Activation of
cannabinoid CB(2) receptors suppresses
neuropathic pain induced by traumatic nerve injury. The present studies were conducted to evaluate the efficacy of
cannabinoid CB(2) receptor activation in suppressing painful
peripheral neuropathy evoked by chemotherapeutic treatment with the
antitumor agent paclitaxel. Rats received
paclitaxel (2 mg/kg i.p./day) on 4 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 EL/
ethanol/saline vehicle at the same times. Two structurally distinct
cannabinoid CB(2) 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 after systemic administration. Pretreatment with the CB(2) 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 CB(1) antagonist
SR141716 [5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl)-1H-
pyrazole-3-carboxamide], blocked the antiallodynic 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 preinjection thresholds, consistent with mediation by CB(2). Administration of either the CB(1) or CB(2) 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 EL vehicle in lieu of
paclitaxel, whereas
AM1714 induced a modest antinociceptive effect. Our data suggest that
cannabinoid CB(2) receptors may be important therapeutic targets for the treatment of
chemotherapy-evoked neuropathy.