J Pharmacol Exp Ther. 2008 Jul 29.
Selective Activation of Cannabinoid CB2 Receptors Suppresses Neuropathic Nociception Induced by Treatment with the Chemotherapeutic Agent Paclitaxel in Rats.
Rahn EJ, Zvonok AM, Thakur GA, Khanolkar AD, Makriyannis A, Hohmann AG.
University of Georgia.
Activation of cannabinoid CB2 receptors suppresses neuropathic pain induced by traumatic nerve injury. The present studies were conducted to evaluate the efficacy of cannabinoid CB2 receptor activation in suppressing painful peripheral neuropathy evoked by chemotherapeutic treatment with the anti-tumor agent paclitaxel. Rats received paclitaxel (2 mg/kg i.p. per day) on four alternate days to induce mechanical hypersensitivity (mechanical allodynia). Mechanical allodynia was defined as a lowering of the threshold for paw withdrawal to stimulation of the plantar hind paw surface with an electronic von Frey stimulator. Mechanical allodynia developed in paclitaxel-treated animals relative to groups receiving the cremophor: ethanol: saline vehicle at the same times. Two structurally distinct cannabinoid CB2 agonists -- the aminoalkylindole (R,S)-AM1241 ((R,S)-(2-iodo-5-nitrophenyl)-[1-((1-methyl-piperidin-2-yl)methyl)-1H-indol-3-yl]-methanone) and the cannabilactone AM1714 (1,9-dihydroxy-3-(1',1'-dimethylheptyl)-6H-benzo[c]chromene-6-one) -- produced a dose-related suppression of established paclitaxel-evoked mechanical allodynia following systemic administration. Pretreatment with the CB2 antagonist SR144528 (5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-N-(1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)-1H-pyrazole-3-carboxamide), but not the CB1 antagonist SR141716 (5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide), blocked the anti-allodynic effects of both (R,S)-AM1241 and AM1714. Moreover, (R)-AM1241, but not (S)-AM1241, suppressed paclitaxel-evoked mechanical allodynia relative to either vehicle treatment or pre-injection thresholds, consistent with mediation by CB2. Administration of either the CB1 or CB2 antagonist alone failed to alter paclitaxel-evoked mechanical allodynia. Moreover, (R,S)-AM1241 did not alter paw withdrawal thresholds in rats that received the cremophor vehicle in lieu of paclitaxel whereas AM1714 induced a modest antinociceptive effect. Our data suggest that cannabinoid CB2 receptors may be important therapeutic targets for the treatment of chemotherapy-evoked neuropathy. |
