Prostaglandin E2 sensitizes the cough reflex centrally via EP3 receptor-dependent activation of NaV 1.8 channels

Abstract 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 E2 (PGE2), have been implicated in both peripheral...

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Autores principales:	Al-Shaimaa A. Al-Kandery, Muddanna S. Rao, Ahmed Z. El-Hashim
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	PGE2 Cough Central sensitization EP1-4 receptors TRPV1 TRPA1 Diseases of the respiratory system RC705-779
Acceso en línea:	https://doaj.org/article/5559fa47dcd2439495e16e56417ad739
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spelling	oai:doaj.org-article:5559fa47dcd2439495e16e56417ad7392021-11-21T12:31:59ZProstaglandin E2 sensitizes the cough reflex centrally via EP3 receptor-dependent activation of NaV 1.8 channels10.1186/s12931-021-01889-41465-993Xhttps://doaj.org/article/5559fa47dcd2439495e16e56417ad7392021-11-01T00:00:00Zhttps://doi.org/10.1186/s12931-021-01889-4https://doaj.org/toc/1465-993XAbstract 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 E2 (PGE2), 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 PGE2 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 PGE2 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 PGE2 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 PGE2 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 AbstractAl-Shaimaa A. Al-KanderyMuddanna S. RaoAhmed Z. El-HashimBMCarticlePGE2CoughCentral sensitizationEP1-4 receptorsTRPV1TRPA1Diseases of the respiratory systemRC705-779ENRespiratory Research, Vol 22, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	PGE2 Cough Central sensitization EP1-4 receptors TRPV1 TRPA1 Diseases of the respiratory system RC705-779
spellingShingle	PGE2 Cough Central sensitization EP1-4 receptors TRPV1 TRPA1 Diseases of the respiratory system RC705-779 Al-Shaimaa A. Al-Kandery Muddanna S. Rao Ahmed Z. El-Hashim Prostaglandin E2 sensitizes the cough reflex centrally via EP3 receptor-dependent activation of NaV 1.8 channels
description	Abstract 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 E2 (PGE2), 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 PGE2 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 PGE2 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 PGE2 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 PGE2 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
format	article
author	Al-Shaimaa A. Al-Kandery Muddanna S. Rao Ahmed Z. El-Hashim
author_facet	Al-Shaimaa A. Al-Kandery Muddanna S. Rao Ahmed Z. El-Hashim
author_sort	Al-Shaimaa A. Al-Kandery
title	Prostaglandin E2 sensitizes the cough reflex centrally via EP3 receptor-dependent activation of NaV 1.8 channels
title_short	Prostaglandin E2 sensitizes the cough reflex centrally via EP3 receptor-dependent activation of NaV 1.8 channels
title_full	Prostaglandin E2 sensitizes the cough reflex centrally via EP3 receptor-dependent activation of NaV 1.8 channels
title_fullStr	Prostaglandin E2 sensitizes the cough reflex centrally via EP3 receptor-dependent activation of NaV 1.8 channels
title_full_unstemmed	Prostaglandin E2 sensitizes the cough reflex centrally via EP3 receptor-dependent activation of NaV 1.8 channels
title_sort	prostaglandin e2 sensitizes the cough reflex centrally via ep3 receptor-dependent activation of nav 1.8 channels
publisher	BMC
publishDate	2021
url	https://doaj.org/article/5559fa47dcd2439495e16e56417ad739
work_keys_str_mv	AT alshaimaaaalkandery prostaglandine2sensitizesthecoughreflexcentrallyviaep3receptordependentactivationofnav18channels AT muddannasrao prostaglandine2sensitizesthecoughreflexcentrallyviaep3receptordependentactivationofnav18channels AT ahmedzelhashim prostaglandine2sensitizesthecoughreflexcentrallyviaep3receptordependentactivationofnav18channels
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Prostaglandin E2 sensitizes the cough reflex centrally via EP3 receptor-dependent activation of NaV 1.8 channels

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