Reversal of Mechanical Hypersensitivity by 2R,6R-Hydroxynorketamine by Activation of Group 2 Metabotropic Glutamate Receptors

Abstract ID 87944 Poster Board 300 (2R,6R)-hydroxynorketamine ((2R,6R)-HNK) is a non-hallucinogenic metabolite of ketamine and a potential analgesic agent. Its mechanism of action for producing analgesia is not known. The literature suggests that (2R,6R)-HNK can modulate glutamatergic neurotransmission and metabotropic glutamate receptors 2/3 (mGlu2/3Rs) are implicated in pain modulation. Activation of mGlu2/3Rs produces anti-nociception in several preclinical pain models. The aim of these studies was to test the hypothesis that mGlu2Rs mediate the analgesic effects of (2R,6R)-HNK on inflammatory pain in mice. ((2R,6R)-HNK) and the mGlu2/3R agonist LY379268 produced dose-dependent reversal of mechanical hypersensitivity produced by injection of λ-carrageenan (2.5% solution, 0.02 ml) injected subcutaneously into the plantar region of the left hind paw. The effects of both drugs were persistent lasting for at least 24 hours post-injection. Combining ((2R,6R)-HNK) with LY379268 produced additive effects. Pretreatment with the selective mGluR2 negative allosteric modulator VU6001966 prevented the analgesic effects of ((2R,6R)-HNK) and LY379268. The results indicate that ((2R,6R)-HNK) produces long-lasting analgesic effects using a mechanism involving the activation of mGluR2Rs.