Please use this identifier to cite or link to this item: https://hdl.handle.net/11000/30712
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dc.contributor.authorMarcotti, Aida-
dc.contributor.authorFernández Trillo, Jorge-
dc.contributor.authorGonzález, Alejandro-
dc.contributor.authorVizcaíno Escoto, Marta-
dc.contributor.authorRos Arlanzón, Pablo-
dc.contributor.authorRomero, Luz-
dc.contributor.authorVela, José Miguel-
dc.contributor.authorGomis García, Ana María-
dc.contributor.authorViana de la Iglesia, Félix-
dc.contributor.authorDe la Peña García, Elvira-
dc.contributor.otherDepartamentos de la UMH::Fisiologíaes_ES
dc.contributor.otherInstituto de Neurocienciases_ES
dc.date.accessioned2024-01-26T10:25:42Z-
dc.date.available2024-01-26T10:25:42Z-
dc.date.created2023-02-13-
dc.identifier.citationBrain 2023 Feb 13;146(2):475-491es_ES
dc.identifier.issn1460-2156 (Electronic)-
dc.identifier.urihttps://hdl.handle.net/11000/30712-
dc.description.abstractChemotherapy-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.es_ES
dc.formatapplication/pdfes_ES
dc.format.extent17es_ES
dc.language.isoenges_ES
dc.publisherOxford University Press [University Publisher]es_ES
dc.rightsinfo:eu-repo/semantics/openAccesses_ES
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectcold allodyniaes_ES
dc.subjectneuropathic paines_ES
dc.subjectTRPA1es_ES
dc.subjectSigma-1 receptores_ES
dc.subjectchemotherapyes_ES
dc.titleTRPA1 modulation by Sigma-1 receptor prevents oxaliplatin-induced painful peripheral neuropathyes_ES
dc.typeinfo:eu-repo/semantics/articlees_ES
dc.relation.publisherversionhttps://doi.org/10.1093/brain/awac273es_ES
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