期刊
EMBO MOLECULAR MEDICINE
卷 3, 期 5, 页码 266-278出版社
WILEY-BLACKWELL
DOI: 10.1002/emmm.201100134
关键词
background potassium channels; chemotherapy-induced neuropathy; cold pain; hyperpolarization activated channels; TRPM8
资金
- Montpellier GenomiX platform
- ARC-InCa
- institut UPSA de la Douleur
- ANR [ANR-08-MNPS-025-03]
- AFM
- Inserm
- CNRS
- University of Auvergne
- MRT
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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