Vincristine-induced
peripheral neuropathy (VIPN) is a common side effect of
vincristine treatment, which is accompanied by
pain and can be dose-limiting. The molecular mechanisms that underlie
vincristine-induced
pain are not well understood. We have established an animal model to investigate pathophysiological mechanisms of
vincristine induced
pain. Our previous studies have shown that the
tetrodotoxin-sensitive (TTX-S)
voltage-gated sodium channel NaV1.6 in medium-diameter dorsal root ganglion (DRG) neurons contributes to the maintenance of
vincristine-induced
allodynia. In this study, we investigated the effects of
vincristine administration on excitability in small-diameter DRG neurons and whether the
tetrodotoxin-resistant (TTX-R) NaV1.8 channels contribute to
mechanical allodynia. Current-clamp recordings demonstrated that small DRG neurons become hyper-excitable following
vincristine treatment, with both reduced current threshold and increased firing frequency. Using voltage-clamp recordings in small DRG neurons we now show an increase in TTX-R current density and a -7.3 mV hyperpolarizing shift in V1/2 of activation of NaV1.8 channels in
vincristine-treated animals, which likely contributes to the hyperexcitability that we observed in these neurons. Notably,
vincristine treatment did not enhance excitability of small DRG neurons from NaV1.8 knockout mice, and the development of
mechanical allodynia was delayed but not abrogated in these mice. Together, our data suggest that
sodium channel NaV1.8 in small DRG neurons contributes to the development of
vincristine-induced
mechanical allodynia.