Abstract
Despite 50 years of clinical use and experimental endeavor the anesthetic, analgesic, and psychomimetic effects of ketamine remain to be fully elucidated. While NMDA receptor antagonism has been long held as ketamine's fundamental molecular action, interrogation of bespoke ketamine analogs with known absent NMDA binding, yet profound anesthetic and analgesia fingerprints, suggests alternative targets are responsible for these effects. Herein we describe experimental findings utilizing such analogs as probes to explore ketamine-based analgesic molecular targets. We have focused on two-pore potassium leak channels, identifying TWIK channels as a rational target to pursue further. While the totality of ketamine's mechanistic action is yet to be fully determined, these investigations raise the intriguing prospect of separating out analgesia and anesthetic effects from ketamine's undesirable psychomimesis—and development of more specific analgesic medications.
Highlights
Ketamine is a dissociative anesthetic and potent analgesic
The role of the NMDA receptors in ketamine analgesia has been largely unquestioned. This view has been strengthened by the likes of compounds such as phencyclidine and dizolcipine, which potently bind to the NMDA receptor complex and are strong analgesics [29]
Our data indicates that targets other than the NMDA receptor are important mediators of analgesia for ketamine analogs
Summary
Ketamine is a dissociative anesthetic and potent analgesic. Its well-documented molecular action as a non-competitive NMDA channel antagonist has long been viewed as the likely mediator of its anesthetic and analgesic properties [1]. Ketamine strongly inhibits cortical seizure-like event (SLE) activity, an effect that is barium chloride (BaCl2) and urethane sensitive—implying involvement of K2P channels [11]. The data implicate opening of barium-sensitive TREK and/or TWIK K2P channels in the cortical depressant effect of R5 in cortical slices. This was examined further with the TREK-1 blocker, spadin [18]. The correlation between ketamine analogs and in vivo hypnotic potency and SLE slice effect is robust (R2 = 36%, p = 0.003), but is much weaker for the analgesic effect (R2 = 17%, p = 0.06) The bearing of these findings on mechanisms of ketamine analgesia must be substantiated in a more relevant model. Reference standards were run as an integral part of each assay to ensure the validity of the results obtained
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