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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Neuropharmacology
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1484387
This article is part of the Research Topic Pharmacological Advances to Treat Pathological Pain View all 3 articles

A functional unbalance of TRPM8 and Kv1 channels underlies orofacial cold allodynia induced by peripheral nerve damage

Provisionally accepted
Ricardo Piña Ricardo Piña 1,2Gonzalo Ugarte Gonzalo Ugarte 1Camilo Guevara Camilo Guevara 1,3Richard Pino Richard Pino 1Katherine Valdebenito Katherine Valdebenito 1Sofía Romero Sofía Romero 1,3,4Ana Gómez del Campo Ana Gómez del Campo 1,3,4Víctor Hugo Cornejo Víctor Hugo Cornejo 4,5María Pertusa María Pertusa 1,3,4Rodolfo Madrid Rodolfo Madrid 1,3,4*
  • 1 Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, 9160000 Santiago, Chile
  • 2 Departamento de Biología, Facultad de Ciencias Básicas, Universidad Metropolitana de Ciencias de la Educación, 7760197 Santiago, Chile
  • 3 Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), 9160000 Santiago, Chile
  • 4 Millennium Nucleus for the Study of Pain (MiNuSPain), 9160000 Santiago, Chile
  • 5 Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, 8331150 Santiago, Chile

The final, formatted version of the article will be published soon.

    Cold allodynia is a debilitating symptom of orofacial neuropathic pain resulting from trigeminal nerve damage. The molecular and neural bases of this sensory alteration are still poorly understood. Here, using chronic constriction injury (CCI) of the infraorbital nerve (IoN) (IoN-CCI) in mice, combined with behavioral analysis, Ca 2+ imaging and patch-clamp recordings of retrogradely labeled IoN neurons in culture, immunohistochemistry, and adeno-associated viral (AAV) vector-based delivery in vivo, we explored the mechanisms underlying the altered orofacial cold sensitivity resulting from axonal damage in this trigeminal branch. We found that cold allodynia induced by IoN-CCI is linked to an increase in the proportion of cold-sensitive neurons (CSNs) contributing to this branch and a shift in their thermal thresholds to higher temperatures. These changes are correlated to a reduction of the Kv1.1-1.2-dependent brake potassium current IKD in IoN CSNs and a rise in the percentage of trigeminal neurons expressing TRPM8. The analysis of the electrophysiological properties of CSNs contributing to the IoN suggests that painful cold hypersensitivity involves the recruitment of silent nociceptive afferents that become sensitive to mild cold in response to nerve damage. Notably, pharmacological suppression of TRPM8 channels and AAV-based transduction of trigeminal neurons with the Kv1.1 channel in vivo effectively reverted the nociceptive phenotype in injured animals. Altogether, our results unveil a crucial role of TRPM8 and Kv1 channels in orofacial cold allodynia, suggesting that both the specific TRPM8-blocking and the AAV-driven expression of potassium channels underlying IKD in trigeminal neurons can be effective tools to revert this damage-triggered sensory alteration.

    Keywords: primary sensory neurons, thermotransduction, Infraorbital nerve, IKD, AAV vectors, 4-AP, PBMC

    Received: 27 Aug 2024; Accepted: 13 Nov 2024.

    Copyright: © 2024 Piña, Ugarte, Guevara, Pino, Valdebenito, Romero, Gómez del Campo, Cornejo, Pertusa and Madrid. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Rodolfo Madrid, Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, 9160000 Santiago, Chile

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.