The role of central and peripheral Cannabinoid(1) receptors in the antihyperalgesic activity of cannabinoids in a model of neuropathic pain

We have examined the effects of cannabinoid agonists on hyperalgesia in a m odel of neuropathic pain in the rat and investigated the possible sites of action. The antihyperalgesic activity of the cannabinoids was compared with their ability to elicit behavioural effects characteristic of central cann abinoid activity. WIN55,212-2 (0.3-10 mg kg(-1)), CP-55,930 (0.03-1 mg kg(- 1)) and HU-210 (0.001-0.03 mg kg(-1)) were all active in a 'tetrad' of test s consisting of tail-flick, catalepsy, rotarod and hypothermia following su bcutaneous administration, with a rank order of potency in each of HU-210 > CP-55,940 > WIN55,212-2. The effects of WIN55,212-2 in each assay were blo cked by the Cannabinoid(1) (CB1) antagonist SR141716A. In the partial sciat ic ligation model of neuropathic pain WIN55,212-2. CP-55,940 and HU-210 pro duced complete reversal of mechanical hyperalgesia within 3 h of subcutaneo us administration with D-50 values of 0.52, 0.08 and 0.005 mg kg(-1), respe ctively. In this model WIN55,212-2 was also effective against thermal hyper algesia and mechanical allodynia. WIN55,212-2 produced pronounced reversal of mechanical hyperalgesia following intrathecal administration that was bl ocked by the CB1 antagonist SR141716A. Following intraplantar administratio n into the ipsilateral hindpaw, WIN55,212-2 produced up to 70% reversal of mechanical hyperalgesia, although activity was also observed at high doses following injection into the contralateral paw. The antihyperalgesic effect of WIN55,212-2 injected into the ipsilateral paw was blocked by subcutaneo usly administered SR141716A, but was not affected by intrathecally administ ered SR141716A. These data show that cannabinoids are highly potent and eff icacious antihyperalgesic agents in a model of neuropathic pain. This activ ity is likely to be mediated via an action in both the CNS and in the perip hery. (C) 2001 International Association for the Study of Pain. Published b y Elsevier Science B.V. All rights reserved.