Papers of the Week

Chronic pain can be challenging to treat and increases the risk of developing psychological disorders such as depression. Identifying novel treatment modalities that effectively alleviate pain is essential to improve clinical treatment and rehabilitation for patients with pain conditions. Ketamine is an effective analgesic for many types of pain. However, its widespread use is limited by its side effect profile and requirement for intranasal/intravenous administration under medical supervision. (2R,6R)-hydroxynorketamine (HNK) is a ketamine metabolite that lacks the psychotomimetic effects of its parent drug but retains ketamine's anti-stress effects. Therefore, it is natural to question whether (2R,6R)-HNK may also possess analgesic activity. Administration of (2R,6R)-HNK produced antinociception in healthy mice exposed to a noxious, painful stimulus 24 hours after injection. The dose response for the delayed-yet-persistent antinociception revealed an inverted U shape with significant antinociception at doses of 10-18 mg/kg for both sexes and 30 mg/kg in female mice. Mice pretreated with different receptor antagonists to examine the potential mechanism for (2R,6R)-HNK mediated antinociception revealed a mechanism dependent on AMPA receptors and not opioid receptors. In contrast, ketamine antinociception was not dependent on AMPA receptors and partially dependent on opioid receptors. These results demonstrate that both (2R,6R)-HNK and the parent drug ketamine produce antinociception but work via different neural mechanisms. In separate studies, (2R,6R)-HNK administration reversed mechanical allodynia associated with localized inflammatory pain induced in mice by injecting λ-carrageenan into the hind paw. The onset for this analgesia-like activity was less than 1 hour with a duration greater than 24 hours following a single administration. (2R,6R)-HNK was effective at reversing mechanical allodynia at doses of 10 & 30 mg/kg in both male and female animals. These results demonstrate (2R,6R)-HNK exhibits great promise for treating inflammatory pain in addition to other pain types. Overall, these data suggest that (2R,6R)-HNK may be a safe alternative therapy for pain that could be made widely available to patients and support the need for continued investigation and development of (2R,6R)-HNK as a novel non-opioid pain treatment.