Oxaliplatin-induced cold hypersensitivity is due to remodelling of ion channel expression in nociceptors.
Bottom Line: To date, pain management strategies have failed to alleviate these symptoms, hence development of adapted analgesics is needed.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).The translational and clinical implication of these findings would be that ivabradine may represent a tailored treatment for oxaliplatin-induced neuropathy.
Affiliation: Département de Physiologie, CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France.Show MeSH
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Mentions: To investigate the cold sensitivity of dorsal root ganglion (DRG) neurons in culture, we measured fluctuations of intracellular calcium in response to cooling. As previously shown (Madrid et al, 2009; Noel et al, 2009), the thresholds of cold-sensitive DRG neurons varied over a large range (35–15°C) as demonstrated by the simultaneous recordings of four cold-sensitive neurons from vehicle-treated mice (Fig 3A). The frequency distribution of threshold temperatures (Fig 3B) shows that cold-sensitive DRGs from vehicle-treated mice can be separated in two subpopulations with high and low thresholds with a limit between the two groups around 25°C. In contrast, the same analysis with cold-sensitive neurons from oxaliplatin-treated mice shows that the vast majority of neurons responds mainly with a low threshold (between 35 and 25°C). Furthermore, we observed in some of these neurons from oxaliplatin-treated mice, episodes of spontaneous intracellular calcium oscillations even before cooling (not shown). In addition, the proportion of cold-sensitive neurons in the culture is doubled by oxaliplatin (Fig 3C) consistent with a state of hyperexcitability of these nociceptors induced by chemotherapy.
Affiliation: Département de Physiologie, CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France.