We have examined the effects of
cannabinoid agonists on
hyperalgesia in a model 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
cannabinoid activity. WIN55,212-2 (0.3-10 mg kg(-1)),
CP-55,940 (0.03-1 mg kg(-1)) and
HU-210 (0.001-0.03 mg kg(-1)) were all active in a 'tetrad' of tests consisting of tail-flick,
catalepsy, rotarod and
hypothermia following subcutaneous 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 blocked by the Cannabinoid1 (CB1) antagonist
SR141716A. In the partial sciatic
ligation model of
neuropathic pain WIN55,212-2,
CP-55,940 and
HU-210 produced complete reversal of
mechanical hyperalgesia within 3 h of subcutaneous administration with D50 values of 0.52, 0.08 and 0.005 mg kg(-1), respectively. In this model WIN55,212-2 was also effective against
thermal hyperalgesia and
mechanical allodynia. WIN55,212-2 produced pronounced reversal of
mechanical hyperalgesia following intrathecal administration that was blocked by the CB1 antagonist
SR141716A. Following intraplantar administration 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 subcutaneously administered
SR141716A, but was not affected by intrathecally administered
SR141716A. These data show that
cannabinoids are highly potent and efficacious antihyperalgesic agents in a model of
neuropathic pain. This activity is likely to be mediated via an action in both the CNS and in the periphery.