Targeting Piezo1 in Peripheral Nerves: Mechanotransduction and Electrostimulation for Pain Control

Piezo1-mediated mechanotransduction (PMT) is a fundamental mechanism in peripheral sensory physiology, converting mechanical stimuli into electrochemical signals that influence neuronal excitability, inflammation, and pain perception. Mechanosensitive (MS) ion channels have been identified as the major contributors to membrane tension sensing and mechanobiological signaling in neuronal and non-neuronal cells. Piezo1 has been implicated in peripheral pain development and maintenance including inflammatory and neuropathic pain through its modulation of Ca2+-dependent signaling pathways, reactive oxygen species production, inflammasome activation, cytoskeleton reorganization, and neuroimmune interactions. Piezo1 is widely expressed in DRG neurons, Schwann cells, keratinocytes, immune cells, and endothelial cells, suggesting a complex role of Piezo1 in peripheral nociceptive processing and mechanical hypersensitivity. Recent advances in pharmacological modulation, genetic targeting, and neuromodulation technologies have brought new insight into the therapeutic potential of Piezo1 in peripheral pain. Preclinical models have demonstrated the modulatory effects of small-molecule agonists and antagonists (e.g., Yoda-series compounds and Dooku1) and gene-silencing techniques on Piezo1 mechanotransduction and inflammatory responses. Meanwhile, the application of peripheral nerve stimulation, transcutaneous electrical nerve stimulation, ultrasound neuromodulation, and bioelectronics interfaces are increasingly recognized as important electrostimulation and neuromodulation strategies for pain control and indirect regulators of Piezo1-mediated mechanotransduction by modulating the membrane biophysics, cytoskeletal dynamics, and intracellular calcium signaling. This Review aims to critically evaluate the mechanistic and therapeutic significance of Piezo1 in peripheral pain, with particular emphasis on its potential as a therapeutic target for pain management. It further covers the novel intersection of mechanotransduction and electrostimulation therapies and potential effects of electrical stimulation and neuromodulation on Piezo1-associated signaling and peripheral pain pathways. The review also examines current limitations and translational barriers to Piezo1-targeted therapies, while highlighting emerging strategies such as precision medicine, sonogenetics, nanotechnology-enabled delivery systems, and adaptive neuromodulator platforms for the development of targeted and personalized pain therapeutics.