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Prostaglandin E(2) sensitizes the cough reflex centrally via EP3 receptor-dependent activation of NaV 1.8 channels

BACKGROUND: Cough hypersensitivity is a major characteristic feature associated with several types of cough, including chronic cough, but its underlying mechanisms remain to be fully understood. Inflammatory mediators, such as prostaglandin E(2) (PGE(2)), have been implicated in both peripheral indu...

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Autores principales: Al-Kandery, Al-Shaimaa A., Rao, Muddanna S., El-Hashim, Ahmed Z.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8603488/
https://www.ncbi.nlm.nih.gov/pubmed/34794450
http://dx.doi.org/10.1186/s12931-021-01889-4
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author Al-Kandery, Al-Shaimaa A.
Rao, Muddanna S.
El-Hashim, Ahmed Z.
author_facet Al-Kandery, Al-Shaimaa A.
Rao, Muddanna S.
El-Hashim, Ahmed Z.
author_sort Al-Kandery, Al-Shaimaa A.
collection PubMed
description BACKGROUND: Cough hypersensitivity is a major characteristic feature associated with several types of cough, including chronic cough, but its underlying mechanisms remain to be fully understood. Inflammatory mediators, such as prostaglandin E(2) (PGE(2)), have been implicated in both peripheral induction and sensitization of the cough reflex. In this study, using a conscious guinea pig model of cough, we investigated whether PGE(2) can sensitize the cough reflex via central actions and, if so, via which mechanisms. METHODS: All drugs were administered by intracerebroventricular (i.c.v.) route and whole-body plethysmograph set-up was used for both induction, using aerosolized citric acid (0.2 M), and recording of cough. Immunohistochemistry was performed to confirm the expression of NaV 1.8 channels in the nucleus tractus solitarius (nTS). RESULTS: We show that both PGE(2) and the non-selective EP1/EP3 agonist, sulprostone, dose-dependently enhanced the citric acid-induced cough (P ≤ 0.001, P ≤ 0.01, respectively). Pretreatment with the EP1 antagonist, ONO-8130, did not affect the sulprostone-induced cough sensitization, whilst the EP3 antagonist, L-798,106, dose-dependently inhibited this effect (P ≤ 0.05). Furthermore, treatment with either the EP2 agonist, butaprost or the EP4 agonist, L-902,688, had no effect on cough sensitization. Additionally, pretreatment with either the TRPV1 antagonist, JNJ-17203212 or the TRPA1 antagonist, HC-030031, alone or in combination, nor with the NaV 1.1, 1.2, 1.3, 1.4, 1.6 and 1.7 channel blocker, tetrodotoxin, had any effect on the cough. In contrast, pretreatment with the NaV 1.8 antagonist, A-803467, dose-dependently inhibited this effect (P ≤ 0.05). Furthermore, NaV 1.8 channels were shown to be expressed in the nTS. CONCLUSION: Collectively, our findings show that PGE(2) sensitizes the cough reflex centrally via EP3 receptor-dependent activation of NaV 1.8 but independently of TRPV1,TRPA1 and TTX-sensitive sodium channel activation. These results indicate that PGE(2) plays an important role in central sensitization of the cough reflex and suggest that central EP3 receptors and/or NaVv 1.8 channels may represent novel antitussive molecular targets. GRAPHICAL ABSTRACT: [Image: see text]
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spelling pubmed-86034882021-11-19 Prostaglandin E(2) sensitizes the cough reflex centrally via EP3 receptor-dependent activation of NaV 1.8 channels Al-Kandery, Al-Shaimaa A. Rao, Muddanna S. El-Hashim, Ahmed Z. Respir Res Research BACKGROUND: Cough hypersensitivity is a major characteristic feature associated with several types of cough, including chronic cough, but its underlying mechanisms remain to be fully understood. Inflammatory mediators, such as prostaglandin E(2) (PGE(2)), have been implicated in both peripheral induction and sensitization of the cough reflex. In this study, using a conscious guinea pig model of cough, we investigated whether PGE(2) can sensitize the cough reflex via central actions and, if so, via which mechanisms. METHODS: All drugs were administered by intracerebroventricular (i.c.v.) route and whole-body plethysmograph set-up was used for both induction, using aerosolized citric acid (0.2 M), and recording of cough. Immunohistochemistry was performed to confirm the expression of NaV 1.8 channels in the nucleus tractus solitarius (nTS). RESULTS: We show that both PGE(2) and the non-selective EP1/EP3 agonist, sulprostone, dose-dependently enhanced the citric acid-induced cough (P ≤ 0.001, P ≤ 0.01, respectively). Pretreatment with the EP1 antagonist, ONO-8130, did not affect the sulprostone-induced cough sensitization, whilst the EP3 antagonist, L-798,106, dose-dependently inhibited this effect (P ≤ 0.05). Furthermore, treatment with either the EP2 agonist, butaprost or the EP4 agonist, L-902,688, had no effect on cough sensitization. Additionally, pretreatment with either the TRPV1 antagonist, JNJ-17203212 or the TRPA1 antagonist, HC-030031, alone or in combination, nor with the NaV 1.1, 1.2, 1.3, 1.4, 1.6 and 1.7 channel blocker, tetrodotoxin, had any effect on the cough. In contrast, pretreatment with the NaV 1.8 antagonist, A-803467, dose-dependently inhibited this effect (P ≤ 0.05). Furthermore, NaV 1.8 channels were shown to be expressed in the nTS. CONCLUSION: Collectively, our findings show that PGE(2) sensitizes the cough reflex centrally via EP3 receptor-dependent activation of NaV 1.8 but independently of TRPV1,TRPA1 and TTX-sensitive sodium channel activation. These results indicate that PGE(2) plays an important role in central sensitization of the cough reflex and suggest that central EP3 receptors and/or NaVv 1.8 channels may represent novel antitussive molecular targets. GRAPHICAL ABSTRACT: [Image: see text] BioMed Central 2021-11-18 2021 /pmc/articles/PMC8603488/ /pubmed/34794450 http://dx.doi.org/10.1186/s12931-021-01889-4 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Al-Kandery, Al-Shaimaa A.
Rao, Muddanna S.
El-Hashim, Ahmed Z.
Prostaglandin E(2) sensitizes the cough reflex centrally via EP3 receptor-dependent activation of NaV 1.8 channels
title Prostaglandin E(2) sensitizes the cough reflex centrally via EP3 receptor-dependent activation of NaV 1.8 channels
title_full Prostaglandin E(2) sensitizes the cough reflex centrally via EP3 receptor-dependent activation of NaV 1.8 channels
title_fullStr Prostaglandin E(2) sensitizes the cough reflex centrally via EP3 receptor-dependent activation of NaV 1.8 channels
title_full_unstemmed Prostaglandin E(2) sensitizes the cough reflex centrally via EP3 receptor-dependent activation of NaV 1.8 channels
title_short Prostaglandin E(2) sensitizes the cough reflex centrally via EP3 receptor-dependent activation of NaV 1.8 channels
title_sort prostaglandin e(2) sensitizes the cough reflex centrally via ep3 receptor-dependent activation of nav 1.8 channels
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8603488/
https://www.ncbi.nlm.nih.gov/pubmed/34794450
http://dx.doi.org/10.1186/s12931-021-01889-4
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