Sonja Lj Joksimovic1,2, Srdjan M Joksimovic1, Francesca M Manzella1,3, Betelehem Asnake4, Peihan Orestes1, Yogendra H Raol5, Kathiresan Krishnan6, Douglas F Covey6,7, Vesna Jevtovic-Todorovic1, Slobodan M Todorovic1,3. 1. Department of Anesthesiology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Co, USA. 2. Pharmacology Graduate Program, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia. 3. Neuroscience Graduate Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA. 4. Department of Anesthesiology and Pain Medicine, University of California, Davis, CA, USA. 5. Department of Pediatrics, Division of Neurology, Translational Epilepsy Research Program, Washington University School of Medicine, St. Louis, MO, USA. 6. Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA. 7. Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, USA.
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 CaV 3.2 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.
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 CaV 3.2 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.
Authors: Michael Schumacher; Philippe Liere; Yvette Akwa; Krzysztof Rajkowski; William Griffiths; Karl Bodin; Jan Sjövall; Etienne-Emile Baulieu Journal: Neurochem Int Date: 2007-10-09 Impact factor: 3.921
Authors: A G Mensah-Nyagan; C Kibaly; V Schaeffer; C Venard; L Meyer; C Patte-Mensah Journal: J Steroid Biochem Mol Biol Date: 2008-03-06 Impact factor: 4.292
Authors: Francesca M Manzella; Douglas F Covey; Vesna Jevtovic-Todorovic; Slobodan M Todorovic Journal: J Neuroendocrinol Date: 2022-01-10 Impact factor: 3.627
Authors: Quy L Tat; Srdjan M Joksimovic; Kathiresan Krishnan; Douglas F Covey; Slobodan M Todorovic; Vesna Jevtovic-Todorovic Journal: Cells Date: 2020-12-12 Impact factor: 6.600