TRPA1 modulation by Sigma-1 receptor prevents oxaliplatin-induced painful peripheral neuropathy

Chemotherapy-induced peripheral neuropathy is a frequent, disabling side effect of anticancer drugs. Oxaliplatin, a platinum compound used in the treatment of advanced colorectal cancer, often leads to a form of chemotherapy-induced peripheral neuropathy characterized by mechanical and cold hypersen...

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Autores: Marcotti, Aida, Fernández-Trillo, Jorge, González, Alejandro, Vizcaíno-Escoto, Marta, Ros-Arlanzón, Pablo, Romero, Luz, Vela, José Miguel, Gomis, Ana, Viana, Félix, Peña, Elvira de la
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/304490
Acesso em linha:http://hdl.handle.net/10261/304490
Access Level:acceso abierto
Palavra-chave:Sigma-1 receptor
TRPA1
Chemotherapy
Neuropathic pain
Cold allodynia
http://metadata.un.org/sdg/3
Ensure healthy lives and promote well-being for all at all ages
id ES_deab69a5467b4077fc220fc2c81bd4d2
oai_identifier_str oai:digital.csic.es:10261/304490
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv TRPA1 modulation by Sigma-1 receptor prevents oxaliplatin-induced painful peripheral neuropathy
title TRPA1 modulation by Sigma-1 receptor prevents oxaliplatin-induced painful peripheral neuropathy
spellingShingle TRPA1 modulation by Sigma-1 receptor prevents oxaliplatin-induced painful peripheral neuropathy
Marcotti, Aida
Sigma-1 receptor
TRPA1
Chemotherapy
Neuropathic pain
Cold allodynia
http://metadata.un.org/sdg/3
Ensure healthy lives and promote well-being for all at all ages
title_short TRPA1 modulation by Sigma-1 receptor prevents oxaliplatin-induced painful peripheral neuropathy
title_full TRPA1 modulation by Sigma-1 receptor prevents oxaliplatin-induced painful peripheral neuropathy
title_fullStr TRPA1 modulation by Sigma-1 receptor prevents oxaliplatin-induced painful peripheral neuropathy
title_full_unstemmed TRPA1 modulation by Sigma-1 receptor prevents oxaliplatin-induced painful peripheral neuropathy
title_sort TRPA1 modulation by Sigma-1 receptor prevents oxaliplatin-induced painful peripheral neuropathy
dc.creator.none.fl_str_mv Marcotti, Aida
Fernández-Trillo, Jorge
González, Alejandro
Vizcaíno-Escoto, Marta
Ros-Arlanzón, Pablo
Romero, Luz
Vela, José Miguel
Gomis, Ana
Viana, Félix
Peña, Elvira de la
author Marcotti, Aida
author_facet Marcotti, Aida
Fernández-Trillo, Jorge
González, Alejandro
Vizcaíno-Escoto, Marta
Ros-Arlanzón, Pablo
Romero, Luz
Vela, José Miguel
Gomis, Ana
Viana, Félix
Peña, Elvira de la
author_role author
author2 Fernández-Trillo, Jorge
González, Alejandro
Vizcaíno-Escoto, Marta
Ros-Arlanzón, Pablo
Romero, Luz
Vela, José Miguel
Gomis, Ana
Viana, Félix
Peña, Elvira de la
author2_role author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Generalitat Valenciana
Ministerio de Educación (España)
Esteve
Agencia Estatal de Investigación (España)
Ministerio de Ciencia, Innovación y Universidades (España)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Sigma-1 receptor
TRPA1
Chemotherapy
Neuropathic pain
Cold allodynia
http://metadata.un.org/sdg/3
Ensure healthy lives and promote well-being for all at all ages
topic Sigma-1 receptor
TRPA1
Chemotherapy
Neuropathic pain
Cold allodynia
http://metadata.un.org/sdg/3
Ensure healthy lives and promote well-being for all at all ages
description Chemotherapy-induced peripheral neuropathy is a frequent, disabling side effect of anticancer drugs. Oxaliplatin, a platinum compound used in the treatment of advanced colorectal cancer, often leads to a form of chemotherapy-induced peripheral neuropathy characterized by mechanical and cold hypersensitivity. Current therapies for chemotherapy-induced peripheral neuropathy are ineffective, often leading to the cessation of treatment. Transient receptor potential ankyrin 1 (TRPA1) is a polymodal, non-selective cation-permeable channel expressed in nociceptors, activated by physical stimuli and cellular stress products. TRPA1 has been linked to the establishment of chemotherapy-induced peripheral neuropathy and other painful neuropathic conditions. Sigma-1 receptor is an endoplasmic reticulum chaperone known to modulate the function of many ion channels and receptors. Sigma-1 receptor antagonist, a highly selective antagonist of Sigma-1 receptor, has shown effectiveness in a phase II clinical trial for oxaliplatin chemotherapy-induced peripheral neuropathy. However, the mechanisms involved in the beneficial effects of Sigma-1 receptor antagonist are little understood. We combined biochemical and biophysical (i.e. intermolecular Förster resonance energy transfer) techniques to demonstrate the interaction between Sigma-1 receptor and human TRPA1. Pharmacological antagonism of Sigma-1R impaired the formation of this molecular complex and the trafficking of functional TRPA1 to the plasma membrane. Using patch-clamp electrophysiological recordings we found that antagonists of Sigma-1 receptor, including Sigma-1 receptor antagonist, exert a marked inhibition on plasma membrane expression and function of human TRPA1 channels. In TRPA1-expressing mouse sensory neurons, Sigma-1 receptor antagonists reduced inward currents and the firing of actions potentials in response to TRPA1 agonists. Finally, in a mouse experimental model of oxaliplatin neuropathy, systemic treatment with a Sigma-1 receptor antagonists prevented the development of painful symptoms by a mechanism involving TRPA1. In summary, the modulation of TRPA1 channels by Sigma-1 receptor antagonists suggests a new strategy for the prevention and treatment of chemotherapy-induced peripheral neuropathy and could inform the development of novel therapeutics for neuropathic pain.
publishDate 2023
dc.date.none.fl_str_mv 2023
2023
2023
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
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status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/304490
url http://hdl.handle.net/10261/304490
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-108194RB-I00
info:eu-repo/grantAgreement/AEI//SEV-2017-0723
Brain
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Oxford University Press
publisher.none.fl_str_mv Oxford University Press
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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spelling TRPA1 modulation by Sigma-1 receptor prevents oxaliplatin-induced painful peripheral neuropathyMarcotti, AidaFernández-Trillo, JorgeGonzález, AlejandroVizcaíno-Escoto, MartaRos-Arlanzón, PabloRomero, LuzVela, José MiguelGomis, AnaViana, FélixPeña, Elvira de laSigma-1 receptorTRPA1ChemotherapyNeuropathic painCold allodyniahttp://metadata.un.org/sdg/3Ensure healthy lives and promote well-being for all at all agesChemotherapy-induced peripheral neuropathy is a frequent, disabling side effect of anticancer drugs. Oxaliplatin, a platinum compound used in the treatment of advanced colorectal cancer, often leads to a form of chemotherapy-induced peripheral neuropathy characterized by mechanical and cold hypersensitivity. Current therapies for chemotherapy-induced peripheral neuropathy are ineffective, often leading to the cessation of treatment. Transient receptor potential ankyrin 1 (TRPA1) is a polymodal, non-selective cation-permeable channel expressed in nociceptors, activated by physical stimuli and cellular stress products. TRPA1 has been linked to the establishment of chemotherapy-induced peripheral neuropathy and other painful neuropathic conditions. Sigma-1 receptor is an endoplasmic reticulum chaperone known to modulate the function of many ion channels and receptors. Sigma-1 receptor antagonist, a highly selective antagonist of Sigma-1 receptor, has shown effectiveness in a phase II clinical trial for oxaliplatin chemotherapy-induced peripheral neuropathy. However, the mechanisms involved in the beneficial effects of Sigma-1 receptor antagonist are little understood. We combined biochemical and biophysical (i.e. intermolecular Förster resonance energy transfer) techniques to demonstrate the interaction between Sigma-1 receptor and human TRPA1. Pharmacological antagonism of Sigma-1R impaired the formation of this molecular complex and the trafficking of functional TRPA1 to the plasma membrane. Using patch-clamp electrophysiological recordings we found that antagonists of Sigma-1 receptor, including Sigma-1 receptor antagonist, exert a marked inhibition on plasma membrane expression and function of human TRPA1 channels. In TRPA1-expressing mouse sensory neurons, Sigma-1 receptor antagonists reduced inward currents and the firing of actions potentials in response to TRPA1 agonists. Finally, in a mouse experimental model of oxaliplatin neuropathy, systemic treatment with a Sigma-1 receptor antagonists prevented the development of painful symptoms by a mechanism involving TRPA1. In summary, the modulation of TRPA1 channels by Sigma-1 receptor antagonists suggests a new strategy for the prevention and treatment of chemotherapy-induced peripheral neuropathy and could inform the development of novel therapeutics for neuropathic pain.During the course of this work, A.M. was supported by a Generalitat Valenciana predoctoral fellowship (GRISOLIA/2015/034), P.R. and M.V.-E. by Spanish Ministry of Education fellowships (Collaboration with Physiology Department Miguel Hernández University). This study was partially funded by ESTEVE Pharmaceuticals S.A., the Spanish Ministry of Science and Innovation (PID2019-108194RB-I00/AEI/10.13039/501100011033) and co-financed by Generalitat Valenciana (PROMETEO/2021/031) and the Severo Ochoa Programme for Centres of Excellence in R&D (ref. SEV-2017-0723).Peer reviewedOxford University PressGeneralitat ValencianaMinisterio de Educación (España)EsteveAgencia Estatal de Investigación (España)Ministerio de Ciencia, Innovación y Universidades (España)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202320232023info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/304490reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-108194RB-I00info:eu-repo/grantAgreement/AEI//SEV-2017-0723BrainSíinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3044902026-05-22T06:33:51Z
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