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Targeting the Cannabinoid System to Produce Analgesia

  • Devi Rani SagarEmail author
  • Maulik Jhaveri
  • Victoria Chapman
Chapter
Part of the Current Topics in Behavioral Neurosciences book series (CTBN, volume 1)

Abstract

Cannabinoid receptors are present at key sites involved in the relay and modulation of nociceptive responses. The analgesic effects of the cannabinoid CB1 receptor are well described. The widespread distribution of these receptors in the brain does, however, also explain the side-effects associated with CB1 receptor agonists. The cannabinoid CB2 receptor also produces analgesic effects in models of acute, inflammatory and neuropathic pain. The sites and mechanisms of CB2 receptor-mediated analgesia are described herein. In addition to targeting cannabinoid receptors directly, protection of endocannabinoids (eCBs) from metabolism also produces analgesic effects. Indeed, reports that noxious stimulation elevates levels of eCBs in the spinal cord and brain provide further rationale for this approach. The effects of inhibition of fatty acid amide hydrolase (FAAH) on nociceptive responses in models of inflammatory and neuropathic pain are discussed.

Keywords

Inflammation Neuropathic Fatty acid amide hydrolase Endocannabinoid Arthritis 

Abbreviations

2AG

2-Arachidonoylglycerol

AEA

N-Arachidonoylethanolamine; Anandamide

CB1

Cannabinoid-1 receptor

CB2

Cannabinoid-2 receptor

CCI

Chronic constriction injury

CFA

Complete Freund’s adjuvant

COX-2

Cyclooxygenase type 2

DGL

Diacylglycerol lipase

DRG

Dorsal root ganglion

FAAH

Fatty acid amide hydrolase

i.p.

Intraperitoneal administration

i.pl.

Intraplantar administration

MAPK

Mitogen activated protein kinase

MGL

Monoacylglycerol lipase

NAAA

N-Acylethanolamine hydrolysing acid amidase

NADA

N-Arachidonoyl dopamine

NAE

N-Acylethanolamines

NAPE

N-Acylphosphatidylethanolamine

OA

Osteoarthritis

OEA

N-Oleoylethanolamine

PAG

Periaqueductal grey

PEA

N-Palmitoyl ethanolamine

PLC

Phospholipase C

PLD

Phospholipase D

p.o.

Oral administration

RA

Rheumatoid arthritis

SNL

Spinal nerve ligation

Δ9-THC

Δ9-Tetrahydrocannabinol

TRPV1

Transient receptor potential vanilloid type 1

Notes

Acknowledgements

We would like to thank the Wellcome Trust, Medical Research Council and GlaxoSmithKline for financial support towards the original research discussed in this review.

References

  1. Agarwal N, Pacher P, Tegeder I et al. (2007) Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors. Nat Neurosci 10:870–879PubMedCrossRefGoogle Scholar
  2. Bab I, Ofek O, Tam J et al. (2008) Endocannabinoids and the regulation of bone metabolism. J Neuroendocrinol 20(Suppl 1):69–74PubMedCrossRefGoogle Scholar
  3. Beaulieu P, Bisogno T, Punwar S et al. (2000) Role of the endogenous cannabinoid system in the formalin test of persistent pain in the rat. Eur J Pharmacol 396:85–92CrossRefGoogle Scholar
  4. Beltramo M, Bernardini N, Bertorelli R et al. (2006) CB2 receptor-mediated antihyperalgesia: possible direct involvement of neural mechanisms. Eur J Neurosci 23:1530–1538PubMedCrossRefGoogle Scholar
  5. Blake DR, Robson P, Ho M et al. (2006) Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis. Rheumatology (Oxford) 45:50–52CrossRefGoogle Scholar
  6. Brown AJ (2007) Novel cannabinoid receptors. Br J Pharmacol 152:567–575PubMedCrossRefGoogle Scholar
  7. Chang L, Luo L, Palmer JA et al. (2006) Inhibition of fatty acid amide hydrolase produces analgesia by multiple mechanisms. Br J Pharmacol 148:102–113PubMedCrossRefGoogle Scholar
  8. Chapman V (1999) The cannabinoid CB1 receptor antagonist, SR141716A, selectively facilitates nociceptive responses of dorsal horn neurones in the rat. Br J Pharmacol 127:1765–1767PubMedCrossRefGoogle Scholar
  9. Chin CL, Tovcimak AE, Hradil VP et al. (2008) Differential effects of cannabinoid receptor agonists on regional brain activity using pharmacological MRI. Br J Pharmacol 153:367–379PubMedCrossRefGoogle Scholar
  10. Clayton N, Marshall FH, Bountra C et al. (2002) CB1 and CB2 cannabinoid receptors are implicated in inflammatory pain. Pain 96:253–260PubMedCrossRefGoogle Scholar
  11. Cox ML, Welch SP (2004) The antinociceptive effect of Delta9-tetrahydrocannabinol in the arthritic rat. Eur J Pharmacol 493:65–74PubMedCrossRefGoogle Scholar
  12. Cox ML, Haller VL, Welch SP (2007a) The antinociceptive effect of Delta9-tetrahydrocannabinol in the arthritic rat involves the CB(2) cannabinoid receptor. Eur J Pharmacol 570:50–56PubMedCrossRefGoogle Scholar
  13. Cox ML, Haller VL, Welch SP (2007b) Synergy between delta9-tetrahydrocannabinol and morphine in the arthritic rat. Eur J Pharmacol 567:125–130PubMedCrossRefGoogle Scholar
  14. Cravatt BF, Giang DK, Mayfield SP et al. (1996) Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 384:83–87PubMedCrossRefGoogle Scholar
  15. Cravatt BF, Demarest K, Patricelli MP et al. (2001) Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc Natl Acad Sci USA 98:9371–9376PubMedCrossRefGoogle Scholar
  16. Deutsch DG, Chin SA (1993) Enzymatic synthesis and degradation of anandamide, a cannabinoid receptor agonist. Biochem Pharmacol 46:791–796PubMedCrossRefGoogle Scholar
  17. Devane WA, Hanus L, Breuer A et al. (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258:1946–1949PubMedCrossRefGoogle Scholar
  18. Dinh TP, Carpenter D, Leslie FM et al. (2002) Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc Natl Acad Sci USA 99:10819–10824PubMedCrossRefGoogle Scholar
  19. Egertova M, Elphick MR (2000) Localisation of cannabinoid receptors in the rat brain using antibodies to the intracellular C-terminal tail of CB. J Comp Neurol 422:159–171PubMedCrossRefGoogle Scholar
  20. Elmes SJ, Jhaveri MD, Smart D et al. (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 20:2311–2320PubMedCrossRefGoogle Scholar
  21. Elmes SJ, Winyard LA, Medhurst SJ et al. (2005) Activation of CB1 and CB2 receptors attenuates the induction and maintenance of inflammatory pain in the rat. Pain 118:327–335PubMedCrossRefGoogle Scholar
  22. Fegley D, Gaetani S, Duranti A et al. (2005) Characterization of the fatty acid amide hydrolase inhibitor cyclohexyl carbamic acid 3′-carbamoyl-biphenyl-3-yl ester (URB597): effects on anandamide and oleoylethanolamide deactivation. J Pharmacol Exp Ther 313:352–358PubMedCrossRefGoogle Scholar
  23. Finn DP, Jhaveri MD, Beckett SR et al. (2003) Effects of direct periaqueductal grey administration of a cannabinoid receptor agonist on nociceptive and aversive responses in rats. Neuropharmacology 45:594–604PubMedCrossRefGoogle Scholar
  24. Fowler CJ (2007) The contribution of cyclooxygenase-2 to endocannabinoid metabolism and action. Br J Pharmacol 152:594–601PubMedCrossRefGoogle Scholar
  25. Galiegue S, Mary S, Marchand J et al. (1995) Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem 232:54–61PubMedCrossRefGoogle Scholar
  26. Gauldie SD, McQueen DS, Pertwee R et al. (2001) Anandamide activates peripheral nociceptors in normal and arthritic rat knee joints. Br J Pharmacol 132:617–621PubMedCrossRefGoogle Scholar
  27. Gong JP, Onaivi ES, Ishiguro H et al. (2006) Cannabinoid CB2 receptors: immunohistochemical localization in rat brain. Brain Res 1071:10–23PubMedCrossRefGoogle Scholar
  28. Guindon J, Hohmann AG (2008) Cannabinoid CB2 receptors: a therapeutic target for the treatment of inflammatory and neuropathic pain. Br J Pharmacol 153:319–334PubMedCrossRefGoogle Scholar
  29. Guindon J, Desroches J, Beaulieu P (2007) The antinociceptive effects of intraplantar injections of 2-arachidonoyl glycerol are mediated by cannabinoid CB2 receptors. Br J Pharmacol 150:693–701PubMedCrossRefGoogle Scholar
  30. Hanus L, Abu-Lafi S, Fride E et al. (2001) 2-Arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor. Proc Natl Acad Sci USA 98:3662–3665PubMedCrossRefGoogle Scholar
  31. Harris J, Drew LJ, Chapman V (2000) Spinal anandamide inhibits nociceptive transmission via cannabinoid receptor activation in vivo. NeuroReport 11:2817–2819PubMedCrossRefGoogle Scholar
  32. Herkenham M, Groen BG, Lynn AB et al. (1991) Neuronal localization of cannabinoid receptors and second messengers in mutant mouse cerebellum. Brain Res 552:301–310PubMedCrossRefGoogle Scholar
  33. Hohmann AG (2002) Spinal and peripheral mechanisms of cannabinoid antinociception: behavioral, neurophysiological and neuroanatomical perspectives. Chem Phys Lipids 121:173–190PubMedCrossRefGoogle Scholar
  34. 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 257:119–122PubMedCrossRefGoogle Scholar
  35. Holt S, Comelli F, Costa B et al. (2005) Inhibitors of fatty acid amide hydrolase reduce carrageenan-induced hind paw inflammation in pentobarbital-treated mice: comparison with indomethacin and possible involvement of cannabinoid receptors. Br J Pharmacol 146:467–476PubMedCrossRefGoogle Scholar
  36. Huang SM, Bisogno T, Trevisani M et al. (2002) An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors. Proc Natl Acad Sci USA 99:8400–8405PubMedCrossRefGoogle Scholar
  37. Ibrahim MM, Porreca F, Lai J et al. (2005) CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Proc Natl Acad Sci USA 102:3093–3098PubMedCrossRefGoogle Scholar
  38. Ibrahim MM, Rude ML, Stagg NJ et al. (2006) CB2 cannabinoid receptor mediation of antinociception. Pain 122:36–42PubMedCrossRefGoogle Scholar
  39. Iversen L, Chapman V (2002) Cannabinoids: a real prospect for pain relief? Curr Opin Pharmacol 2:50–55PubMedCrossRefGoogle Scholar
  40. Jayamanne A, Greenwood R, Mitchell VA et al. (2006) Actions of the FAAH inhibitor URB597 in neuropathic and inflammatory chronic pain models. Br J Pharmacol 147:281–288PubMedCrossRefGoogle Scholar
  41. Jhaveri MD, Richardson D, Kendall DA et al. (2006) Analgesic effects of fatty acid amide hydrolase inhibition in a rat model of neuropathic pain. J Neurosci 26:13318–13327PubMedCrossRefGoogle Scholar
  42. Jhaveri MD, Richardson D, Chapman V (2007a) Endocannabinoid metabolism and uptake: novel targets for neuropathic and inflammatory pain. Br J Pharmacol 152:624–632PubMedCrossRefGoogle Scholar
  43. Jhaveri MD, Sagar DR, Elmes SJ et al. (2007b) Cannabinoid CB(2) receptor-mediated anti-nociception in models of acute and chronic pain. Mol Neurobiol 36:26–35PubMedCrossRefGoogle Scholar
  44. Jhaveri MD, Elmes SJ, Richardson D et al. (2008a) Evidence for a novel functional role of cannabinoid CB receptors in the thalamus of neuropathic rats. Eur J Neurosci 27:1722–1730PubMedCrossRefGoogle Scholar
  45. Jhaveri MD, Richardson D, Robinson I et al. (2008b) Inhibition of fatty acid amide hydrolase and cyclooxygenase-2 increases levels of endocannabinoid related molecules and produces analgesia via peroxisome proliferator-activated receptor-alpha in a model of inflammatory pain. Neuropharmacology 55:85–93PubMedCrossRefGoogle Scholar
  46. Johns DG, Behm DJ, Walker DJ et al. (2007) The novel endocannabinoid receptor GPR55 is activated by atypical cannabinoids but does not mediate their vasodilator effects. Br J Pharmacol 152:825–831PubMedCrossRefGoogle Scholar
  47. Karsak M, Cohen-Solal M, Freudenberg J et al. (2005) Cannabinoid receptor type 2 gene is associated with human osteoporosis. Hum Mol Genet 14:3389–3396PubMedCrossRefGoogle Scholar
  48. Kathuria S, Gaetani S, Fegley D et al. (2003) Modulation of anxiety through blockade of anandamide hydrolysis. Nat Med 9:76–81PubMedCrossRefGoogle Scholar
  49. Kelly S, Chapman V (2001) Selective cannabinoid CB1 receptor activation inhibits spinal nociceptive transmission in vivo. J Neurophysiol 86:3061–3064PubMedGoogle Scholar
  50. Kelly S, Chapman V (2002) Spinal administration of capsazepine inhibits noxious evoked responses of dorsal horn neurons in non-inflamed and carrageenan inflamed rats. Brain Res 935:103–108PubMedCrossRefGoogle Scholar
  51. Kelly S, Chapman V (2003) Cannabinoid CB(1) receptor inhibition of mechanically evoked responses of spinal neurones in control rats, but not in rats with hindpaw inflammation. Eur J Pharmacol 474:209–216PubMedCrossRefGoogle Scholar
  52. Kelly S, Jhaveri MD, Sagar DR et al. (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 18:2239–2243PubMedCrossRefGoogle Scholar
  53. Lauckner JE, Jensen JB, Chen HY et al. (2008) GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current. Proc Natl Acad Sci USA 105:2699–2704PubMedCrossRefGoogle Scholar
  54. Leung D, Saghatelian A, Simon GM et al. (2006) Inactivation of N-acyl phosphatidylethanolamine phospholipase D reveals multiple mechanisms for the biosynthesis of endocannabinoids. Biochemistry 45:4720–4726PubMedCrossRefGoogle Scholar
  55. Lichtman AH, Cook SA, Martin BR (1996) Investigation of brain sites mediating cannabinoid-induced antinociception in rats: evidence supporting periaqueductal gray involvement. J Pharmacol Exp Ther 276:585–593PubMedGoogle Scholar
  56. Lichtman AH, Leung D, Shelton CC et al. (2004a) Reversible inhibitors of fatty acid amide hydrolase that promote analgesia: evidence for an unprecedented combination of potency and selectivity. J Pharmacol Exp Ther 311:441–448PubMedCrossRefGoogle Scholar
  57. Lichtman AH, Shelton CC, Advani T et al. (2004b) Mice lacking fatty acid amide hydrolase exhibit a cannabinoid receptor-mediated phenotypic hypoalgesia. Pain 109:319–327PubMedCrossRefGoogle Scholar
  58. Liu J, Wang L, Harvey-White J et al. (2006) A biosynthetic pathway for anandamide. Proc Natl Acad Sci USA 103:13345–13350PubMedCrossRefGoogle Scholar
  59. Liu J, Wang L, Harvey-White J et al. (2008) Multiple pathways involved in the biosynthesis of anandamide. Neuropharmacology 54:1–7PubMedCrossRefGoogle Scholar
  60. Mackie K (2006) Cannabinoid receptors as therapeutic targets. Annu Rev Pharmacol Toxicol 46:101–122PubMedCrossRefGoogle Scholar
  61. Maione S, De Petrocellis L, de Novellis V et al. (2007) Analgesic actions of N-arachidonoyl-serotonin, a fatty acid amide hydrolase inhibitor with antagonistic activity at vanilloid TRPV1 receptors. Br J Pharmacol 150:766–781PubMedCrossRefGoogle Scholar
  62. Malan TP Jr, Ibrahim MM, Deng H et al. (2001) CB2 cannabinoid receptor-mediated peripheral antinociception. Pain 93:239–245PubMedCrossRefGoogle Scholar
  63. Malan TP Jr, Ibrahim MM, Lai J et al. (2003) CB2 cannabinoid receptor agonists: pain relief without psychoactive effects? Curr Opin Pharmacol 3:62–67PubMedCrossRefGoogle Scholar
  64. Martin WJ, Coffin PO, Attias E et al. (1999) Anatomical basis for cannabinoid-induced antinociception as revealed by intracerebral microinjections. Brain Res 822:237–242PubMedCrossRefGoogle Scholar
  65. Mechoulam R, Ben-Shabat S, Hanus L et al. (1995) Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol 50:83–90PubMedCrossRefGoogle Scholar
  66. Meng ID, Manning BH, Martin WJ et al. (1998) An analgesia circuit activated by cannabinoids. Nature 395:381–383PubMedCrossRefGoogle Scholar
  67. Mitrirattanakul S, Ramakul N, Guerrero AV et al. (2006) Site-specific increases in peripheral cannabinoid receptors and their endogenous ligands in a model of neuropathic pain. Pain 126:102–114PubMedCrossRefGoogle Scholar
  68. Ofek O, Karsak M, Leclerc N et al. (2006) Peripheral cannabinoid receptor, CB2, regulates bone mass. Proc Natl Acad Sci USA 103:696–701PubMedCrossRefGoogle Scholar
  69. Pertwee RG (2001) Cannabinoid receptors and pain. Prog Neurobiol 63:569–611PubMedCrossRefGoogle Scholar
  70. Petrosino S, Palazzo E, de Novellis V et al. (2007) Changes in spinal and supraspinal endocannabinoid levels in neuropathic rats. Neuropharmacology 52:415–422PubMedCrossRefGoogle Scholar
  71. Porter AC, Sauer JM, Knierman MD et al. (2002) Characterization of a novel endocannabinoid, virodhamine, with antagonist activity at the CB1 receptor. J Pharmacol Exp Ther 301:1020–1024PubMedCrossRefGoogle Scholar
  72. Rice AS, Farquhar-Smith WP, Nagy I (2002) Endocannabinoids and pain: spinal and peripheral analgesia in inflammation and neuropathy. Prostaglandins Leukot Essent Fatty Acids 66:243–256PubMedCrossRefGoogle Scholar
  73. Richardson JD, Kilo S, Hargreaves KM (1998) Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors. Pain 75:111–119PubMedCrossRefGoogle Scholar
  74. Richardson D, Pearson RG, Kurian N et al. (2008) Characterisation of the cannabinoid receptor system in synovial tissue and fluid in patients with osteoarthritis and rheumatoid arthritis. Arthritis Res Ther 10:R43PubMedCrossRefGoogle Scholar
  75. Romero-Sandoval A, Nutile-McMenemy N, DeLeo JA (2008) Spinal microglial and perivascular cell cannabinoid receptor type 2 activation reduces behavioral hypersensitivity without tolerance after peripheral nerve injury. Anesthesiology 108:722–734PubMedCrossRefGoogle Scholar
  76. Russo R, Loverme J, La Rana G et al. (2007) The fatty-acid amide hydrolase inhibitor URB597 (cyclohexyl carbamic acid 3′-carbamoyl-biphenyl-3-yl ester) reduces neuropathic pain after oral administration in mice. J Pharmacol Exp Ther 322:236–242PubMedCrossRefGoogle Scholar
  77. Ryberg E, Larsson N, Sjogren S et al. (2007) The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol 152:1092–1101PubMedCrossRefGoogle Scholar
  78. Sagar DR, Kelly S, Millns PJ et al. (2005) Inhibitory effects of CB1 and CB2 receptor agonists on responses of DRG neurons and dorsal horn neurons in neuropathic rats. Eur J Neurosci 22:371–379PubMedCrossRefGoogle Scholar
  79. Schuelert N, McDougall JJ (2008) Cannabinoid-mediated antinociception is enhanced in rat osteoarthritic knees. Arthritis Rheum 58:145–153PubMedCrossRefGoogle Scholar
  80. Scott DA, Wright CE, Angus JA (2004) Evidence that CB-1 and CB-2 cannabinoid receptors mediate antinociception in neuropathic pain in the rat. Pain 109:124–131PubMedCrossRefGoogle Scholar
  81. Simon GM, Cravatt BF (2008) Anandamide biosynthesis catalyzed by the phosphodiesterase GDE1 and detection of glycerophospho-N-acyl ethanolamine precursors in mouse brain. J Biol Chem 283:9341–9349PubMedCrossRefGoogle Scholar
  82. Smith FL, Fujimori K, Lowe J et al. (1998) Characterization of delta9-tetrahydrocannabinol and anandamide antinociception in nonarthritic and arthritic rats. Pharmacol Biochem Behav 60:183–191PubMedCrossRefGoogle Scholar
  83. Sokal DM, Elmes SJ, Kendall DA et al. (2003) Intraplantar injection of anandamide inhibits mechanically-evoked responses of spinal neurones via activation of CB2 receptors in anaesthetised rats. Neuropharmacology 45:404–411PubMedCrossRefGoogle Scholar
  84. Tam J, Ofek O, Fride E et al. (2006) Involvement of neuronal cannabinoid receptor CB1 in regulation of bone mass and bone remodeling. Mol Pharmacol 70:786–792PubMedCrossRefGoogle Scholar
  85. Tsou K, Brown S, Sanudo-Pena MC et al. (1998) Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system. Neuroscience 83:393–411PubMedCrossRefGoogle Scholar
  86. Tsuboi K, Takezaki N, Ueda N (2007) The N-acylethanolamine-hydrolyzing acid amidase (NAAA). Chem Biodivers 4:1914–1925PubMedCrossRefGoogle Scholar
  87. Valenzano KJ, Tafesse L, Lee G et al. (2005) Pharmacological and pharmacokinetic characterization of the cannabinoid receptor 2 agonist, GW405833, utilizing rodent models of acute and chronic pain, anxiety, ataxia and catalepsy. Neuropharmacology 48:658–672PubMedCrossRefGoogle Scholar
  88. Van Sickle MD, Duncan M, Kingsley PJ et al. (2005) Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science 310:329–332PubMedCrossRefGoogle Scholar
  89. Walker JM, Huang SM (2002) Cannabinoid analgesia. Pharmacol Ther 95:127–135PubMedCrossRefGoogle Scholar
  90. Walker JM, Huang SM, Strangman NM et al. (1999) Pain modulation by release of the endogenous cannabinoid anandamide. Proc Natl Acad Sci USA 96:12198–12203PubMedCrossRefGoogle Scholar
  91. Welch SP, Stevens DL (1992) Antinociceptive activity of intrathecally administered cannabinoids alone, and in combination with morphine, in mice. J Pharmacol Exp Ther 262:10–18PubMedGoogle Scholar
  92. Welch SP, Huffman JW, Lowe J (1998) Differential blockade of the antinociceptive effects of centrally administered cannabinoids by SR141716A. J Pharmacol Exp Ther 286:1301–1308PubMedGoogle Scholar
  93. Wright S, Ware M, Guy G (2006) The use of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis. Rheumatology (Oxford) 45, 781; author reply 781–782Google Scholar
  94. Yamamoto W, Mikami T, Iwamura H (2008) Involvement of central cannabinoid CB2 receptor in reducing mechanical allodynia in a mouse model of neuropathic pain. Eur J Pharmacol 583:56–61PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  • Devi Rani Sagar
    • 1
    Email author
  • Maulik Jhaveri
    • 1
  • Victoria Chapman
    • 1
  1. 1.School of Biomedical SciencesUniversity of NottinghamNottinghamUK

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