Oxaliplatin is a highly effective, third generation platinum-based chemotherapeutic in clinical use for treatment of colorectal cancers. Severe acute and chronic neuropathic side effects limit the applicable dosage. Already during intravenous application patients suffer from cold-aggravated unpleasant sensations in the hands and feet as well as from muscle cramps. We investigated the effects of oxaliplatin on TTX-sensitive sodium channels in dissociated large diameter sensory dorsal root ganglion neurons (DRGs) using whole-cell patch-clamp recordings at 30°C and 22°C, mimicking normal and cool skin temperature. Activation and steady-state fast inactivation remained almost unchanged by oxaliplatin preincubation. At 30°C, resurgent and persistent currents were not altered by oxaliplatin preincubation, but cooling to 22°C induced a large increase in both current types after oxaliplatin preincubation. In functional terms, this would be expected to increase excitability. Resurgent currents are thought to occur when the open pore of the sodium channel, mostly of the subtype Nav1.6, is occluded by a blocking particle, probably part of the beta4 subunit. As no subtype-selective sodium channel blocker is available yet, we investigated large DRGs of Scn8a^med mice, which lack functional Nav1.6. The oxaliplatin-induced increase in persistent and resurgent current at 22°C in large DRGs from homozygous Scn8a^med mice is strongly attenuated compared to wildtype.

Our data show that oxaliplatin induces Nav1.6-dependent resurgent and persistent currents in large diameter DRG neurons at 22°C, but not at a higher temperature (30°C).

These findings suggest, that acute oxaliplatin-induced cold-aggravated symptoms in patients might be due to increased excitability based on enhancement of persistent and resurgent currents in their sensory neurons.