title: 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: Département de Physiologie, CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France.
authors: Juliette
authors: J
authors: Descoeur
authors: Vanessa
authors: V
authors: Pereira
authors: Anne
authors: A
authors: Pizzoccaro
authors: Amaury
authors: A
authors: Francois
authors: Bing
authors: B
authors: Ling
authors: Violette
authors: V
authors: Maffre
authors: Brigitte
authors: B
authors: Couette
authors: Jérôme
authors: J
authors: Busserolles
authors: Christine
authors: C
authors: Courteix
authors: Jacques
authors: J
authors: Noel
authors: Michel
authors: M
authors: Lazdunski
authors: Alain
authors: A
authors: Eschalier
authors: Nicolas
authors: N
authors: Authier
authors: Emmanuel
authors: E
authors: Bourinet
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D003080:Cold Temperature; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced*; D051379:Mice; D009619:Nociceptors / Q000187:drug effects* / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000009:adverse effects*; D000077150:Oxaliplatin; D015221:Potassium Channels / Q000378:metabolism; D050053:TRPM Cation Channels / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D015221:Potassium Channels; D050053:TRPM Cation Channels; D000077150:Oxaliplatin