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Preemptive Analgesic Effect of Intrathecal Applications of Neuroactive Steroids in a Rodent Model of Post-Surgical Pain: Evidence for the Role of T-Type Calcium Channels

Preemptive management of post-incisional pain remains challenging. Here, we examined the role of preemptive use of neuroactive steroids with activity on low-voltage activated T-type Ca(2+) channels (T-channels) and γ-aminobutyric acid A (GABA(A)) receptors in the development and maintenance of post-...

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Autores principales: Tat, Quy L., Joksimovic, Srdjan M., Krishnan, Kathiresan, Covey, Douglas F., Todorovic, Slobodan M., Jevtovic-Todorovic, Vesna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763050/
https://www.ncbi.nlm.nih.gov/pubmed/33322727
http://dx.doi.org/10.3390/cells9122674
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author Tat, Quy L.
Joksimovic, Srdjan M.
Krishnan, Kathiresan
Covey, Douglas F.
Todorovic, Slobodan M.
Jevtovic-Todorovic, Vesna
author_facet Tat, Quy L.
Joksimovic, Srdjan M.
Krishnan, Kathiresan
Covey, Douglas F.
Todorovic, Slobodan M.
Jevtovic-Todorovic, Vesna
author_sort Tat, Quy L.
collection PubMed
description Preemptive management of post-incisional pain remains challenging. Here, we examined the role of preemptive use of neuroactive steroids with activity on low-voltage activated T-type Ca(2+) channels (T-channels) and γ-aminobutyric acid A (GABA(A)) receptors in the development and maintenance of post-incisional pain. We use neuroactive steroids with distinct effects on GABA(A) receptors and/or T-channels: Alphaxalone (combined GABAergic agent and T-channel inhibitor), ECN (T-channel inhibitor), CDNC24 (GABAergic agent), and compared them with an established analgesic, morphine (an opioid agonist without known effect on either T-channels or GABA(A) receptors). Adult female rats sustained the skin and muscle incision on the plantar surface of the right paw. We injected the agents of choice intrathecally either before or after the development of post-incisional pain. The pain development was monitored by studying mechanical hypersensitivity. Alphaxalone and ECN, but not morphine, are effective in alleviating mechanical hyperalgesia when administered preemptively whereas morphine provides dose-dependent pain relief only when administered once the pain had developed. CDNC24 on the other hand did not offer any analgesic benefit. Neuroactive steroids that inhibit T-currents—Alphaxalone and ECN—unlike morphine, are effective preemptive analgesics that may offer a promising therapeutic approach to the treatment of post-incisional pain, especially mechanical hypersensitivity.
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spelling pubmed-77630502020-12-27 Preemptive Analgesic Effect of Intrathecal Applications of Neuroactive Steroids in a Rodent Model of Post-Surgical Pain: Evidence for the Role of T-Type Calcium Channels Tat, Quy L. Joksimovic, Srdjan M. Krishnan, Kathiresan Covey, Douglas F. Todorovic, Slobodan M. Jevtovic-Todorovic, Vesna Cells Article Preemptive management of post-incisional pain remains challenging. Here, we examined the role of preemptive use of neuroactive steroids with activity on low-voltage activated T-type Ca(2+) channels (T-channels) and γ-aminobutyric acid A (GABA(A)) receptors in the development and maintenance of post-incisional pain. We use neuroactive steroids with distinct effects on GABA(A) receptors and/or T-channels: Alphaxalone (combined GABAergic agent and T-channel inhibitor), ECN (T-channel inhibitor), CDNC24 (GABAergic agent), and compared them with an established analgesic, morphine (an opioid agonist without known effect on either T-channels or GABA(A) receptors). Adult female rats sustained the skin and muscle incision on the plantar surface of the right paw. We injected the agents of choice intrathecally either before or after the development of post-incisional pain. The pain development was monitored by studying mechanical hypersensitivity. Alphaxalone and ECN, but not morphine, are effective in alleviating mechanical hyperalgesia when administered preemptively whereas morphine provides dose-dependent pain relief only when administered once the pain had developed. CDNC24 on the other hand did not offer any analgesic benefit. Neuroactive steroids that inhibit T-currents—Alphaxalone and ECN—unlike morphine, are effective preemptive analgesics that may offer a promising therapeutic approach to the treatment of post-incisional pain, especially mechanical hypersensitivity. MDPI 2020-12-12 /pmc/articles/PMC7763050/ /pubmed/33322727 http://dx.doi.org/10.3390/cells9122674 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Tat, Quy L.
Joksimovic, Srdjan M.
Krishnan, Kathiresan
Covey, Douglas F.
Todorovic, Slobodan M.
Jevtovic-Todorovic, Vesna
Preemptive Analgesic Effect of Intrathecal Applications of Neuroactive Steroids in a Rodent Model of Post-Surgical Pain: Evidence for the Role of T-Type Calcium Channels
title Preemptive Analgesic Effect of Intrathecal Applications of Neuroactive Steroids in a Rodent Model of Post-Surgical Pain: Evidence for the Role of T-Type Calcium Channels
title_full Preemptive Analgesic Effect of Intrathecal Applications of Neuroactive Steroids in a Rodent Model of Post-Surgical Pain: Evidence for the Role of T-Type Calcium Channels
title_fullStr Preemptive Analgesic Effect of Intrathecal Applications of Neuroactive Steroids in a Rodent Model of Post-Surgical Pain: Evidence for the Role of T-Type Calcium Channels
title_full_unstemmed Preemptive Analgesic Effect of Intrathecal Applications of Neuroactive Steroids in a Rodent Model of Post-Surgical Pain: Evidence for the Role of T-Type Calcium Channels
title_short Preemptive Analgesic Effect of Intrathecal Applications of Neuroactive Steroids in a Rodent Model of Post-Surgical Pain: Evidence for the Role of T-Type Calcium Channels
title_sort preemptive analgesic effect of intrathecal applications of neuroactive steroids in a rodent model of post-surgical pain: evidence for the role of t-type calcium channels
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763050/
https://www.ncbi.nlm.nih.gov/pubmed/33322727
http://dx.doi.org/10.3390/cells9122674
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