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: Pharmacological characterization of cold-sensitive neurons in vitro using chemical agonists showed that these cells from both vehicle- and oxaliplatin-treated mice similarly use TRPM8 as the major cold transduction mechanism (Supporting Fig 2). Moreover, cool allodynia develops in the range of temperatures activating the thermoreceptor TRPM8 (McKemy et al, 2002; Peier et al, 2002). Thus, we evaluated whether the effects of oxaliplatin would be abolished in mice deficient for this channel. As presented in Fig 4A, in the cold tolerance paradigm used, TRPM8- mice did not elicit nocifencive behaviour to noxious cold either before or 90 h after oxaliplatin injection. Similarly, in the thermal preference test (Fig 4B), oxaliplatin failed to induce cool allodynia in TRMP8 nice in contrast to wild type animals (Fig 1D). However, the mechanical pain symptoms still developed in these knock out (KO) mice (Fig 4C). Collectively, these results indicate that oxaliplatin mediates a cold hypersensitivity (both hyperalgesia to noxious cold, and allodynia to innocuous cool) via TRPM8 afferent fibres, but the mechanism remains to be determined.
Affiliation: Département de Physiologie, CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France.