The nonhallucinogenic ketamine metabolite (2R,6R)-hydroxynorketamine is a novel analgesic in animal models of pain

Current treatment options for acute and chronic pain provide limited efficacy and safety. There is an urgent need to develop drugs with new, non-opioid treatment strategies that produce fewer adverse consequences. Preclinical evidence across multiple models of acute and chronic pain demonstrate that (2R,6R)-Hydroxynorketamine [(2R,6R)-HNK], a nonhallucinogenic metabolite of ketamine, promotes potent and long-lasting analgesic effects. This review summarizes the growing evidence for the analgesic action of (2R,6R)-HNK in rodent models of acute and chronic pain. (2R,6R)-HNK produces antinociceptive effects in studies using standard tests for acute pain such as the hot plate test, although not in all studies, as well as reversal of mechanical hypersensitivity in models of acute pain like the carrageenan model (inflammatory pain). However, the most consistent anti-allodynic effects are seen in animal models aimed at mimicking chronic pain conditions, such as models of neuropathic pain (Spared Nerve Injury and Chemotherapy-induced peripheral neuropathy), low-back pain (disc puncture), complex regional pain syndrome type-1 (tibial fracture) and chronic primary pain (low-frequency percutaneous electrical nerve stimulation). Unlike ketamine, doses of (2R,6R)-HNK that counteract pain hypersensitivity do not cause sedation, dissociation, or sustain self-administration associated with abuse liability. Furthermore, distinct pharmacological effects of (2R,6R)-HNK, longer functional duration of action, non-opioid-mediated analgesia, and glutamatergic-mediated mechanisms, may distinguish (2R,6R)-HNK from ketamine and other analgesic drugs and contribute to the treatment of acute and chronic pain.