Paclitaxel in vitro reversibly sensitizes the excitability of IB4(-) and IB4(+) sensory neurons from male and female rats

Abstract

Background and Purpose: Paclitaxel produces a chemotherapy-induced peripheral neuropathy that persists in 50–60% of cancer patients upon treatment. Evidence from animal models suggests an axonopathy of peripheral A- and C-type fibres that affects their excitability. However, direct effects of paclitaxel on sensory neuron excitability and sexual dimorphism remain poorly understood. Experimental Approach: We used a long-lasting (10 days in vitro) primary culture of rat dorsal root ganglion (DRG) neurons to investigate the time course effect of paclitaxel on the electrical activity of IB4( ) and IB4(+) sensory neurons of female and male adult Wistar rats. Key Results: Paclitaxel strongly and reversibly stimulated spontaneous activity and augmented action potential tonic firing in IB4( ) and IB4(+) neurons in both sexes, peaking at 48 h post-treatment and virtually disappearing at 96 h. Paclitaxel decreased the current rheobase for action potential firing by reducing and accelerating the after-hyperpolarization phase. Molecularly, paclitaxel modulated Na+ and K+ ion currents. Particularly, the drug significantly augmented the function of Nav1.8, TRPV1 and TRPM8 channels. Furthermore, paclitaxel increased Nav1.8 and TRPV1 expression at 48 h post-treatment. Notably, we observed that female DRG neurons appear more sensitive to paclitaxel sensitization than their male counterparts. Conclusions and Implications: Our data indicate that paclitaxel similarly potentiated IB4( ) and IB4(+) electrogenicity and uncover a potential sex dimorphism in paclitaxel-induced chemotherapy-induced peripheral neuropathy. Our in vitro, preclinical, chemotherapy-induced peripheral neuropathy paradigm provides a tool for studying the dynamics and underlying molecular mechanisms contributing to nociceptor sensitization in peripheral neuropathies and for testing desensitizing compounds.