Novel neuroactive steroid with hypnotic and T-type calcium channel blocking properties exerts effective analgesia in a rodent model of post-surgical pain

Sonja Lj Joksimovic, Srdjan M. Joksimovic, Francesca M. Manzella, Betelehem Asnake, Peihan Orestes, Yogendra H. Raol, Kathiresan Krishnan, Douglas F. Covey, Vesna Jevtovic-Todorovic, Slobodan M. Todorovic

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Background and Purpose: Neuroactive 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 Approach: Analgesic 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 Results: A 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 CaV3.2 T-calcium channels are important for anti-hyperalgesic effect of 3β-OH and are contributing to its hypnotic effect. Conclusion and Implications: Our 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.

Original languageEnglish
Pages (from-to)1735-1753
Number of pages19
JournalBritish Journal of Pharmacology
Volume177
Issue number8
DOIs
StatePublished - Apr 1 2020

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