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 assess cold sensitivity in mice, we first measured acute tail withdrawal response to a noxious cold stimulation (Fig 1A). Vehicle-treated mice showed stable thresholds through the duration of the experiments (one daily test for 1 week). In contrast, oxaliplatin-treated animals exhibited altered cold sensitivity. Oxaliplatin induced a clear dose-dependent and transient reduction of withdrawal thresholds that peaked 90 h post injection and reversed towards control values thereafter (Fig 1A). At 6 mg/kg (therapeutic dose), the cold hypersensitivity was manifested by a 50% threshold decrease. The tail immersion test is mainly supported by a spinal reflex arc, thus, in order to have a more integrated behaviour, we challenged the mice on a dynamic cold plate (Yalcin et al, 2009). This test entails the slow lowering of temperature of the test arena floor from warm to cold and quantifying spontaneous nocifencive behaviour to ascertain the tolerance threshold to noxious cold. Vehicle-treated animals manifested escape behaviour at approximately 5°C, whilst oxaliplatin-treated mice presented the same escape behaviour at a much more elevated temperature (∼15°C), reflecting a clear cold hypersensitivity (Fig 1B). To discriminate allodynic effects, we performed the tail immersion test at an innocuous temperature (21°C). This temperature does not elicit any withdrawal in vehicle-treated animals, whilst it induced withdrawals in oxaliplatin-treated mice, with the same dose dependency as for cold hyperalgesia (Fig 1C). Spontaneous allodynia was assessed in these animals through their ability to discriminate between warm and cool surfaces. Mice were allowed to explore adjacent surfaces, with one held at 25°C and the other ranging from 25 to 15°C, a temperature range considered to be innocuously cool (Rainville et al, 1999) (Fig 1D). When both sides were at the same temperature (both 25°C), neither vehicle- nor oxaliplatin-treated mice displayed any preference. As the variable plate was cooled, vehicle-treated mice started to show a preference for the warm side when the variable side was below 19°C. With oxaliplatin treatment, the preference of the mice for the warm side developed as soon as the variable side was set to 23°C, demonstrating clear allodynic behaviour to cool temperatures (Fig 1D). In parallel, we assessed sensitivity of the mice to noxious heat through their response to tail immersion at 46°C (Supporting Fig 1A). Vehicle- or oxaliplatin-treated mice at all doses showed indistinguishable thresholds during the entire duration of the experiments (one daily test for 1 week), reflecting an unaltered response to heat.
Affiliation: Département de Physiologie, CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France.