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

作　　者：Mingli Duan Yurui Jia Lifang Huo Yiting Gao Jia Wang Wei Zhang Zhanfeng Jia 

机构地区：[1]Department of Pharmacology,Hebei Medical University,Shijiazhuang 050017,China [2]Center of Innovative Drug Research and Evaluation,Institute of Medical Science and Health,Hebei Medical University,Shijiazhuang 050017,China [3]The Key Laboratory of Neural and Vascular Biology,Ministry of Education,Shijiazhuang 050017,China [4]The Key Laboratory of New Drug Pharmacology and Toxicology,Shijiazhuang 050017,China [5]The Hebei Collaboration Innovation Center for Mechanism,Diagnosis and Treatment of Neurological and Psychiatric Disease,Shijiazhuang 050017,China [6]Department of Pharmacology,Institute of Chinese Integrative Medicine,Hebei Medical University,Shijiazhuang 050017,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第8期3365-3381,共17页药学学报（英文版）

基　　金：supported by NSFC grant 81571080(Zhanfeng Jia,China),81872848(Wei Zhang,China);the Central Government Guiding Local Funding Project for Scientific and Technological Development 206Z7703G(Zhanfeng Jia,China);Key Project and Cultivation Project of Precision Medicine Joint Fund of Natural Science Foundation of Hebei Province H2021206406(Zhanfeng Jia,China),H2022206211(Wei Zhang,China)and H2020206165(Zhanfeng Jia,China);Science and Technology Project of Hebei Education Department ZD2020107(Zhanfeng Jia,China);Science Fund for Creative Research Groups of Natural Science Foundation of Hebei Province H2020206474,China.

摘　　要：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 vincristineinduced mechanical allodynia and hyperalgesia in rats.Targeting to inhibit PIEZO2 channels may be an effective analgesic method to attenuate vincristine-induced mechanical hypersensitivity.

关 键 词：VINCRISTINE Peripheral neuropathic pain Mechanical hypersensitivity Dorsal root ganglion neurons PIEZO2mechanically-activated currents 

分 类 号：TG1[金属学及工艺—金属学]