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

Autores
Marcotti, Aída; Fernández Trillo, Jorge; González, Alejandro; Vizcaíno Escoto, Marta; Ros Arlanzón, Pablo; Romero, Luz; Vela, Jos Miguel; Gomis, Ana; Viana, Flix; De La Peña, Elvira
Año de publicación
2023
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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.
Fil: Marcotti, Aída. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; Argentina. Universidad de Miguel Hernández; España. Consejo Superior de Investigaciones Científicas; España
Fil: Fernández Trillo, Jorge. Universidad de Miguel Hernández; España. Consejo Superior de Investigaciones Científicas; España
Fil: González, Alejandro. Consejo Superior de Investigaciones Científicas; España. Universidad de Miguel Hernández; España
Fil: Vizcaíno Escoto, Marta. Universidad de Miguel Hernández; España. Consejo Superior de Investigaciones Científicas; España
Fil: Ros Arlanzón, Pablo. Universidad de Miguel Hernández; España. Consejo Superior de Investigaciones Científicas; España
Fil: Romero, Luz. Parc Cientific de Barcelona; España
Fil: Vela, Jos Miguel. Parc Cientific de Barcelona; España. Consejo Superior de Investigaciones Científicas; España
Fil: Gomis, Ana. Universidad de Miguel Hernández; España. Consejo Superior de Investigaciones Científicas; España
Fil: Viana, Flix. Universidad de Miguel Hernández; España. Consejo Superior de Investigaciones Científicas; España
Fil: De La Peña, Elvira. Universidad de Miguel Hernández; España. Consejo Superior de Investigaciones Científicas; España
Materia
CHEMOTHERAPY
COLD ALLODYNIA
NEUROPATHIC PAIN
SIGMA-1 RECEPTOR
TRPA1
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/204540
Acceder
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network_acronym_str CONICETDig
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network_name_str CONICET Digital (CONICET)
spelling TRPA1 modulation by Sigma-1 receptor prevents oxaliplatin-induced painful peripheral neuropathyMarcotti, AídaFernández Trillo, JorgeGonzález, AlejandroVizcaíno Escoto, MartaRos Arlanzón, PabloRomero, LuzVela, Jos MiguelGomis, AnaViana, FlixDe La Peña, ElviraCHEMOTHERAPYCOLD ALLODYNIANEUROPATHIC PAINSIGMA-1 RECEPTORTRPA1https://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Chemotherapy-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.Fil: Marcotti, Aída. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; Argentina. Universidad de Miguel Hernández; España. Consejo Superior de Investigaciones Científicas; EspañaFil: Fernández Trillo, Jorge. Universidad de Miguel Hernández; España. Consejo Superior de Investigaciones Científicas; EspañaFil: González, Alejandro. Consejo Superior de Investigaciones Científicas; España. Universidad de Miguel Hernández; EspañaFil: Vizcaíno Escoto, Marta. Universidad de Miguel Hernández; España. Consejo Superior de Investigaciones Científicas; EspañaFil: Ros Arlanzón, Pablo. Universidad de Miguel Hernández; España. Consejo Superior de Investigaciones Científicas; EspañaFil: Romero, Luz. Parc Cientific de Barcelona; EspañaFil: Vela, Jos Miguel. Parc Cientific de Barcelona; España. Consejo Superior de Investigaciones Científicas; EspañaFil: Gomis, Ana. Universidad de Miguel Hernández; España. Consejo Superior de Investigaciones Científicas; EspañaFil: Viana, Flix. Universidad de Miguel Hernández; España. Consejo Superior de Investigaciones Científicas; EspañaFil: De La Peña, Elvira. Universidad de Miguel Hernández; España. Consejo Superior de Investigaciones Científicas; EspañaOxford University Press2023-02info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/204540Marcotti, Aída; Fernández Trillo, Jorge; González, Alejandro; Vizcaíno Escoto, Marta; Ros Arlanzón, Pablo; et al.; TRPA1 modulation by Sigma-1 receptor prevents oxaliplatin-induced painful peripheral neuropathy; Oxford University Press; Brain; 146; 2; 2-2023; 475-4910006-8950CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/brain/article/146/2/475/6649421info:eu-repo/semantics/altIdentifier/doi/10.1093/brain/awac273info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T14:26:29Zoai:ri.conicet.gov.ar:11336/204540instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-15 14:26:29.643CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
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, Aída
CHEMOTHERAPY
COLD ALLODYNIA
NEUROPATHIC PAIN
SIGMA-1 RECEPTOR
TRPA1
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, Aída
Fernández Trillo, Jorge
González, Alejandro
Vizcaíno Escoto, Marta
Ros Arlanzón, Pablo
Romero, Luz
Vela, Jos Miguel
Gomis, Ana
Viana, Flix
De La Peña, Elvira
author Marcotti, Aída
author_facet Marcotti, Aída
Fernández Trillo, Jorge
González, Alejandro
Vizcaíno Escoto, Marta
Ros Arlanzón, Pablo
Romero, Luz
Vela, Jos Miguel
Gomis, Ana
Viana, Flix
De La Peña, Elvira
author_role author
author2 Fernández Trillo, Jorge
González, Alejandro
Vizcaíno Escoto, Marta
Ros Arlanzón, Pablo
Romero, Luz
Vela, Jos Miguel
Gomis, Ana
Viana, Flix
De La Peña, Elvira
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv CHEMOTHERAPY
COLD ALLODYNIA
NEUROPATHIC PAIN
SIGMA-1 RECEPTOR
TRPA1
topic CHEMOTHERAPY
COLD ALLODYNIA
NEUROPATHIC PAIN
SIGMA-1 RECEPTOR
TRPA1
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv 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.
Fil: Marcotti, Aída. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; Argentina. Universidad de Miguel Hernández; España. Consejo Superior de Investigaciones Científicas; España
Fil: Fernández Trillo, Jorge. Universidad de Miguel Hernández; España. Consejo Superior de Investigaciones Científicas; España
Fil: González, Alejandro. Consejo Superior de Investigaciones Científicas; España. Universidad de Miguel Hernández; España
Fil: Vizcaíno Escoto, Marta. Universidad de Miguel Hernández; España. Consejo Superior de Investigaciones Científicas; España
Fil: Ros Arlanzón, Pablo. Universidad de Miguel Hernández; España. Consejo Superior de Investigaciones Científicas; España
Fil: Romero, Luz. Parc Cientific de Barcelona; España
Fil: Vela, Jos Miguel. Parc Cientific de Barcelona; España. Consejo Superior de Investigaciones Científicas; España
Fil: Gomis, Ana. Universidad de Miguel Hernández; España. Consejo Superior de Investigaciones Científicas; España
Fil: Viana, Flix. Universidad de Miguel Hernández; España. Consejo Superior de Investigaciones Científicas; España
Fil: De La Peña, Elvira. Universidad de Miguel Hernández; España. Consejo Superior de Investigaciones Científicas; España
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 2023-02
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/204540
Marcotti, Aída; Fernández Trillo, Jorge; González, Alejandro; Vizcaíno Escoto, Marta; Ros Arlanzón, Pablo; et al.; TRPA1 modulation by Sigma-1 receptor prevents oxaliplatin-induced painful peripheral neuropathy; Oxford University Press; Brain; 146; 2; 2-2023; 475-491
0006-8950
CONICET Digital
CONICET
url http://hdl.handle.net/11336/204540
identifier_str_mv Marcotti, Aída; Fernández Trillo, Jorge; González, Alejandro; Vizcaíno Escoto, Marta; Ros Arlanzón, Pablo; et al.; TRPA1 modulation by Sigma-1 receptor prevents oxaliplatin-induced painful peripheral neuropathy; Oxford University Press; Brain; 146; 2; 2-2023; 475-491
0006-8950
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/brain/article/146/2/475/6649421
info:eu-repo/semantics/altIdentifier/doi/10.1093/brain/awac273
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc/2.5/ar/
dc.format.none.fl_str_mv application/pdf
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:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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