Spinal cannabinoid CB2 receptors as a target for neuropathic pain: an investigation using chronic constriction injury.
Agonists for the cannabinoid CB2 receptor are antinociceptive in several rodent models and several reports have suggested that the target for these drugs is CB2 expressed in the spinal cord pain pathway. After confirming the efficacy of a systemically delivered CB2-selective agonist, GW405833, we tested this hypothesis by administering the CB2 agonists GW405833 and JWH-133, via intrathecal cannulation, to the lumbar spinal cord of rats that had undergone chronic constriction injury to induce mechanical allodynia. We found that although the non-selective CB1/CB2 cannabinoid receptor agonist WIN55,212-2 reversed mechanical allodynia in both ipsilateral and contralateral hind paws, neither GW405833 nor JWH-133 reversed mechanical allodynia. In addition, we investigated the expression of CB2 receptors in the neuropathic spinal cord using immunohistochemistry, Western blot and CB2 agonist stimulated [(35)S]GTPγS binding. Although protein-based analysis of CB2 partially matched the results of earlier studies using the same antibody, we found evidence that this antibody may be insufficiently specific for the detection of CB2 in native tissue. Using [(35)S]GTPγS binding assays, we found no evidence of functional CB2 in the spinal cord, in sham or surgery-treated tissue. However, WIN55,212-2 stimulated [(35)S]GTPγS binding showed clear evidence of functional CB1 receptors consistent with the known distribution of elements of the pain pathway, and we concluded that spinal CB2 receptors are not a likely target for cannabinoid-mediated antinociception in this model.
Department of Pharmacology and Toxicology, School of Medical Sciences, University of Otago, Adams Building, Frederick Street, Dunedin, New Zealand.
P W
PW
Brownjohn
J C
JC
Ashton
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D048588:Benzoxazines / Q000494:pharmacology / Q000627:therapeutic use; D016466:CHO Cells; D002186:Cannabinoids / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D006224:Cricetinae; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D009025:Morpholines / Q000494:pharmacology / Q000627:therapeutic use; D009281:Naphthalenes / Q000494:pharmacology / Q000627:therapeutic use; D009437:Neuralgia / Q000188:drug therapy / Q000378:metabolism*; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*
C463040:1-(2,3-dichlorobenzoyl)-5-methoxy-2-methyl-(2-(mopholin-4-yl)ethyl)-1H-indole; D048588:Benzoxazines; D002186:Cannabinoids; D007211:Indoles; D009025:Morpholines; D009281:Naphthalenes; D043885:Receptor, Cannabinoid, CB2; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C432747:1,1-dimethylbutyl-1-deoxy-Delta(9)-THC