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

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.

• Authors: Jeffrey S Kroin, Vaskar Das, Mario Moric, Asokumar Buvanendran
• Journal: Regional anesthesia and pain medicine (Reg Anesth Pain Med) Vol. 44 Issue 1 Pg. 111-117 (01 2019) ISSN: 1532-8651 [Electronic] England
• PMID: 30640662 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © American Society of Regional Anesthesia & Pain Medicine 2019. No commercial re-use. See rights and permissions. Published by BMJ.

Chemical References

• Ketamine
• norketamine

Topics

• Animals
• Disease Models, Animal
• Female
• Ketamine (analogs & derivatives, metabolism, therapeutic use)
• Mice
• Mice, Inbred C57BL
• Neuralgia (drug therapy, metabolism)
• Treatment Outcome