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

Juliette Descoeur,Michel Lazdunski,Anne Pizzoccaro,Christine Courteix,Bing Ling,Vanessa Pereira,Brigitte Couette,Jérôme Busserolles,Emmanuel Bourinet,Nicolas Authier,Alain Eschalier,Jacques Noel,Violette Maffre,Amaury Francois

doi:10.1002/emmm.201100134

Abstract

Cold 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 oxaliplatin 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.

Highlights

Chemotherapy-induced peripheral neuropathy is a common side effect of several anticancer agents including platinum analogues, vinca alkaloids, taxanes (Postma et al, 2005), and newer agents, such as epothilones, thalidomide, suramin, and (1) Departement de Physiologie, CNRS, UMR-5203, Institut de Genomique Fonctionnelle, Montpellier, France.(2) INSERM, U661, Montpellier, France. (3) Universites de Montpellier 1 and 2, UMR-5203, Montpellier, France. (4) Clermont Universite, Universite d’Auvergne, Pharmacologie Fondamentale et Clinique de la Douleur, Clermont-Ferrand, France. (5) INSERM, U 766, Clermont-Ferrand, France. (6) Institut de Pharmacologie Moleculaire et Cellulaire, CNRS, UMR 6097, Most chemotherapy-induced neuropathies improve after the drug is withdrawn, but long-term neuropathy can be found in a significant number of patients
The tail immersion test is mainly supported by a spinal reflex arc, in order to have a more integrated behaviour, we challenged the mice on a dynamic cold plate (Yalcin et al, 2009)
Among the currently used chemotherapy treatments, the third generation platinum compound oxaliplatin is unique in producing early onset neuropathic pain signs associated to exacerbated cold perception in almost all patients (Attal et al, 2009)

Summary

Introduction

Chemotherapy-induced peripheral neuropathy is a common side effect of several anticancer agents including platinum analogues, vinca alkaloids, taxanes (Postma et al, 2005), and newer agents, such as epothilones, thalidomide, suramin, and (1) Departement de Physiologie, CNRS, UMR-5203, Institut de Genomique Fonctionnelle, Montpellier, France.(2) INSERM, U661, Montpellier, France. (3) Universites de Montpellier 1 and 2, UMR-5203, Montpellier, France. (4) Clermont Universite, Universite d’Auvergne, Pharmacologie Fondamentale et Clinique de la Douleur, Clermont-Ferrand, France. (5) INSERM, U 766, Clermont-Ferrand, France. (6) Institut de Pharmacologie Moleculaire et Cellulaire, CNRS, UMR 6097, Most chemotherapy-induced neuropathies improve after the drug is withdrawn, but long-term neuropathy can be found in a significant number of patients (van der Hoop et al, 1990). (6) Institut de Pharmacologie Moleculaire et Cellulaire, CNRS, UMR 6097, Most chemotherapy-induced neuropathies improve after the drug is withdrawn, but long-term neuropathy can be found in a significant number of patients (van der Hoop et al, 1990). While this complication is increasingly important, no very effective preventive or curative treatment is available. EMBO Mol Med 3, 266–278 www.embomolmed.org or preventive treatment fails to improve patients (Wolf et al, 2008), there is a need to advance the understanding of the pathogenesis behind these neuropathies in order to propose effective therapeutic pain management. The emerging picture is that cold-sensing neurons would express a particular set of ion channels that determine their excitability at cold temperatures

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