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

Mingli Duan; Yurui Jia; Lifang Huo; Yiting Gao; Jia Wang; Wei Zhang; Zhanfeng Jia

doi:10.1016/j.apsb.2023.05.010

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

Acta Pharm Sin B. 2023 Aug;13(8):3365-3381. doi: 10.1016/j.apsb.2023.05.010. Epub 2023 May 15.

Authors

Mingli Duan^{1

2

3

4

5}, Yurui Jia^{1

2

3

4

5}, Lifang Huo^{1

2

3

4

5

6}, Yiting Gao^{1

2

3

4

5}, Jia Wang^{1

2

3

4

5}, Wei Zhang^{6

2

3}, Zhanfeng Jia^{1

2

3

4

5}

Affiliations

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.

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.

Keywords: Dorsal root ganglion neurons; Mechanical hypersensitivity; Membrane tension; Microtubules; PIEZO2 mechanically-activated currents; Peripheral neuropathic pain; Vincristine; Whole-cell patch-clamp recording.