Received for publication June 9, 2008.
Revised July 25, 2008.
Accepted for publication July 28, 2008.

Selective Activation of Cannabinoid CB₂ Receptors Suppresses Neuropathic Nociception Induced by Treatment with the Chemotherapeutic Agent Paclitaxel in Rats

Abstract

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.

Key words: CB1, CB2, cancer, cannabinoid, chemotherapy, neuropathic pain