Cannabinoids attenuate capsaicin-evoked hyperalgesia through spinal and peripheral mechanisms

Previous studies in our laboratory have demonstrated that cannabinoids admi nistered intravenously attenuate the duration of nocifensive behavior and b lock the development of hyperalgesia produced by intraplantar injection of capsaicin. In the present study, we extended these observations and determi ned whether cannabinoids attenuate capsaicin-evoked pain and hyperalgesia t hrough spinal and peripheral mechanisms, and whether the antihyperalgesia w as receptor mediated. Separate groups of rats were pretreated 7 min before capsaicin with an intrathecal injection of vehicle or the cannabinoid recep tor agonist WIN 55,212-2 at doses of 0.1, 1.0 or 10 mug in 10 mul. Although the intrathecal application of WIN 55,212-2 did not alter nocifensive beha vior following capsaicin, it produced a dose-dependent decrease in hyperalg esia to heat and mechanical stimuli. Intrathecal pretreatment with the CB1 receptor antagonist SR141716A (10 mug) blocked the antihyperalgesia produce d by WIN 55,212-2. The ability of intrathecal administration of WIN 55,212- 2 to attenuate hyperalgesia was not due to motor deficits since the highest dose of WIN 55,212-2 did not alter performance on the rota-rod test. To in vestigate whether cannabinoids attenuated capsaicin-evoked hyperalgesia thr ough peripheral mechanisms, separate groups of rats were pretreated with an intraplantar injection of WIN 55,212-2 at doses of 0.1, 1.0, 10 or 30 mug in 100 mul 5 min before capsaicin. Intraplantar pretreatment with WIN 55,21 2-2 produced a dose-dependent attenuation of hyperalgesia to heat, but did not attenuate mechanical hyperalgesia or the duration of nocifensive behavi or. The inactive enantiomer WIN 55,212-3 did not alter the development of h yperalgesia. SR141716A (100 mug) coinjected with WIN 55,212-2 (30 mug) part ially attenuated the effects of WIN 55,212-2 on hyperalgesia to heat. Intra plantar injection of the highest dose of WIN 55,212-2 did not interfere wit h the development of hyperalgesia following capsaicin injection into the co ntralateral paw. These data show that cannabinoids possess antihyperalgesic properties at doses that alone do not produce antinociception, and are cap able of acting at both spinal and peripheral sites. Copyright (C) 2001 Inte rnational Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved.