Activation of CB 2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: Pain inhibition by receptors not present in the CNS

• DOI: 10.1073/pnas.1834309100
• Publication Date: 2003-09-02T17:27:00Z
• Authors: Mohab M. Ibrahim; Hongfeng Deng; Alexander Zvonok; Debra A. Cockayne; Joyce Kwan; Heriberto P. Mata; Todd W. Vanderah; Josephine Lai; Frank Porreca; Alexandros Makriy...; T. Philip Malan
• Keywords: Male; 0301 basic medicine; Analgesics; Dose-Response Relationship, Drug; Cannabinoids; Receptors, Drug; Brain; Pain; Rats; 3. Good health; Mice, Inbred C57BL; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB2; Mice; 03 medical and health sciences; Animals; Receptors, Cannabinoid

We designed AM1241, a selective CB 2 cannabinoid receptor agonist, and used it to test the hypothesis that CB 2 receptor activation would reverse the sensory hypersensitivity observed in neuropathic pain states. AM1241 exhibits high affinity and selectivity for CB 2 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 CB 2 but not by a CB 1 receptor antagonist, suggesting that they were produced by actions of AM1241 at CB 2 receptors. AM1241 was also active in blocking spinal nerve ligation-induced tactile and thermal hypersensitivity in mice lacking CB 1 receptors (CB 1 -/- mice), confirming that AM1241 reverses sensory hypersensitivity independent of actions at CB 1 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 CB 2 receptor-selective agonists for treatment of human neuropathic pain, a condition currently without consistently effective therapies. CB 2 receptor-selective agonist medications are predicted to be without the CNS side effects that limit the effectiveness of currently available medications.