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: Collectively, our results demonstrate that oxaliplatin induces peripheral neuropathy in mice with a clear exacerbation of cold detection and development of mechanical hyperalgesia. Cold-sensitive sensory fibres expressing TRPM8 and mechano-sensitive fibres expressing TRPA1 are potently affected by this toxic chemotherapy side effect. We found that within these neurons, oxaliplatin alters ion channel gene expression in agreement with transcriptional effects reported on cancer cell lines. The potassium channels TREK1, TRAAK, and, to a lesser extent, KV1.1 are repressed while TRPA1, NaV1.8, and HCN1 channels are transcriptionally up-regulated in these particular subclasses of sensory fibres as illustrated in Fig 10. The translational consequences of these findings for patients would be that pharmacological activators of the repressed potassium channels or antagonists of the up-regulated channels are potential tailored preventive treatments of the painful side effects of oxaliplatin. The availability of such molecules like ivabradine currently used in clinic could be of interest, especially as effective drugs for prevention are few and do not exist for curative care (Wolf et al, 2008). Further development of even more specific ligands for the identified channels is pivotal in future treatment of chemotherapy-induced neuropathies.
Affiliation: Département de Physiologie, CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France.