Efficacy of the ketamine metabolite (2R, 6R)-hydroxynorketamine in mice models of pain

Background and objectives Ketamine has been shown to reduce chronic pain; however, the adverse events associated with ketamine makes it challenging for use outside of the perioperative setting. The ketamine metabolite (2R, 6R)-hydroxynorketamine ((2R, 6R)-HNK) has a therapeutic effect in mice models of depression, with minimal side effects. The objective of this study is to determine if (2R, 6R)-HNK has efficacy in both acute and chronic mouse pain models. Methods Mice were tested in three pain models: nerve-injury neuropathic pain, tibia fracture complex regional pain syndrome type-1 (CRPS1) pain, and plantar incision postoperative pain. Once mechanical allodynia had developed, systemic (2R, 6R)-HNK or ketamine was administered as a bolus injection and compared with saline control in relieving allodynia. Results In all three models, 10 mg/kg ketamine failed to produce sustained analgesia. In the neuropathic pain model, a single intraperitoneal injection of 10 mg/kg (2R, 6R)-HNK elevated von Frey thresholds over a time period of 1-24hours compared with saline (F= 121.6, p< 0.0001), and three daily (2R, 6R)-HNK injections elevated von Frey thresholds for 3 days compared with saline (F= 33.4, p= 0.0002). In the CRPS1 model, three (2R, 6R)-HNK injections elevated von Frey thresholds for 3 days and then an additional 4 days compared with saline (F= 116.1, p< 0.0001). In the postoperative pain model, three (2R, 6R)-HNK injections elevated von Frey thresholds for 3 days and then an additional 5 days compared with saline (F= 60.6, p< 0.0001). Conclusions This study demonstrates that (2R, 6R)-HNK is superior to ketamine in reducing mechanical allodynia in acute and chronic pain models and suggests it may be a new non-opioid drug for future therapeutic studies.