Abstract
Vincristine, a widely used chemotherapeutic agent, produces painful peripheral neuropathy. The underlying mechanisms are not well understood. In this study, we investigated whether voltage-gated sodium channels are involved in the development of vincristine-induced neuropathy. We established a mouse model in which repeated systemic vincristine treatment results in the development of significant mechanical allodynia. Histological examinations did not reveal major structural changes at proximal sciatic nerve branches or distal toe nerve fascicles at the vincristine dose used in this study. Immunohistochemical studies and in vivo two-photon imaging confirmed that there is no significant change in density or morphology of intra-epidermal nerve terminals throughout the course of vincristine treatment. These observations suggest that nerve degeneration is not a prerequisite of vincristine-induced mechanical allodynia in this model. We also provided the first detailed characterization of tetrodotoxin-sensitive (TTX-S) and resistant (TTX-R) sodium currents in dorsal root ganglion neurons following vincristine treatment. Accompanying the behavioural hyperalgesia phenotype, voltage-clamp recordings of small and medium dorsal root ganglion neurons from vincristine-treated animals revealed a significant upregulation of TTX-S Na+ current in medium but not small neurons. The increase in TTX-S Na+ current density is likely mediated by Nav1.6, because in the absence of Nav1.6 channels, vincristine failed to alter TTX-S Na+ current density in medium dorsal root ganglion neurons and, importantly, mechanical allodynia was significantly attenuated in conditional Nav1.6 knockout mice. Our data show that TTX-S sodium channel Nav1.6 is involved in the functional changes of dorsal root ganglion neurons following vincristine treatment and it contributes to the maintenance of vincristine-induced mechanical allodynia.
Role of Tetrodotoxin-Resistant Na+Current Slow Inactivation in Adaptation of Action Potential Firing in Small-Diameter Dorsal Root Ganglion Neurons