Novel neuroactive steroid with hypnotic and T-type calcium channel blocking properties exerts effective analgesia in a rodent model of post-surgical pain
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2020
Authors
Joksimović, Sonja
Joksimović, Srđan

Manzella, Francesca
Asnake, Betelehem
Orestes, Peihan
Raol, Yogendra
Krishnan, Kathiresan
Covey, Douglas
Jevtović-Todorović, Vesna

Todorović, Slobodan

Article (Published version)

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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.
Source:
British Journal of Pharmacology, 2020, 177, 8, 1735-1753Publisher:
- John Wiley and Sons Inc.
Funding / projects:
- NIH, Grant/Award Number: 1 R01GM123746-01
DOI: 10.1111/bph.14930
ISSN: 0007-1188
WoS: 000508903500001
Scopus: 2-s2.0-85078672847
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PharmacyTY - JOUR AU - Joksimović, Sonja AU - Joksimović, Srđan AU - Manzella, Francesca AU - Asnake, Betelehem AU - Orestes, Peihan AU - Raol, Yogendra AU - Krishnan, Kathiresan AU - Covey, Douglas AU - Jevtović-Todorović, Vesna AU - Todorović, Slobodan PY - 2020 UR - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3610 AB - 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. PB - John Wiley and Sons Inc. T2 - British Journal of Pharmacology T1 - Novel neuroactive steroid with hypnotic and T-type calcium channel blocking properties exerts effective analgesia in a rodent model of post-surgical pain VL - 177 IS - 8 SP - 1735 EP - 1753 DO - 10.1111/bph.14930 ER -
@article{ author = "Joksimović, Sonja and Joksimović, Srđan and Manzella, Francesca and Asnake, Betelehem and Orestes, Peihan and Raol, Yogendra and Krishnan, Kathiresan and Covey, Douglas and Jevtović-Todorović, Vesna and Todorović, Slobodan", year = "2020", 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.", publisher = "John Wiley and Sons Inc.", journal = "British Journal of Pharmacology", title = "Novel neuroactive steroid with hypnotic and T-type calcium channel blocking properties exerts effective analgesia in a rodent model of post-surgical pain", volume = "177", number = "8", pages = "1735-1753", doi = "10.1111/bph.14930" }
Joksimović, S., Joksimović, S., Manzella, F., Asnake, B., Orestes, P., Raol, Y., Krishnan, K., Covey, D., Jevtović-Todorović, V.,& Todorović, S.. (2020). Novel neuroactive steroid with hypnotic and T-type calcium channel blocking properties exerts effective analgesia in a rodent model of post-surgical pain. in British Journal of Pharmacology John Wiley and Sons Inc.., 177(8), 1735-1753. https://doi.org/10.1111/bph.14930
Joksimović S, Joksimović S, Manzella F, Asnake B, Orestes P, Raol Y, Krishnan K, Covey D, Jevtović-Todorović V, Todorović S. Novel neuroactive steroid with hypnotic and T-type calcium channel blocking properties exerts effective analgesia in a rodent model of post-surgical pain. in British Journal of Pharmacology. 2020;177(8):1735-1753. doi:10.1111/bph.14930 .
Joksimović, Sonja, Joksimović, Srđan, Manzella, Francesca, Asnake, Betelehem, Orestes, Peihan, Raol, Yogendra, Krishnan, Kathiresan, Covey, Douglas, Jevtović-Todorović, Vesna, Todorović, Slobodan, "Novel neuroactive steroid with hypnotic and T-type calcium channel blocking properties exerts effective analgesia in a rodent model of post-surgical pain" in British Journal of Pharmacology, 177, no. 8 (2020):1735-1753, https://doi.org/10.1111/bph.14930 . .