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 García, Ana María, Viana de la Iglesia, Félix, De La Peña García, Elvira María
Tipo de recurso: artículo
Fecha de publicación:2023
País:España
Institución:Universidad Miguel Hernández de Elche
Repositorio:REDIUMH. Depósito Digital de la UMH
OAI Identifier:oai:dspace.umh.es:11000/30712
Acceso en línea:https://hdl.handle.net/11000/30712
Access Level:acceso abierto
Palabra clave:cold allodynia
neuropathic pain
TRPA1
Sigma-1 receptor
chemotherapy
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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 García, Ana MaríaViana de la Iglesia, FélixDe La Peña García, Elvira Maríacold allodynianeuropathic painTRPA1Sigma-1 receptorchemotherapyChemotherapy-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.Oxford University Press [University Publisher]Departamentos de la UMH::FisiologíaInstituto de Neurociencias202420242023info:eu-repo/semantics/articleapplication/pdf17application/pdfhttps://hdl.handle.net/11000/30712reponame:REDIUMH. Depósito Digital de la UMHinstname:Universidad Miguel Hernández de ElcheIngléshttps://doi.org/10.1093/brain/awac273info:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by-nc-nd/4.0/oai:dspace.umh.es:11000/307122026-05-27T13:36:21Z
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
cold allodynia
neuropathic pain
TRPA1
Sigma-1 receptor
chemotherapy
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 García, Ana María
Viana de la Iglesia, Félix
De La Peña García, Elvira María
author Marcotti, Aida
author_facet Marcotti, Aida
Fernández Trillo, Jorge
González, Alejandro
Vizcaíno Escoto, Marta
Ros Arlanzón, Pablo
Romero, Luz
Vela, José Miguel
Gomis García, Ana María
Viana de la Iglesia, Félix
De La Peña García, Elvira María
author_role author
author2 Fernández Trillo, Jorge
González, Alejandro
Vizcaíno Escoto, Marta
Ros Arlanzón, Pablo
Romero, Luz
Vela, José Miguel
Gomis García, Ana María
Viana de la Iglesia, Félix
De La Peña García, Elvira María
author2_role author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Departamentos de la UMH::Fisiología
Instituto de Neurociencias
dc.subject.none.fl_str_mv cold allodynia
neuropathic pain
TRPA1
Sigma-1 receptor
chemotherapy
topic cold allodynia
neuropathic pain
TRPA1
Sigma-1 receptor
chemotherapy
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
2024
2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/11000/30712
url https://hdl.handle.net/11000/30712
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv https://doi.org/10.1093/brain/awac273
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.format.none.fl_str_mv application/pdf
17
application/pdf
dc.publisher.none.fl_str_mv Oxford University Press [University Publisher]
publisher.none.fl_str_mv Oxford University Press [University Publisher]
dc.source.none.fl_str_mv reponame:REDIUMH. Depósito Digital de la UMH
instname:Universidad Miguel Hernández de Elche
instname_str Universidad Miguel Hernández de Elche
reponame_str REDIUMH. Depósito Digital de la UMH
collection REDIUMH. Depósito Digital de la UMH
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869422219476598784
score 15,301603

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