CB₂ cannabinoid receptor-mediated peripheral antinociception

Cannabinoid receptor agonists diminish responses to painful stimuli. Extensive evidence implicates the CB₁ receptor in the production of antinociception. However, the capacity of CB₂ receptors, which are located outside the central nervous system (CNS), to produce antinociception is not known. Using AM1241, a CB₂ receptor-selective agonist, we demonstrate that CB₂ receptors produce antinociception to thermal stimuli. Injection of AM1241 in the hindpaw produced antinociception to a stimulus applied to the same paw. Injection of an equivalent dose of AM1241 into the paw contralateral to the side of testing did not. The antinociceptive actions of AM1241 were blocked by the CB₂ receptor-selective antagonist AM630, but not by the CB₁ receptor-selective antagonist AM251. AM1241 also produced antinociception when injected systemically (intraperitoneally). The antinociceptive actions of systemic AM1241 were blocked by injection of AM630 into the paw where the thermal stimulus was applied, but not the contralateral paw. These findings demonstrate the local, peripheral nature of CB₂ cannabinoid antinociception. AM1241 did not produce the CNS cannabinoid effects of hypothermia, catalepsy, inhibition of activity or impaired ambulation, while this tetrad of effects was produced by the mixed CB₁/CB₂ receptor agonist WIN55,212-2. Peripheral antinociception without CNS effects is consistent with the peripheral distribution of CB₂ receptors. CB₂ receptor agonists may have promise clinically for the treatment of pain without CNS cannabinoid side effects.