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

Background and purpose: Oxaliplatin-induced peripheral neuropathy (OIPN) is a painful, debilitating, and prevalent drug side effect occurring in cancer patients. The molecular mechanism and sex differences underlying OIPN remain elusive. Experimental approach: We use a long-term primary culture of rat male and female nociceptors to investigate the electrogenic effect and time course of 1 µg·mL oxaliplatin exposure for 24 and 48h. Key results: Oxaliplatin primarily and reversibly increased the excitability of IB4(+) male and female nociceptors, peaking after drug exposure and gradually dissipating thereafter. Female nociceptors were more affected than male, exhibiting a depolarized resting membrane potential, a reduced current rheobase, and an augmented overshoot and amplitude of their action potentials. Oxaliplatin increased Na currents in female nociceptors without affecting their voltage dependency and up-regulated and depolarized A-type K currents. In male nociceptors, oxaliplatin reduced Na currents, slowed current inactivation and accelerated their recovery from inactivation. Moreover, oxaliplatin augmented the transcriptional expression and ionic activities of TRPV1 and TRPA1 channels without affecting TRPM8. Oxaliplatin similarly increased TRPV1 currents in male and female IB4(+) nociceptors and augmented the percentage of TRPA1 responsive neurons in male IB4(+) neurons. Conclusions and implications: 48h oxaliplatin exposure affected IB4(+) nociceptor electrogenic activity in a reversible and sex dependent manner by modulating Na, fast-inactivating K, TRPV1 and TRPA1 currents. Our findings signal to TRPV1 and TRPA1 as therapeutic targets to attenuate OIPN and substantiate the use of long-term nociceptor cultures as in vitro preclinical models for investigating the signalling pathways and sexual dimorphism of peripheral neuropathies.