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Efficacy of the ketamine metabolite (2R,6R)-hydroxynorketamine in mice models of pain
  1. Jeffrey S Kroin,
  2. Vaskar Das,
  3. Mario Moric and
  4. Asokumar Buvanendran
  1. Department of Anesthesiology, Rush University Medical Center, Chicago, Illinois, USA
  1. Correspondence to Asokumar Buvanendran, Department of Anesthesiology, Rush University Medical Center, Chicago, IL 60612, USA; asokumar{at}aol.com

Abstract

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.

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Footnotes

  • Funding This work was supported by University Anesthesiologists, S.C., Chicago, Illinois, USA.

  • Competing interests None declared.

  • Ethics approval IACUC of Rush University Medical Center.

  • Provenance and peer review Not commissioned; externally peer reviewed

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