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.

We describe an animal model of nociceptive sensory neuropathy induced by repeat intravenous administration of oxaliplatin in which treated animals partly reproduce the characteristic pain symptoms in oxaliplatin-treated patients. We tested the ability of 1, 2 and 4 mg/kg oxaliplatin doses injected twice-weekly for four-and-a-half consecutive weeks to induce a nociceptive peripheral neuropathy in male Sprague-Dawley rats. The behavioral assessment revealed cold allodynia (10 degrees C) and hyperalgesia (4 degrees C) symptoms associated with a mechanical allodynia. The rats maintained a good general clinical status without motor dysfunction. The 2mg/kg oxaliplatin dose and the tail-immersion test in cold water (10 degrees C) were selected to compare pharmacological sensitivity between single administered drugs as morphine, lidocaine, carbamazepine, gabapentin and repeated administration of drugs as clomipramine, venlafaxine, calcium and magnesium solutions. Magnesium solution (90 mg/kg) and venlafaxine (7.5 mg/kg) administration induced an antinociceptive effect whereas gabapentin (300 mg/kg), clomipramine (2.5 mg/kg) and lidocaine (3 and 6 mg/kg) only induced an antiallodynic effect.

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