Potentiation of PIEZO2 mechanically-activated currents in sensory neurons mediates vincristine-induced mechanical hypersensitivity.
10.1016/j.apsb.2023.05.010
- Author:
Mingli DUAN
1
;
Yurui JIA
1
;
Lifang HUO
1
;
Yiting GAO
1
;
Jia WANG
1
;
Wei ZHANG
2
;
Zhanfeng JIA
1
Author Information
1. Department of Pharmacology, Hebei Medical University, Shijiazhuang 050017, China.
2. Department of Pharmacology, Institute of Chinese Integrative Medicine, Hebei Medical University, Shijiazhuang 050017, China.
- Publication Type:Journal Article
- Keywords:
Dorsal root ganglion neurons;
Mechanical hypersensitivity;
Membrane tension;
Microtubules;
PIEZO2 mechanically-activated currents;
Peripheral neuropathic pain;
Vincristine;
Whole-cell patch-clamp recording
- From:
Acta Pharmaceutica Sinica B
2023;13(8):3365-3381
- CountryChina
- Language:English
-
Abstract:
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.
