Oxaliplatin-induced Cold Hypersensitivity is Due to Remodelling of Ion Channel Expression in Nociceptors

Overview

Journal EMBO Mol Med

Specialty Molecular Biology

Date 2011 Mar 26

PMID 21438154

Citations 177

Authors

Juliette Descoeur

Vanessa Pereira

Anne Pizzoccaro

Amaury Francois

Bing Ling

Violette Maffre

Brigitte Couette

Jerome Busserolles

Christine Courteix

Jacques Noel

Michel Lazdunski

Alain Eschalier

Nicolas Authier

Emmanuel Bourinet

Affiliations

Soon will be listed here.

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.

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