FM, et al. Brain monoglyceride lipase participating in endocan-nabinoid inactivation. Proc Natl Acad Sci USA. 2002;99:10819-10824.
Hohmann AG, Suplita RL, Bolton NM, et al. An endocannabinoid mechanism for stress-induced analgesia. Nature. 2005;435:1108-1112.
Egertová M, Cravatt BF, Elphick MR. 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. 2003;119:481-496.
Egertov M, Giang DK, Cravatt BF, Elphick MR. A new perspective on cannabinoid signal-ling: complementary localization of fatty acid amide hydrolase and the CB1 receptor in rat brain. Proc R Soc Lond B Biol Sci. 1998;265:2081-2085.
Tsou K, Nogueron MI, Muthian S, et al. Fatty acid amide hydrolase is located preferentially in large neurons in the rat central nervous system as revealed by immunohistochemistry. Neurosci Lett. 1998;254:137-140.
Wilson RI, Nicoll RA. Endogenous cannabinoids mediate retrograde signalling at hippocam-pal synapses. Nature. 2001;410:588-592.
Wilson RI, Nicoll RA. Endocannabinoid signaling in the brain. Science. 2002;296:678-682.
Goparaju SK, Ueda N, Yamaguchi H, Yamamoto S. Anandamide amidohydrolase reacting with 2-arachidonoylglycerol, another cannabinoid receptor ligand. FEBS Lett. 1998;422:69-73.
Gulyas AI, Cravatt BF, Bracey MH, et al. Segregation of two endocannabinoid-hydrolyzing enzymes into pre- and postsynaptic compartments in the rat hippocampus, cerebellum and amy-gdala. Eur J Neurosci. 2004;20:441-458.
Dinh TP, Kathuria S, Piomelli D. RNA interference suggests a primary role for monoacylg-lycerol lipase in the degradation of the endocannabinoid 2-arachidonoylglycerol. Mol Pharmacol. 2004;66:1260-1264.
Lichtman AH, Hawkins EG, Griffin G, Cravatt BF. Pharmacological activity of fatty acid amides is regulated, but not mediated, by fatty acid amide hydrolase in vivo. J Pharmacol Exp Ther. 2002;302:73-79.
Ledent C, Valverde O, Cossu G, et al. Unresponsiveness to cannabinoids and reduced addic-tive effects of opiates in CB1 receptor knockout mice. Science. 1999;283:401-404.
Cravatt BF, Demarest K, Patricelli MP, et al. Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc Natl Acad Sci USA. 2001;98:9371-9376.
Cravatt BF, Saghatelian A, Hawkins EG, Clement AB, Bracey MH, Lichtman AH. Functional disassociation of the central and peripheral fatty acid amide signaling systems. Proc Natl Acad Sci USA. 2004;101:10821-10826.
Rinaldi-Carmona M, Barth F, Heaulme M, et al. SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett. 1994;350:240-244.
Showalter VM, Compton DR, Martin BR, Abood ME. Evaluation of binding in a trans-fected cell line expressing a peripheral cannabinoid receptor (CB2): identification of can-nabinoid receptor subtype selective ligands. J Pharmacol Exp Ther. 1996;278:989-999.
Palmer SL, Thakur GA, Makriyannis A. Cannabinergic ligands. Chem Phys Lipids. 2002;121:3-19.
Kathuria S, Gaetani S, Fegley D, et al. Modulation of anxiety through blockade of anandamide hydrolysis. Nat Med. 2003;9:76-81.
Bisogno T, Melck D, De Petrocellis L, et al. Arachidonoylserotonin and other novel inhibitors of fatty acid amide hydrolase. Biochem Biophys Res Commun. 1998;248:515-522.
Makara JK, Mor M, Fegley D, et al. Selective inhibition of 2-AG hydrolysis enhances endo-cannabinoid signaling in hippocampus. Nat Neurosci. 2005;8:1139-1141.
Kozak KR, Prusakiewicz JJ, Marnett LJ. Oxidative metabolism of endocannabinoids by COX-2. Curr Pharm Des. 2004;10:659-667.
Moore SA, Nomikos GG, Dickason-Chesterfield AK, et al. Identification of a high-affinity binding site involved in the transport of endocannabinoids. Proc Natl Acad Sci USA. 2005;102:17852-17857.
Jarrahian A, Manna S, Edgemond WS, Campbell WB, Hillard CJ. Structure-activity relation-ships among N-arachidonylethanolamine (Anandamide) head group analogues for the ananda-mide transporter. J Neurochem. 2000;74:2597-2606.
Beltramo M, Stella N, Calignano A, Lin SY, Makriyannis A, Piomelli D. Functional role of high-affinity anandamide transport, as revealed by selective inhibition. Science. 1997;277:1094-1097.
De Petrocellis L, Bisogno T, Davis JB, Pertwee RG, Di Marzo V. Overlap between the ligand recognition properties of the anandamide transporter and the VR1 vanilloid receptor: inhibi-tors of anandamide uptake with negligible capsaicin-like activity. FEBS Lett. 2000;483:52-56.
Dixon WE. The pharmacology of cannabis. Indica Brit Med J. 1899;2:1354-1357. PubMed
Bicher HI, Mechoulam R. Pharmacological effects of two active constituents of marihuana. Arch Int Pharmacodyn Ther. 1968;172:24-31.
Kosersky DS, Dewey WL, Harris LS. Antipyretic, analgesic and anti-inflammatory effects of delta 9-tetrahydrocannabinol in the rat. Eur J Pharmacol. 1973;24:1-7.
Bloom AS, Dewey WL, Harris LS, Brosius KK. 9-nor-9beta-hydroxyhexahydrocannabinol, a cannabinoid with potent antinociceptive activity: comparisons with morphine. J Pharmacol Exp Ther. 1977;200:263-270.
Buxbaum DM. Analgesic activity of9-tetrahydrocannabinol in the rat and mouse. Psychopharmacologia. 1972;25:275-280.
Martin BR, Compton DR, Thomas BF, et al. Behavioral, biochemical, and molecular mode-ling evaluations of cannabinoid analogs. Pharmacol Biochem Behav. 1991;40:471-478.
Drew LJ, Harris J, Millns PJ, Kendall DA, Chapman V. 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. 2000;12:2079-2086.
Harris J, Drew LJ, Chapman V. Spinal anandamide inhibits nociceptive transmission via can-nabinoid receptor activation in vivo. Neuroreport. 2000;11:2817-2819.
Hohmann AG, Martin WJ, Tsou K, Walker JM. Inhibition of noxious stimulus-evoked activity of spinal cord dorsal horn neurons by the cannabinoid WIN 55,212-2. Life Sci. 1995;56:2111-2118.
Hohmann AG, Tsou K, Walker JM. Cannabinoid modulation of wide dynamic range neurons in the lumbar dorsal horn of the rat by spinally administered WIN55,212-2. Neurosci Lett. 1998;257:119-122.
Hohmann AG, Tsou K, Walker JM. Cannabinoid suppression of noxious heat-evoked activity in wide dynamic range neurons in the lumbar dorsal horn of the rat. J Neurophysiol. 1999;81:575-583.
Kelly S, Chapman V. Selective cannabinoid CB1 receptor activation inhibits spinal nocicep-tive transmission in vivo. J Neurophysiol. 2001;86:3061-3064.
Martin WJ, Hohmann AG, Walker JM. Suppression of noxious stimulus-evoked activity in the ventral posterolateral nucleus of the thalamus by a cannabinoid agonist: correlation between electrophysiological and antinociceptive effects . J Neurosci . 1996;16:6601-6611.
Meng ID, Manning BH, Martin WJ, Fields HL. An analgesia circuit activated by cannabi-noids. Nature. 1998;395:381-384.
Strangman NM, Walker JM. Cannabinoid WIN 55,212-2 inhibits the activity-dependent facil-itation of spinal nociceptive responses. J Neurophysiol. 1999;82:472-477.
Hohmann AG, Tsou K, Walker JM. Intrathecal cannabinoid administration suppresses nox-ious stimulus-evoked Fos protein-like immunoreactivity in rat spinal cord: comparison with morphine. Acta Pharmacol Sin. 1999;20:1132-1136.
Tsou K, Lowitz KA, Hohmann AG, et al. Suppression of noxious stimulus-evoked expression of FOS protein-like immunoreactivity in rat spinal cord by a selective cannabinoid agonist. Neuroscience. 1996;70:791-798.
Elmes SJ, Jhaveri MD, Smart D, Kendall DA, Chapman V. Cannabinoid CB2 receptor activa-tion 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 Neurosci. 2004;20:2311-2320.
Hunt SP, Pini A, Evan G. Induction of c-fos-like protein in spinal cord neurons following sensory stimulation. Nature. 1987;328:632-634.
Farquhar-Smith WP, Jaggar SI, Rice AS. Attenuation of nerve growth factor-induced vis-ceral hyperalgesia via cannabinoid CB(1) and CB(2)-like receptors. Pain. 2002;97:11-21.
Martin WJ, Loo CM, Basbaum AI. Spinal cannabinoids are anti-allodynic in rats with persistent inflammation. Pain. 1999;82:199-205.
Nackley AG, Makriyannis A, Hohmann AG. Selective activation of cannabinoid CB2 recep-tors suppresses spinal Fos protein expression and pain behavior in a rat model of inflamma-tion. Neuroscience. 2003;119:747-757.
Finn DP, Jhaveri MD, Beckett SR, et al. Effects of direct periaqueductal grey administration of a cannabinoid receptor agonist on nociceptive and aversive responses in rats. Neuropharmacology. 2003;45:594-604.
Maione S, Bisogno T, de Novellis V, et al. Elevation of endocannabinoid levels in the vent-rolateral periaqueductal grey through inhibition of fatty acid amide hydrolase affects descending nociceptive pathways via both CB1 and TRPV1 receptors. J Pharmacol Exp Ther. 2005;316:969-982.
Gutierrez T, Nackley AG, Neely MH, Freeman KG, Edwards GL, Hohmann AG. Effects of neurotoxic destruction of descending noradrenergic pathways on cannabinoid antinocicep-tion in models of acute and tonic nociception. Brain Res. 2003;987:176-185.
Herzberg U, Eliav E, Dorsey JM, Gracely RH, Kopin IJ. NGF involvement in pain induced by chronic constriction injury of the rat sciatic nerve. Neuroreport. 1997;8:1613-1618.
Bridges D, Ahmad K, Rice AS. The synthetic cannabinoid WIN55,212-2 attenuates hyper-algesia and allodynia in a rat model of neuropathic pain. Br J Pharmacol. 2001;133:586-594.
Mao J, Price DD, Lu J, Keniston L, Mayer DJ. Two distinctive antinociceptive systems in rats with pathological pain. Neurosci Lett. 2000;280:13-16.
Farquhar-Smith WP, Egertova M, Bradbury EJ, McMahon SB, Rice AS, Elphick MR. Cannabinoid CB(1) receptor expression in rat spinal cord. Mol Cell Neurosci. 2000;15:510-521.
Arner S, Meyerson BA. Lack of analgesic effect of opioids on neuropathic and idiopathic forms of pain. Pain. 1988;33:11-23.
Chapman V. Functional changes in the inhibitory effect of spinal cannabinoid (CB) receptor activation in nerve injured rats. Neuropharmacology. 2001;41:870-877.
Fox A, Kesingland A, Gentry C, et al. The role of central and peripheral Cannabinoid1 receptors in the antihyperalgesic activity of cannabinoids in a model of neuropathic pain. Pain. 2001;92:91-100.
Monhemius R, Azami J, Green DL, Roberts MH. CB1 receptor mediated analgesia from the Nucleus Reticularis Gigantocellularis pars alpha is activated in an animal model of neuro-pathic pain. Brain Res. 2001;908:67-74.
Landsman RS, Burkey TH, Consroe P, Roeske WR, Yamamura HI. SR141716A is an inverse agonist at the human cannabinoid CB1 receptor. Eur J Pharmacol. 1997;334: R1-R2.
Rice AS, Beaulieu P, Bisogno T, et al. Role of the endogenous cannabinoid system in the formalin test of persistent pain in the rat. Eur J Pharmacol. 2000;396:85-92.
Lichtman AH, Martin BR. Spinal and supraspinal components of cannabinoid-induced anti-nociception. J Pharmacol Exp Ther. 1991;258:517-523.
Martin WJ, Lai NK, Patrick SL, Tsou K, Walker JM. Antinociceptive actions of cannabi-noids following intraventricular administration in rats. Brain Res. 1993;629:300-304.
Lichtman AH, Cook SA, Martin BR. Investigation of brain sites mediating cannabinoid-induced antinociception in rats: evidence supporting periaqueductal gray involvement. J Pharmacol Exp Ther. 1996;276:585-593.
Martin WJ, Coffin PO, Attias E, Balinsky M, Tsou K, Walker JM. Anatomical basis for cannabinoid-induced antinociception as revealed by intracerebral microinjections. Brain Res. 1999;822:237-242.
Martin WJ, Patrick SL, Coffin PO, Tsou K, Walker JM. An examination of the central sites of action of cannabinoid-induced antinociception in the rat. Life Sci. 1995;56:2103-2109.
Martin WJ, Tsou K, Walker JM. Cannabinoid receptor-mediated inhibition of the rat tail- flick reflex after microinjection into the rostral ventromedial medulla. Neurosci Lett. 1998;242:33-36.
Finn DP, Jhaveri MD, Beckett SR, Kendall DA, Marsden CA, Chapman V. Cannabinoids modulate ultrasound-induced aversive responses in rats. Psychopharmacology (Berl). 2004;172:41-51.
Cannon JT, Prieto GJ, Lee A, Liebeskind JC. Evidence for opioid and non-opioid forms of stimulation-produced analgesia in the rat. Brain Res. 1982;243:315-321.
Reynolds DV. Surgery in the rat during electrical analgesia induced by focal brain stimula-tion. Science. 1969;164:444-445.
Walker JM, Huang SM, Strangman NM, Tsou K, Sanudo-Pena MC. Pain modulation by release of the endogenous cannabinoid anandamide. Proc Natl Acad Sci USA. 1999;96:12198-12203.
Suplita RL, II, Farthing JN, Gutierrez T, Hohmann AG. Inhibition of fatty-acid amide hydro-lase enhances cannabinoid stress-induced analgesia: sites of action in the dorsolateral periaq-ueductal gray and rostral ventromedial medulla. Neuropharmacology. 2005;49:1201-1209.
Vaughan CW, Connor M, Bagley EE, Christie MJ. Actions of cannabinoids on membrane properties and synaptic transmission in rat periaqueductal gray neurons in vitro. Mol Pharmacol. 2000;57:288-295.
Palazzo E, Marabese I, de Novellis V, et al. Metabotropic and NMDA glutamate receptors participate in the cannabinoid-induced antinociception. Neuropharmacology. 2001;40:319-326.
Vaughan CW, McGregor IS, Christie MJ. Cannabinoid receptor activation inhibits GABAergic neurotransmission in rostral ventromedial medulla neurons in vitro. Br J Pharmacol. 1999;127:935-940.
Meng ID, Johansen JP. Antinociception and modulation of rostral ventromedial medulla neuronal activity by local microinfusion of a cannabinoid receptor agonist. Neuroscience. 2004;124:685-693.
Davis M, Whalen PJ. The amygdala: vigilance and emotion. Mol Psychiatry. 2001;6:13-34.
Marsicano G, Wotjak CT, Azad SC, et al. The endogenous cannabinoid system controls extinction of aversive memories. Nature. 2002;418:530-534.
Medina JF, Repa CJ, Mauk MD, LeDoux JE. Parallels between cerebellum- and amygdala-dependent conditioning. Nat Rev Neurosci. 2002;3:122-131.
Helmstetter FJ, Bellgowan PS, Poore LH. Microinfusion of mu, but not delta or kappa opi-oid agonists into the basolateral amygdala results in inhibition of the tail flick reflex in pentobarbital-anesthetized rats. J Pharm Exp Ther. 1995;275:381-388.
Helmstetter FJ, Bellgowan PS, Tershner SA. Modulation of spinal nociceptive reflexes by the microinjection of morphine into the amygdala. Neuroreport. 1993;4:471-474.
Manning BH, Mayer DJ. The central nucleus of the amygdala contributes to the production of morphine antinociception in the rat tail-flick test. J Neurosci. 1995;15:8199-8213.
Manning BH, Merin NM, Meng ID, Amaral DG. Reduction in opioid- and cannabinoid-induced antinociception in rhesus monkeys after bilateral lesions of the amygdaloid com-plex. J Neurosci. 2001;21:8238-8246.
Manning BH, Martin WJ, Meng ID. The rodent amygdala contributes to the production of cannabinoid-induced antinociception. Neuroscience. 2003;120:1157-1170.
Helmstetter FJ. The amygdala is essential for the expression of conditional hypoalgesia. Behav Neurosci. 1992;106:518-528.
Helmstetter FJ, Bellgowan PS. Lesions of the amygdala block conditional hypoalgesia on the tail flick test. Brain Res. 1993;612:253-257.
Bellgowan PS, Helmstetter FJ. Neural systems for the expression of hypoalgesia during nonasso-ciative fear. Behav Neurosci. 1996;110:727-736.
Akil H, Young E, Walker JM, Watson SJ. The many possible roles of opioids and related peptides in stress-induced analgesia. Ann N Y Acad Sci. 1986;467:140-153.
Lewis JW, Cannon JT, Liebeskind JC. Opioid and nonopioid mechanisms of stress analge-sia. Science. 1980;208:623-625.
Terman GW, Lewis JW, Liebeskind JC. Two opioid forms of stress analgesia: studies of tolerance and cross-tolerance. Brain Res. 1986;368:101-106.
Finn DP, Beckett SR, Richardson D, Kendall DA, Marsden CA, Chapman V. Evidence for differential modulation of conditioned aversion and fear-conditioned analgesia by CB1 recep-tors. Eur J Neurosci. 2004;20:848-852.
Suplita RL, II, Gutierrez T, Fegley D, Piomelli D, Hohmann AG. Endocannabinoids at the spinal level regulate, but do not mediate, nonopioid stress-induced analgesia. Neuropharmacology. 2005;262:25.
Heinricher MM, Morgan MM, Tortorici V, Fields HL. Disinhibition of off-cells and antino-ciception produced by an opioid action within the rostral ventromedial medulla. Neuroscience. 1994;63:279-288.
Smith PB, Martin BR. Spinal mechanisms of delta 9-tetrahydrocannabinol-induced analge-sia. Brain Res. 1992;578:8-12.
Welch SP, Stevens DL. Antinociceptive activity of intrathecally administered cannabinoids alone, and in combination with morphine, in mice. J Pharmacol Exp Ther. 1992;262:10-18.
Welch SP, Thomas C, Patrick GS. Modulation of cannabinoid-induced antinociception after intracerebroventricular versus intrathecal administration to mice: possible mechanisms for interaction with morphine. J Pharmacol Exp Ther. 1995;272:310-321.
Yaksh TL. The antinociceptive effects of intrathecally administered levonantradol and desacetyllevonantradol in the rat. J Clin Pharmacol. 1981;21:334S-340S.
Richardson JD, Aanonsen L, Hargreaves KM. Antihyperalgesic effects of spinal cannabinoids. Eur J Pharmacol. 1998;345:145-153.
Cannich A, Wotjak CT, Kamprath K, Hermann H, Lutz B, Marsicano G. CB1 cannabinoid receptors modulate kinase and phosphatase activity during extinction of conditioned fear in mice. Learn Mem. 2004;11:625-632.
Bernard JF, Bester H, Besson JM. Involvement of the spino-parabrachio-amygdaloid and -hypothalamic pathways in the autonomic and affective emotional aspects of pain. Prog Brain Res. 1996;107:243-255.
Katona I, Rancz EA, Acsady L, et al. Distribution of CB1 cannabinoid receptors in the amygdala and their role in the control of GABAergic transmission. J Neurosci. 2001;21:9506-9518.
Connell K, Bolton N, Olsen D, Piomelli D, Hohmann AG. Role of the basolateral nucleus of the amygdala in endocannabinoid-mediated stress-induced analgesia. Neurosci Lett. 2005;12:22.
Valverde O, Ledent C, Beslot F, Parmentier M, Roques BP. Reduction of stress-induced analgesia but not of exogenous opioid effects in mice lacking CB1 receptors. Eur J Neurosci. 2000;12:533-539.
Atkinson JH, Slater MA, Wahlgren DR, et al. Effects of noradrenergic and serotonergic antidepressants on chronic low back pain intensity. Pain. 1999;83:137-145.
Portenoy RK, Foley KM. Chronic use of opioid analgesics in non-malignant pain: report of 38 cases. Pain. 1986;25:171-186.
Cravatt BF, Lichtman AH. Fatty acid amide hydrolase: an emerging therapeutic target in the endocannabinoid system. Curr Opin Chem Biol. 2003;7:469-475.
Yesilyurt O, Dogrul A, Gul H, et al. Topical cannabinoid enhances topical morphine antino-ciception. Pain. 2003;105:303-308.
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© 2008 American Association of Pharmaceutical Scientists
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Hohmann, A.G., Suplita, R.L. (2008). Endocannabinoid Mechanisms of Pain Modulation. In: Rapaka, R.S., Sadée, W. (eds) Drug Addiction. Springer, New York, NY. https://doi.org/10.1007/978-0-387-76678-2_44
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