A dual role of PIEZO2 in neuropathic pain: driving peripheral sensitization and enabling mechanical loading-induced analgesia.

Abstract

Background: Mechanotherapy, a form of mechanical loading (ML), effectively relieves tactile allodynia-associated neuropathic pain by targeting sensitization points stimulated by PIEZO2, a mechanosensitive ion channel. However, the molecular mechanisms underlying peripheral sensitization and ML-induced analgesia remain unclear. The study aimed to investigate the role of PIEZO2 in neuroinflammatory processes in a rat model of chronic compression injury (CCD) of dorsal root ganglia (DRG).

Methods: Mechanical allodynia was assessed via paw withdrawal threshold in male Sprague-Dawley rats. ML was applied at intensities of 2.5-5 N, targeting either sensitization or non-sensitization points, with or without intrathecal administration of the PIEZO2 channel blocker D-GsMTx4. Behavioral assays, patch-clamp electrophysiology, western blot, enzyme-linked immunosorbent assay, RNA sequencing, and non-targeted metabolomics of skin, DRG, and spinal dorsal horn (SDH) were performed to evaluate neuronal excitability, inflammatory markers, and omics-level responses.

Results: CCD upregulates PIEZO2 expression in all tissues, indicating mechanical hypersensitivity and neuroinflammation. ML alleviates allodynia while suppressing SDH inflammation and MAPK signaling, especially at 5 N. Functionally blocking PIEZO2 attenuates ML-induced analgesia and downregulates rectifier K⁺ currents in DRG neurons. ML and the inhibition of PIEZO2 function exhibit similar lipid metabolism profiles and downregulate PGE₂ and all-trans-5,6-epoxyretinoic acid.

Conclusions: PIEZO2 is essential for peripheral sensitization, as well as ML-induced analgesia, anti-inflammatory, and ion-channel-modulating effects, which may inform the development of novel non-pharmacological strategies.