Oxaliplatin-induced cold hypersensitivity is due to remodeling of ion channels in nociseptors

L’oxaliplatine, largement utilisé dans le traitement du cancer colorectal, est susceptible d’induire précocement des dysesthésies pharyngées et des extrémités, majorées par l’exposition au froid. Il s’agit d’une toxicité cumulative et limitante. L’efficacité des traitements actuellement disponibles est médiocre, ce qui justifie d’évaluer de nouvelles approches pharmacologiques. Le but de ce travail est de développer un modèle de souris reproduisant cette hypersensibilité au froid afin d’en étudier les mécanismes physiopathologiques. Comme chez les patients, l’administration d’oxaliplatine entraîne une amplification importante de la perception du froid chez la souris. Nous montrons que ces symptômes sont médiés par les nocicepteurs exprimant le thermorécepteur TRPM8. D’un point de vue physiopathologique, l’oxaliplatine favorise l’excitabilité de ces nocicepteurs en diminuant l’expression de plusieurs canaux potassiques (TREK1 et TRAAK en particulier), et en augmentant l’expression de canaux pro excitateurs tels que les canaux cationiques activés par l’hyperpolarisation (HCN1 notamment). Ces constatations sont confortées, au niveau comportemental, par l’analyse de la lignée de souris invalidées pour TREK1 et TRAAK et par l’utilisation de l’ivabradine, un inhibiteur pharmacologique spécifique des canaux HCNs. L’ivabradine, déjà utilisé en clinique pour le traitement de l’insuffisance cardiaque, entraîne une suppression de l’hypersensibilité au froid induite par l’oxaliplatine. L’ensemble de ces résultats suggère que l’oxaliplatine exacerbe la perception du froid en remodelant le patron d’expression de plusieurs canaux ioniques qui coordonnent la réponse au froid. Ils constituent un rationnel pour l’évaluation de l’ivabradine dans le traitement des neuropathies induites par l’oxaliplatine.The hallmark of oxaliplatin-induced neuropathy is a hypersensibility to cold that develops in nearly all patients ultimately leading to cessation of this chemotherapy treatment. To date, classical pain management strategies have failed to alleviate these painful symptoms, and hence there is a need for developing new and efficient pharmacologic agents. Here we report that, as in patients, oxaliplatin mediates a clear development of exaggerated perception of cold temperatures in mice. These symptoms are mediated by nociceptors expressing the thermoreceptor TRPM8. Mechanistically, we find that oxaliplatin promotes excitability in nociceptors drastically lowering the expression of distinct potassium channels (TREK1, TRAAK) that act as excitability brakes for cold perception, and by increasing the expression of pro-excitatory channels such as the hyperpolarisation-activated channels (HCNs). These findings are corroborated by the analysis of the TREK1-TRAAK null mice, and by the use a specific HCN channel inhibitor abolishing the oxaliplatin-induced cold hypersensibility. Collectively, these results suggest that oxaliplatin exacerbates cold perception in cold sensing neurons by transcriptionally remodeling a combination of ionic conductances that together shape the final response to cold. A direct promising clinical consequence of these findings for patients would be that the HCN inhibitor ivabradine could represent a tailored treatment for oxaliplatin-induced neuropathy

Oxaliplatin‐induced cold hypersensitivity is due to remodelling of ion channel expression in nociceptors

International audienceCold hypersensitivity is the hallmark of oxaliplatin-induced neuropathy, which develops in nearly all patients under this chemotherapy. To date, pain management strategies have failed to alleviate these symptoms, hence development of adapted analgesics is needed. Here, we report that oxaliplatin exaggerates cold perception in mice as well as in patients. These symptoms are mediated by primary afferent sensory neurons expressing the thermoreceptor TRPM8. Mechanistically, oxaliplatin promotes over-excitability by drastically lowering the expression of distinct potassium channels (TREK1, TRAAK) and by increasing the expression of pro-excitatory channels such as the hyperpolarization-activated channels (HCNs). These findings are corroborated by the analysis of TREK1-TRAAK null mice and use of the specific HCN inhibitor ivabradine, which abolishes the oxaliplatin-induced cold hypersensibility. These results suggest that oxali-platin exacerbates cold perception by modulating the transcription of distinct ionic conductances that together shape sensory neuron responses to cold. The translational and clinical implication of these findings would be that ivabradine may represent a tailored treatment for oxaliplatin-induced neuropathy