Referenced in: none

Automatically associated channels: TRP , TRPM , TRPM8

Title: Oxaliplatin-induced cold hypersensitivity is due to remodelling of ion channel expression in nociceptors.

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

Journal, date & volume: , 2011 Mar 24 , ,

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/21438154

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.