Premium
Activation of cannabinoid CB 1 and CB 2 receptors suppresses neuropathic nociception evoked by the chemotherapeutic agent vincristine in rats
Author(s) -
Rahn E J,
Makriyannis A,
Hohmann A G
Publication year - 2007
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0707333
Subject(s) - pharmacology , agonist , cannabinoid , allodynia , vincristine , neuropathic pain , medicine , cannabinoid receptor , morphine , chemistry , nociception , receptor , hyperalgesia , chemotherapy , cyclophosphamide
Background and purpose: The ability of cannabinoids to suppress mechanical hypersensitivity (mechanical allodynia) induced by treatment with the chemotherapeutic agent vincristine was evaluated in rats. Sites of action were subsequently identified. Experimental approach: Mechanical hypersensitivity developed over the course of ten daily injections of vincristine relative to groups receiving saline at the same times. Effects of the CB 1 /CB 2 receptor agonist WIN55,212‐2, the receptor‐inactive enantiomer WIN55,212‐3, the CB 2 ‐selective agonist (R,S)‐AM1241, the opiate agonist morphine and vehicle on chemotherapy‐induced neuropathy were evaluated. WIN55,212‐2 was administered intrathecally (i.t.) or locally in the hindpaw to identify sites of action. Pharmacological specificity was established using competitive antagonists for CB 1 (SR141716) or CB 2 receptors (SR144528). Key results: Systemic administration of WIN55,212‐2, but not WIN55,212‐3, suppressed vincristine‐evoked mechanical allodynia. A leftward shift in the dose‐response curve was observed following WIN55,212‐2 relative to morphine treatment. The CB 1 (SR141716) and CB 2 (SR144528) antagonists blocked the anti‐allodynic effects of WIN55,212‐2. (R,S)‐AM1241 suppressed vincristine‐induced mechanical hypersensitivity through a CB 2 mechanism. Both cannabinoid agonists suppressed vincristine‐induced mechanical hypersensitivity without inducing catalepsy. Spinal sites of action are implicated in cannabinoid modulation of chemotherapy‐induced neuropathy. WIN55,212‐2, but not WIN55,212‐3, administered i.t. suppressed vincristine‐evoked mechanical hypersensitivity at doses that were inactive following local hindpaw administration. Spinal coadministration of both the CB 1 and CB 2 antagonists blocked the anti‐allodynic effects of WIN55,212‐2. Conclusions and implications: Cannabinoids suppress the maintenance of vincristine‐induced mechanical allodynia through activation of CB 1 and CB 2 receptors. These anti‐allodynic effects are mediated, at least in part, at the level of the spinal cord. British Journal of Pharmacology (2007) 152 , 765–777; doi: 10.1038/sj.bjp.0707333 ; published online 18 June 2007