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Mode of action of cannabinoids on nociceptive nerve endings

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Abstract

In recent years, cannabinoids have emerged as attractive alternatives or supplements to therapy for chronic pain states. However, in humans the activation of cannabinoid receptors in neurons of the central nervous system is associated with psychotropic side effects, temporary memory impairment and dependence, which arise via the effects of cannabinoids on forebrain circuits. For clinical exploitation of the analgesic properties of cannabinoids, a major challenge is to devise strategies that reduce or abolish their adverse effects on cognitive, affective and motor functions without attenuating their analgesic effects. The cannabinoid receptor family currently includes two cloned metabotropic receptors: CB1, CB2 and possibly GPR55 which are distributed widely across many key loci in pain-modulating pathways, including the peripheral terminals of primary afferents. Modulation of transducer ion channels expressed at nociceptive terminals occurs upon activation of metabotropic cannabinoid receptors, but direct cannabinoid action on ion channels involved in sensory transduction or regulation of neuron excitability likely contributes to the peripheral cannabinoid effects.

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References

  • Agarwal N, Pacher P, Tegeder I, Amaya F, Constantin CE, Brenner GJ, Rubino T, Michalski CW, Marsicano G, Monory K, Mackie K, Marian C, Batkai S, Parolaro D, Fischer MJ, Reeh W, Kunos G, Kress M, Lutz B, Woolf CJ, Kuner R (2007) Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors. Nat Neurosci 10:870–879

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Akopian AN, Ruparel NB, Patwardhan AM, Hargreaves KM (2008) Cannabinoids desensitize capsaicin and mustard oil responses in sensory neurons via TRPA1 activation. J Neurosci 30:1064–1075

    Article  CAS  Google Scholar 

  • Akopian AN, Ruparel NB, Jeske NA, Patwardahan AM, Hargreaves KM (2009) Role of ionotropic cannabinoid receptors in peripheral antinociception and antihyperalgesia. Trends Pharmacol Sci (in press)

  • Amaya F, Shimosato G, Kawasaki Y, Hashimoto S, Tanaka Y, Ji RR, Tanaka M (2006) Induction of CB1 cannabinoid receptor by inflammation in primary afferent neurons facilitates antihyperalgesic effect of peripheral CB1 agonist. Pain 124:175–183

    Article  PubMed  CAS  Google Scholar 

  • Anand U, Otto WR, Sanchez-Herrera D, Facer P, Yiangou Y, Korchev Y, Birch R, Benham C, Bountra C, Chessel IP, Anand P (2008) Cannabinoid receptor CB2 localisation and agonist-mediated inhibition of capsaicin responses in human sensory neurons. Pain 138:667–680

    Article  PubMed  CAS  Google Scholar 

  • Ashton JC, Milligan ED (2008) Cannabinoids for the treatment of neuropathic pain: clinical evidence. Curr Opin Invest Drugs 9:65–75

    CAS  Google Scholar 

  • Bautista DM, Jordt SE, Nikai T, Tsuruda PR, Read AJ, Poblete J, Yamoah EN, Basbaum AI, Julius D (2006) TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell 124:1269–1282

    Article  PubMed  CAS  Google Scholar 

  • 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 277:1097

    Article  Google Scholar 

  • Beltramo M, Bernardini N, Bertorelli R, Campanella M, Nicolussi E, Fredduzzi S, Reggiani A (2006) CB2 receptor-mediated antihyperalgesia: possible direct involvement of neural mechanisms. Eur J Neurosci 23:1530–1538

    Article  PubMed  CAS  Google Scholar 

  • Belvisi MG, Patel HJ, Freund-Michel V, Hele DJ, Crispino N, Birrell MA (2008) Inhibitory activity of the novel CB2 receptor agonist GW833972A on guinea-pig and human sensory nerve function in the airways. Br J Pharmacol 155:547–557

    Article  PubMed  CAS  Google Scholar 

  • Binzen U, Greffrath W, Hennessy S, Bausen M, Saaler-Reinhardt S, Treede RD (2006) Co-expression of the voltage-gated potassium channel Kv1.4 with transient receptor potential channels (TRPV1 and TRPV2) and the cannabinoid receptor CB1 in rat dorsal root ganglion neurons. Neuroscience 142:527–539

    Article  PubMed  CAS  Google Scholar 

  • 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 119:812

    Article  CAS  Google Scholar 

  • Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389:816–824

    Article  PubMed  CAS  Google Scholar 

  • Caterina MJ, Rosen TA, Tominaga M, Brake AJ, Julius D (1999) A capsaicin-receptor homologue with a high threshold for noxious heat. Nature 398:436–441

    Article  PubMed  CAS  Google Scholar 

  • Chuang HH, Prescott ED, Kong H, Shields S, Jordt S-E, Basbaum AI, Chao MV, Julius D (2001) Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4, 5)P2-mediated inhibition. Nature 411:957–962

    Article  PubMed  CAS  Google Scholar 

  • Coutts AA, Irving AJ, Mackie K, Pertwee RG, Anavi-Goffer S (2002) Localisation of cannabinoid CB1 receptor immunoreactivity in the guinea pig and rat myenteric plexus. J Comp Neurol 448:410–422

    Article  PubMed  CAS  Google Scholar 

  • Davis JB, Gray J, Gunthorpe MJ, Hatcher JP, Davey PT, Overend P, Harries MH, Latcham J, Clapham C, Atkinson K, Hughes SA, Rance K, Grau E, Harper AJ, Pugh PL, Rogers DC, Bingham S, Randall A, Sheardown SA (2000) Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Nature 405:183–187

    Article  PubMed  CAS  Google Scholar 

  • De Petrocellis L, Vellani V, Schiano-Moriello A, Marini P, Magherini PC, Orlando P, Di Marzo V (2008) Plant-derived cannabinoids modulate the activity of transient receptor potential channels of ankyrin type-1 and melastatin type-8. J Pharmacol Exp Ther 325:1007–1015

    Article  PubMed  CAS  Google Scholar 

  • Di Marzo V (2006) Endocannabinoids: synthesis and degradation. Rev Physiol Biochem Pharmacol 160:1–24

    Article  CAS  Google Scholar 

  • 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 372:686–691

    Article  PubMed  CAS  Google Scholar 

  • Di Marzo V, Bifulco M, De Petrocellis L (2004) The endocannabinoid system and its therapeutic exploitation. Nat Rev Drug Discov 3:771–784

    Article  PubMed  CAS  Google Scholar 

  • Dinh TP, Freund TF, Piomelli D (2002) A role for monoglyceride lipase in 2-arachidonoylglycerol inactivaiton. Chem Phys Lipids 121:149–158

    Article  PubMed  CAS  Google Scholar 

  • Elmes SJ, 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 Neurosci 20:2320

    Article  Google Scholar 

  • Evans RM, Wease KN, MacDonald CJ, Khairy HA, Ross RA, Scott RH (2008) Modulation of sensory neuron potassium conductances by anandamide indicates roles for metabolites. Br J Pharmacol 154:480–492

    Article  PubMed  CAS  Google Scholar 

  • Fan P (1995) Cannabinoid agonist inhibit the activation of 5-HT3 receptors in rat nodose ganglion neurons. J Neurophysiol 73:910

    Google Scholar 

  • Fegley D, Kathuria S, Mercier R, Li C, Goutopoulos A, Makriyannis A, Piomelli D (2004) Anandamide transport is independent of fatty-acid amide hydrolase activity and is blocked by the hydrolysis-resistant inhibitor AM1172. Proc Natl Acad Sci USA 101:8756–8761

    Article  PubMed  CAS  Google Scholar 

  • Fernandez-Ruiz J, Romero J, Velasco G, Tolon RM, Ramos JA, Guzman M (2007) Cannabinoid CB2 receptor: a new target for controlling neural cell survival. Trends Pharmacol Sci 28:39–45

    Article  PubMed  CAS  Google Scholar 

  • Fischbach T, Greffrath W, Nawrath H, Treede R-D (2007) Effects of anandamide and noxious heat on intracellular calcium concentration in nociceptive DRG neurons of the rat. J Neurophysiol 98:929–938

    Article  PubMed  CAS  Google Scholar 

  • Freund TF, Katona I, Piomelli D (2003) Role of endogenous cannabinoids in synaptic signaling. Physiol Rev 83:1017–1066

    PubMed  CAS  Google Scholar 

  • Guerrero AV, Quang P, Dekker N, Jordan RCK, Schmidt BL (2008) Peripheral cannabinoids attenuate carcinoma-induced nociception in mice. Neurosci Lett 433:77–81

    Article  PubMed  CAS  Google Scholar 

  • Guindon J, Hohmann AG (2008) Cannabinoid CB2 receptors: a therapeutic target for the treatment of inflammatory and neuropathic pain. Br J Pharmacol 153:319–334

    Article  PubMed  CAS  Google Scholar 

  • Handwerker HO, Reeh PW, Steen KH (1990) Effects of 5HT on nociceptors. In: Besson J-M (ed) Serotonin and pain. Elsevier, Amsterdam, pp 1–15

    Google Scholar 

  • Hillard CJ, Edgemond WS, Jarrahian A, Campbell WB (1997) Accumulation of N-arachidonoylethanolamine (anandamide) into cerebellar granule cells occurs via facilitated diffusion. J Neurochem 69:631–638

    Article  PubMed  CAS  Google Scholar 

  • Hillsley K, McCaul C, Aerssens J, Peeters PJ, Gijsen H, Moechars D, Coulie B, Grundy D, Stead RH (2007) Activation of the cannabinoid 2 (CB2) receptor inhibits murine mesenteric afferent nerve activity. Neurogastroenterol Motil 19:769–777

    Article  PubMed  CAS  Google Scholar 

  • Hohmann AG, Herkenham M (1999) 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

    Article  PubMed  CAS  Google Scholar 

  • Howlett AC (2005) Cannabinoid receptor signaling. Handb Exp Pharmacol 53–79

  • Ibrahim MM, Deng H, Zvonok AM, Cockayne DA, Kwan J, Mata H, 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

    Article  PubMed  CAS  Google Scholar 

  • Ibrahim MM, Porreca F, Lai J, Albrecht PJ, Rice FL, Khodorova A, Davar G, Makriyannis A, Vanderah TW, Mata H, Malan TP (2005) CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Proc Natl Acad Sci USA 102:3093–3098

    Article  PubMed  CAS  Google Scholar 

  • Ibrahim MM, Rude ML, Stagg NJ, Mata HP, Lai J, Vanderah TW, Porreca F, Veerappan V, Tian X, George C, Parrish DA, Papahatjis DP, Makriyannis A (2006) CB2 cannabinoid receptor mediation of antinociception. Pain 122:36–42

    Article  PubMed  CAS  Google Scholar 

  • Jerman JC, Gray J, Brough SJ, Ooi L, Owen D, Davis JB, Smart D (2002) Comparison of effects of anandamide at recombinant and endogenous rat vanilloid receptors. Br J Anaesth 89:882–887

    Article  PubMed  CAS  Google Scholar 

  • Jeske NA, Patwardahan AM, Gamper N, Price TJ, Akopian AN, Hargreaves KM (2006) Cannabinoid WN55, 212-2 regulates TRPV1 phosphorylation in sensory neurons. J Biol Chem 281:32879–32890

    Article  PubMed  CAS  Google Scholar 

  • Jhaveri MD, Sagar DR, Elmes SJ, Kendall DA, Chapman V (2007) Cannabinoid CB2 receptor-mediated anti-nociception in models of acute and chronic pain. Mol Neurobiol 36:26–35

    Article  PubMed  CAS  Google Scholar 

  • Jordt S-E, McKemy DD, Julius D (2003) Lessons from peppers and peppermint: the molecular logic of thermosensation. Curr Opin Neurobiol 13:487–492

    Article  PubMed  CAS  Google Scholar 

  • Kelly S, Donaldson LF (2008) Peripheral cannabinoid CB1 receptors inhibit evoked responses of nociceptive neurons in vivo. Eur J Pharmacol 586:160–163

    Article  PubMed  CAS  Google Scholar 

  • Kelly S, Jhaveri MD, Sagar DR, Kendall DA, Chapman V (2003) Activation of peripheral cannabinoid CB1 receptors inhibits mechanically evoked responses of spinal neurons in noninflamed rats and rats with hindpaw inflammation. Eur J Neurosci 18:2239–2243

    Article  PubMed  Google Scholar 

  • Khanolkar AD, Lu D, Ibrahim MM, Duclos RI, Thakur GA, Malan TP, Porreca F, Veerappan V, Tian X, George C, Parrish DA, Papahatjis DP, Makriyannis A (2007) Cannabilactones: a novel class of CB2 selective agonists with peripheral analgesic activity. J Med Chem 50:6493–6500

    Article  PubMed  CAS  Google Scholar 

  • Khasabova IA, Simone DA, Seybold VS (2002) Cannabinoids attenuate depolarization-dependent Ca2+ influx in intermediate-size primary afferent neurons of adult rats. Neuroscience 115:613–625

    Article  PubMed  CAS  Google Scholar 

  • 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 24:1744–1753

    Article  PubMed  CAS  Google Scholar 

  • Khasabova IA, Khasabov SG, Harding-Rose C, Coicou LG, Seybold BA, Lindberg AE, Steevens CD, Simone DA, Seybold VS (2008) A decrease in anandamide signaling contributes to the maintenance of cutaneous mechanical hyperalgesia in a model of bone cancer pain. J Neurosci 28:11141–11152

    Article  PubMed  CAS  Google Scholar 

  • Kim HI, Kim TH, Shin YK, Lee CS, Park M, Song J-H (2005) Anandamide suppression of Na+ currents in rat dorsal root ganglion neurons. Brain Res 1062:39–47

    Article  PubMed  CAS  Google Scholar 

  • Krishtal O, Lozovaya N, Fedorenko A, Savelyev I, Chizhamakov I (2006) The agonists for nociceptors are ubiquitous, but the modulators are specific: P2X receptors in the sensory neurons are modulated by cannabinoids. Pflugers Arch Eur J Physiol 453:353–360

    Article  CAS  Google Scholar 

  • La Rana G, Russo R, Campolongo P, Bortolato M, Mangieri RA, Cuomo V, Iacono A, Mattace Raso G, Meli R, Piomelli D, Calignano A (2008) Modulation of neuropathic and inflammatory pain by the endocannabinoid transport inhibitor AM404 [N-(4-hydroxyphenyl)-eicosa-5,8,11,14-tetraenamide]. J Pharmacol Exp Ther 317:1365–1371

    Article  CAS  Google Scholar 

  • Lauckner JE, Hille B, Mackie K (2005) The cannabinoid agonist WIN55, 212-2 increases intracellular calcium via CB1 receptor coupling to Gq/11 G proteins. Proc Natl Acad Sci USA 102:19144–19149

    Article  PubMed  CAS  Google Scholar 

  • Lauckner JE, Jenson JB, Chen H-Y, Lu H-C, Hille B, Mackie K (2008) GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M currents. Proc Natl Acad Sci USA 105:2699–2704

    Article  PubMed  CAS  Google Scholar 

  • Ligresti A, Morera E, van der Stelt M, Monory K, Lutz B, Ortar G, Di Marzo V (2004) Further evidence for the existence of a specific process for the membrane transport of anandamide. Biochem J 380:265–272

    Article  PubMed  CAS  Google Scholar 

  • Mackie K, Stella N (2006) Cannabinoid receptors and endocannabinoids: evidence for new players. Am Assoc Pharm Sci J 8:E298–E306

    Google Scholar 

  • Maingret F, Patel AJ, Lazdunski M, Honore E (2001) The endocannabinoid anandamide is a direct and selective blocker of the background K+ channel TASK-1. EMBO J 20:47–54

    Article  PubMed  CAS  Google Scholar 

  • Malan TP, Ibrahim MM, Deng H, Liu Q, Mata H, Vanderah TW, Porreca F, Makriyannis A (2001) CB2 cannabinoid receptor-mediated peripheral antinociception. Pain 93:239–245

    Article  PubMed  CAS  Google Scholar 

  • Malan TP, Ibrahim MM, Vanderah TW, Makriyannis A, Porreca F (2002) Inhibition of pain responses by activation of CB2 cannabinoid receptors. Chem Phys Lipids 121:191–200

    Article  PubMed  CAS  Google Scholar 

  • Marsicano G, Goodenough S, Monory K, Hermann K, Eder M, Cannich A, Azad SC, Cascio MG, Gutierrez SO, van der Stelt M, Lopez-Rodriguez ML, Casanova E, Schütz G, Zieglgänsberger W, Di Marzo V, Behl C, Lutz B (2003) CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science 302:84–88

    Article  PubMed  CAS  Google Scholar 

  • Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346:561–564

    Article  PubMed  CAS  Google Scholar 

  • Mitrirattanakul S, Ramakul N, Guerrero AV, Matsuka Y, Ono T, Iwase H, Mackie K, Faull KF, Spigelman I (2006) Site-specific increases in peripheral cannabinoid receptors and their endogenous ligands in a model of neuropathic pain. Pain 126:102–114

    Article  PubMed  CAS  Google Scholar 

  • Montell C, Birnbaumer L, Flockerzi V, Bindels RJ, Brudford EA, Caterina MJ, Clapham CE, Harteneck C, Heller S, Julius D, Kojima I, Mori Y, Penner R, Prawitt D, Scharenberg AM, Schultz G, Shimizu N, Zhu MX (2002) A unified nomenclature for the superfamily of TRP cation channels. Mol Cell 9:229–231

    Article  PubMed  CAS  Google Scholar 

  • Morisset V, Urban L (2001) Cannabinoid-induced presynaptic inhibition of glutamatergic EPSCs in substantia gelatinosa neurons of the rat spinal cord. J Neurophysiol 86:40–48

    PubMed  CAS  Google Scholar 

  • Munro S, Thomas KL, Abu-Shaar M (1993) Molecular characterisation of a peripheral receptor for cannabinoids. Nature 365:61–65

    Article  PubMed  CAS  Google Scholar 

  • 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 92:3562–3574

    Article  PubMed  CAS  Google Scholar 

  • Nyilas R, Dudok B, Uran GB, Mackie K, Watanabe M, Cravatt BF, Freund TF, Katona I (2008) Enzymatic machinery for endocannabinoid biosynthesis associated with calcium stores glutamatergic axon terminals. J Neurosci 28:1058–1063

    Article  PubMed  CAS  Google Scholar 

  • Ocana M, Cendan CM, Cobos EJ, Entrena JM, Baeyens JM (2004) Potassium channels and pain: present realities and future opportunities. Eur J Pharmacol 500:203–219

    Article  PubMed  CAS  Google Scholar 

  • Offermanns S (2003) G-proteins as transducers ion transmembrane signalling. Progr Biophys Mol Biol 83:101–130

    Article  CAS  Google Scholar 

  • Oka S, Nakajima K, Yamashita A, Kishimoto S, Sugiura T (2007) Identification of GPR55 as a lysophosphatidylinositol receptor. Biochem Biophys Res Comm 362:928–934

    Article  PubMed  CAS  Google Scholar 

  • Onaivi ES, Ishiguro H, Gong JP, Patel S, Perchuk A, Meozzi PA et al (2006) Discovery of the presence and functional expression of cannabinoid CB2 receptors in the brain. Ann NY Acad Sci 1074:514–536

    Article  PubMed  CAS  Google Scholar 

  • Pacher P, Barkai S, Kunos G (2006) The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev 58:389–462

    Article  PubMed  CAS  Google Scholar 

  • Patel HJ, Birrell MA, Crispino N, Hele DJ, Venkatesan P, Barnes PJ et al (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

    Article  PubMed  CAS  Google Scholar 

  • Patwardahan AM, Jeske NA, Price TJ, Gamper N, Akopian AN, Hargreaves KM (2006) The cannabinoid WIN55, 212–2 inhibits transient receptor potential vanilloid 1 (TRPV1) and evokes peripheral antihyperalgesia via calcineurin. Proc Natl Acad Sci USA 103:11393–11398

    Article  CAS  Google Scholar 

  • Potenzieri C, Brink TS, Pacharinsak C, Simone DA (2008) Cannabinoid modulation of cutaneous Aδ nociceptors during inflammation. J Neurophysiol 100:2794–2806

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Qin N, Neeper MP, Liu Y, Hutchinson TL, Lubin ML, Flores CM (2008) TRPV2 is activated by cannabidiol and mediates CGRP release in cultured rat dorsal root ganglion neurons. J Neurosci 28:6231–6238

    Article  PubMed  CAS  Google Scholar 

  • Quartilho A, Mata H, Ibrahim MM, Vanderah TW, Porreca F, Makriyannis A, Malan TP (2003) Inhibition of inflammatory hyperalgesia by activation of peripheral CB2 cannabinoid receptors. Anesthesiology 99:955–960

    Article  PubMed  CAS  Google Scholar 

  • Rácz I, Bilkei-Gorzo A, Markert A, Stamer F, Göthert M, Zimmer A (2008) Anandamide effects on 5-HT3 receptors in vivo. Eur J Pharmacol 596:98–101

    Article  PubMed  CAS  Google Scholar 

  • Rimmerman N, Hughes HV, Bradshaw HB, Pazos MX, Mackie K, Prieto AL, Walker JM (2008) Compartmentalization of endocannabinoids into lipid rafts in a dorsal root ganglion cell line. Br J Pharmacol 153:380–389

    Article  PubMed  CAS  Google Scholar 

  • Ross RA, Coutts AA, McFarlane SM, Anavi-Goffer S, Irving AJ, Pertwee RG et al (2001) Actions of cannabinoid receptor ligands on rat cultured sensory neurons: implications for antinociception. Neuropharmacology 40:221–232

    Article  PubMed  CAS  Google Scholar 

  • Ross RA, Evans RM, Scott RH (2004) Cannabinoids and sensory neurons. Curr Neuropharmacol 1:59–73

    Article  Google Scholar 

  • Ross HR, Napier I, Connor M (2008) Inhibition of recombinant human T-type calcium channels by Δ9-tetrahydrocannabinol and cannabidiol. J Biol Chem 283:16124–16134

    Article  PubMed  CAS  Google Scholar 

  • Ryberg E, Larsson N, Sjögren S, Hjorth S, Hermansson NO, Leonova J, Elebring T, Nilsson K, Drmota T, Greasley PJ (2007) The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol 152:1092–1101

    Article  PubMed  CAS  Google Scholar 

  • Sagar DR, Kelly S, Millns PJ, O’Shaughnessey CT, Kendall DA, Chapman V (2005) Inhibitory effects of CB1 and CB2 receptor antagonists on responses of DRG neurons and dorsal horn neurons in neuropathic rats. Eur J Pharmacol 22:371–379

    Google Scholar 

  • Salio C, Fischer J, Franzoni MF, Conrath M (2002) Pre- and post-synaptic localization of the CB1 cannabinoid receptor in the dorsal horn of the rat spinal cord. Neuroscience 110:755–764

    Article  PubMed  CAS  Google Scholar 

  • Schuelert N, McDougall JJ (2008) Cannabinoid-mediated antinociception is enhanced in rat osteoarthritic knees. Arthritis Rheum 58:145–153

    Article  PubMed  CAS  Google Scholar 

  • 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. J Biol Chem 270:3726–3731

    Article  PubMed  CAS  Google Scholar 

  • Ständer S, Schmelz M, Metze D, Luger T, Rukwied R (2005) Distribution of cannabinoid receptor 1 (CB1) an d2 (CB2) on sensory nerve fibers and adnexal structures in human skin. J Dermatol Sci 38:177–188

    Article  PubMed  CAS  Google Scholar 

  • Starowicz K, Nigam S, Di Marzo V (2007) Biochemistry and Pharmacology of endovanilloids. Pharmacol Ther 114:13–33

    Article  PubMed  CAS  Google Scholar 

  • Staton PC, Hatcher JP, Walker DJ, Morrison AD, Shapland EM, Hughes JP, Chong E, Mander PK, Green PJ, Billinton A, Fulleylove M, Lancaster HC, Smith JC, Bailey LT, Wise A, Brown AJ, Richardson JC, Chessel IP (2008) The putative cannabinoid receptor GPR55 plays a role in mechanical hyperalgesia associated with inflammatory and neuropathic pain. Pain 139:225–236

    Article  PubMed  CAS  Google Scholar 

  • 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 21:1104–1109

    PubMed  CAS  Google Scholar 

  • Tominaga M, Caterina MJ, Malmberg AB, Rosen TA, Gilbert H, Skinner K, Raumann BE, Basbaum AI, Julius D (1998) The cloned capsaicin receptor integrates multiple pain-producing stimuli. Biophys J 21:531–543

    CAS  Google Scholar 

  • van der Stelt M, Trevisani M, Vellani V, De Petrocellis L, Moriello AS, Campi B, McNaughton P, Geppetti P, Di Marzo V (2005) Anandamide acts as an intracellular messenger amplifying Ca2+ influx via TRPV1 channels. EMBO J 24:3026–3037

    Article  PubMed  CAS  Google Scholar 

  • Veale EL, Buswell R, Clarke CE, Mathie A (2007) Identification of a region in the TASK3 two pore domain potassium channel that is critical for its blockade by methanandamide. Br J Pharmacol 152:778–786

    Article  PubMed  CAS  Google Scholar 

  • Walker JM, Hohmann AG (2005) Cannabinoid mechanisms of pain suppression. Handb Exp Pharmacol 168:509–554

    Article  PubMed  CAS  Google Scholar 

  • Wotherspoon G, Fox A, McIntyre P, Colley S, Bevan S, Winter J (2005) Peripheral nerve injury induces cannabinoid receptor 2 protein expression in rat sensory neurons. Neuroscience 135:235–245

    Article  PubMed  CAS  Google Scholar 

  • Yao BB, Hsieh GC, Frost JM, Fan Y, Garrison TR, Daza AV, Grayson GK, Zhu CZ, Pai M, Chandran P, Salyers AK, Wensink EJ, Honore P, Sullivan JP, Dart MJ, Meyer MD (2008) In vitro and in vivo characterization of A-796260: a selective cannabinoid CB2 receptor agonist exhibiting analgesic activity in rodent pain models. Br J Pharmacol 153:401

    Article  CAS  Google Scholar 

  • Yiangou Y, Facer P, Smith JA, Sangameswaran L, Eglen R, Birch R, Knowles C, Williams N, Anand P (2001) Increased acid-sensing ion channel ASIC-3 in inflamed human intestine. Eur J Gastroenterol Hepatol 13:891–896

    Article  PubMed  CAS  Google Scholar 

  • Zygmunt PM, Andersson DA, Hogestatt ED (2002) Delta 9-tetrahydrocannabinol and cannabinol activate capsaicin-sensitive sensory nerves via a CB1 and CB2 cannabinoid receptor-independent mechanism. J Neurosci 22:4720–4727

    PubMed  CAS  Google Scholar 

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Kress, M., Kuner, R. Mode of action of cannabinoids on nociceptive nerve endings. Exp Brain Res 196, 79–88 (2009). https://doi.org/10.1007/s00221-009-1762-0

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  • DOI: https://doi.org/10.1007/s00221-009-1762-0

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