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

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.

• Authors: Juliette Descoeur, Vanessa Pereira, Anne Pizzoccaro, Amaury Francois, Bing Ling, Violette Maffre, Brigitte Couette, Jérôme Busserolles, Christine Courteix, Jacques Noel, Michel Lazdunski, Alain Eschalier, Nicolas Authier, Emmanuel Bourinet
• Journal: EMBO molecular medicine (EMBO Mol Med) Vol. 3 Issue 5 Pg. 266-78 (May 2011) ISSN: 1757-4684 [Electronic] England
• PMID: 21438154 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 EMBO Molecular Medicine.

Chemical References

• Antineoplastic Agents
• Organoplatinum Compounds
• Potassium Channels
• TRPM Cation Channels
• Oxaliplatin

Topics

• Animals
• Antineoplastic Agents (adverse effects)
• Cold Temperature
• Humans
• Hyperalgesia (chemically induced)
• Mice
• Nociceptors (drug effects, metabolism)
• Organoplatinum Compounds (adverse effects)
• Oxaliplatin
• Potassium Channels (metabolism)
• TRPM Cation Channels (metabolism)