长春新碱是治疗不同癌症的广泛使用的化疗药物，在体外常诱导严重的周围神经病理性疼痛。长春新碱引发的周围神经病理性疼痛的常见症状是机械性触痛和过敏性疼痛。然而，长春新碱引发机械性触痛和过敏性疼痛的机制尚不明确。本研究通过对大鼠进行行为评估证明，长春新碱诱导的机械性触痛和过敏性疼痛依赖于PIEZO2通道，因为基因沉默或药物抑制PIEZO2通道可以缓解长春新碱诱导的机械性过敏。电生理结果表明，长春新碱增强大鼠脊神经节( DRG )神经元中PIEZO2快速适应(MA)机械激活的电流。我们发现，长春新碱引发的PIEZO2 MA电流增强是由于细胞经长春新碱处理后静态负荷膜张力的增强。通过使用肌动蛋白破酒石酸二甲酯(CD)减少DRG神经元的负荷膜张力，消除了长春新碱引发的PIEZO2 MA电流增强，抑制了大鼠长春新碱引发的机械性过敏。总的来说，增强初级传入神经元的负荷膜张力，并随之增强PIEZO2 MA电流，可能是长春新碱引发大鼠机械性触痛和过敏性疼痛的潜在机制。针对PIEZO2通道的抑制可能是减轻长春新碱诱导机械性过敏的有效镇痛方法。© 2023中国药学会和中国医学科学院药物研究所。该作品由Elsevier B.V.制作和托管。

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 mechanical allodynia and hyperalgesia are not well understood. In the present study, we show with behavioral 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 alleviates vincristine-induced mechanical hypersensitivity. Electrophysiological results show that vincristine 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.