Mechanisms Underlying Gastrodin Alleviating Vincristine-Induced Peripheral Neuropathic Pain

Gastrodin (GAS) is the main bioactive ingredient of Gastrodia, a famous Chinese herbal medicine widely used as an analgesic, but the underlying analgesic mechanism is still unclear. In this study, we first observed the effects of GAS on the vincristine-induced peripheral neuropathic pain by alleviating the mechanical and thermal hyperalgesia. Further studies showed that GAS could inhibit the current density of Na_V1.7 and Na_V1.8 channels and accelerate the inactivation process of Na_V1.7 and Na_V1.8 channel, thereby inhibiting the hyperexcitability of neurons. Additionally, GAS could significantly reduce the over-expression of Na_V1.7 and Na_V1.8 on DRG neurons from vincristine-treated rats according to the analysis of Western blot and immunofluorescence results. Moreover, based on the molecular docking and molecular dynamic simulation, the binding free energies of the constructed systems were calculated, and the binding sites of GAS on the sodium channels (Na_V1.7 and Na_V1.8) were preliminarily determined. This study has shown that modulation of Na_V1.7 and Na_V1.8 sodium channels by GAS contributing to the alleviation of vincristine-induced peripheral neuropathic pain, thus expanding the understanding of complex action of GAS as a neuromodulator.