Potentiation of PIEZO2 mechanically-activated currents in sensory neurons mediates vincristine-induced mechanical hypersensitivity

Vincristine, a widely used chemotherapeutic agent for treating different cancer, often induces severe peripheral neuropathic pain. A common symptom of vincristine-induced peripheral neuropathic pain is mechanical allodynia and hyperalgesia. However, mechanisms underlying vincristine-induced me-chanical allodynia and hyperalgesia are not well understood. In the present study, we show with behav-ioral assessment in rats that vincristine induces mechanical allodynia and hyperalgesia in a PIEZO2 channel-dependent manner since gene knockdown or pharmacological inhibition of PIEZO2 channels al-leviates vincristine-induced mechanical hypersensitivity. Electrophysiological results show that vincris-tine potentiates PIEZO2 rapidly adapting (RA) mechanically-activated (MA) currents in rat dorsal root ganglion (DRG) neurons. We have found that vincristine-induced potentiation of PIEZO2 MA currents is due to the enhancement of static plasma membrane tension (SPMT) of these cells following vincristine treatment. Reducing SPMT of DRG neurons by cytochalasin D (CD), a disruptor of the actin filament, abolishes vincristine-induced potentiation of PIEZO2 MA currents, and suppresses vincristine-induced mechanical hypersensitivity in rats. Collectively, enhancing SPMT and subsequently potentiating PIEZO2 MA currents in primary afferent neurons may be an underlying mechanism responsible for vincristine-induced mechanical allodynia and hyperalgesia in rats. Targeting to inhibit PIEZO2 channels may be an effective analgesic method to attenuate vincristine-induced mechanical hypersensitivity. 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

The study found that vincristine-induced mechanical allodynia and hyperalgesia in rats are related to the PIEZO2 channel. By gene knockdown and pharmacological inhibition of the PIEZO2 channel, mechanical hypersensitivity caused by vincristine can be alleviated. Further experiments showed that vincristine enhances the mechanical activation of PIEZO2 currents by increasing the static plasma membrane tension of cells. Therefore, inhibiting the PIEZO2 channel may be an effective method to attenuate vincristine-induced mechanical hypersensitivity.