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

Abstract

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). 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. 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. 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.