Activation of CB₂ cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: Pain inhibition by receptors not present in the CNS

We designed AM1241, a selective CB₂, cannabinoid receptor agonist, and used it to test the hypothesis that CB₂ receptor activation would reverse the sensory hypersensitivity observed in neuropathic pain states. AM1241 exhibits high affinity and selectivity for CB₂ receptors. It also exhibits high potency in vivo. AM1241 dose-dependently reversed tactile and thermal hypersensitivity produced by ligation of the L5 and L6 spinal nerves in rats. These effects were selectively antagonized by a CB₂ but not by a CB₁ receptor antagonist, suggesting that they were produced by actions of AM1241 at CB₂ receptors. AM1241 was also active in blocking spinal nerve ligation-induced tactile and thermal hypersensitivity in mice lacking CB₁ receptors (CB₁ ^-/- mice), confirming that AM1241 reverses sensory hypersensitivity independent of actions at CB₁ receptors. These findings demonstrate a mechanism leading to the inhibition of pain, one that targets receptors localized exclusively outside the CNS. Further, they suggest the potential use of CB₂ receptor-selective agonists for treatment of human neuropathic pain, a condition currently without consistently effective therapies. CB₂ receptor-selective agonist medications are predicted to be without the CNS side effects that limit the effectiveness of currently available medications.