Oxaliplatin reversibly and differentially affects electrogenic activity of small IB4(+) of male and female rat sensory neurons

Oxaliplatin-induced peripheral neuropathy (OIPN) is a prevalent drug side effect with unclear molecular mechanism and sex differences. We report that a 48-hour exposure of 1 µg·mL^-1 oxaliplatin potently and reversibly increased the excitability of IB4(+) male and female nociceptors. In females, oxaliplatin augmented spontaneous and tonic activity, increased the overshoot and amplitude of action potentials, depolarized the membrane potential, reduced the rheobase, and raised the firing frequency, primarily due to the depolarization of K_V currents and a mild up-regulation of TTX-resistant (TTX-r) Na_V currents. In males, oxaliplatin reduced the rheobase, augmented the firing frequency, and prolonged the action potential peak time, mediated by increased TTX-r Na_V currents, hyperpolarization of their activation curve, and a faster recovery from inactivation. Oxaliplatin also up-regulated TRPV1 currents in male and female IB4(+) nociceptors and augmented TRPA1 responses in male IB4(+) neurons. These findings highlight Na_V1.8, TRPV1, and TRPA1 as therapeutic targets to mitigate OIPN and validate the use of long-term nociceptor cultures as preclinical models for studying peripheral neuropathies.