(2R,6R)-hydroxynorketamine, a Ketamine Metabolite, is a Novel Pain Therapeutic

Over 20 percent of adults in the U.S. experience pain most or every day that is sufficiently debilitating to contribute to limited work capability and decreased quality of life. Pain is also a problem among our military population. Over 40 percent of soldiers deployed to Iraq or Afghanistan reported a pain condition. Currently available analgesics have significant risk and frequently fall short of pain reduction goals. Identifying novel and effective pharmaceutical pain treatments is an integral part of addressing the problem of pain and would promote health and fitness among the general population and increase readiness to deploy within the military. Ketamine is an anesthetic agent in use since 1970 that is also used to treat pain. Front-line medics use ketamine to treat battlefield injuries because it is safer than opioids and still effective at reducing pain. However, the dissociation and motor impairment side effects of ketamine and concern for recreational abuse limit its use, making ketamine unavailable for patients to administer and treat their pain at home. (2R,6R)-HNK is a ketamine metabolite thought to share some of ketamines beneficial treatment effects for depression. It lacks the psychotomimetic properties of its parent drug while retaining anti-stress effects in preclinical research. Because ketamine is recognized for pain reduction, it is natural to question whether (2R,6R)-HNK may also possess analgesic activity. The overall goal of this thesis was to expand upon what little was known regarding the pain reduction-like effects of (2R,6R)-HNK. The results showed initially that (2R,6R)-HNK produced antinociception to a noxious thermal stimulus in healthy mice. The onset for (2R,6R)-HNK antinociception was delayed (greater than 10 hours) and showed an inverted U-shaped dose response. (2R,6R)-HNK also reversed mechanical allodynia in neuropathic and inflammatory pain models using C57BL/6J mice to model the conditions tested.