• Sonja Lj Joksimovic, Srdjan M Joksimovic, Francesca M Manzella, Betelehem Asnake, Peihan Orestes, Yogendra H Raol, Kathiresan Krishnan, Douglas F Covey, Vesna Jevtovic-Todorovic, and Slobodan M Todorovic.
• Department of Anesthesiology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Co, USA.
• Br. J. Pharmacol. 2020 Apr 1; 177 (8): 1735-1753.

Background And PurposeNeuroactive steroid (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile (3β-OH) is a novel hypnotic and voltage-dependent blocker of T-type calcium channels. Here, we examine its potential analgesic effects and adjuvant anaesthetic properties using a post-surgical pain model in rodents.Experimental ApproachAnalgesic properties of 3β-OH were investigated in thermal and mechanical nociceptive tests in sham or surgically incised rats and mice, with drug injected either systemically (intraperitoneal) or locally via intrathecal or intraplantar routes. Hypnotic properties of 3β-OH and its use as an adjuvant anaesthetic in combination with isoflurane were investigated using behavioural experiments and in vivo EEG recordings in adolescent rats.Key ResultsA combination of 1% isoflurane with 3β-OH (60 mg·kg-1 , i.p.) induced suppression of cortical EEG and stronger thermal and mechanical anti-hyperalgesia during 3 days post-surgery, when compared to isoflurane alone and isoflurane with morphine. 3β-OH exerted prominent enantioselective thermal and mechanical antinociception in healthy rats and reduced T-channel-dependent excitability of primary sensory neurons. Intrathecal injection of 3β-OH alleviated mechanical hyperalgesia, while repeated intraplantar application alleviated both thermal and mechanical hyperalgesia in the rats after incision. Using mouse genetics, we found that CaV 3.2 T-calcium channels are important for anti-hyperalgesic effect of 3β-OH and are contributing to its hypnotic effect.Conclusion And ImplicationsOur study identifies 3β-OH as a novel analgesic for surgical procedures. 3β-OH can be used to reduce T-channel-dependent excitability of peripheral sensory neurons as an adjuvant for induction and maintenance of general anaesthesia while improving analgesia and lowering the amount of volatile anaesthetic needed for surgery.© 2019 The British Pharmacological Society.

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