Trigeminal nerve root compression induced neuroinflammatory response promotes mechanical allodynia through the CGRP/SP-Piezo2 axis via Ca(2+) signaling.

Trigeminal neuralgia (TN) is one of the most severe types of neuropathic pain, but its pathological mechanisms remain unknown. In this study, we identified a unique neuroinflammatory response induced by chronic compression of trigeminal root entry zone (TREZ) in a TN rat model, establishing a connection between ATP-driven intracellular pathways and Piezo2-mediated mechanotransduction. Piezo2, the pain-related neuropeptide calcitonin gene-related peptide (CGRP) receptor complex CRLR-RAMP1 and the neuropeptide substance-P (SP) receptor NK1R are co-expressed on rat Merkel cells. Protein kinase C (PKC) plays a crucial role in upregulating Piezo2 and CGRP/SP expression in both the trigeminal ganglion (TG) and whisker pad, thereby facilitating orofacial mechanical allodynia in TN rats. Furthermore, the inhibition of cAMP signaling in the whisker pads effectively alleviated mechanical allodynia, while Piezo2 knockdown in both the TG and whisker pads significantly reversed db cAMP-induced allodynia. In vitro studies demonstrated that extracellular ATP not only enhances CGRP and SP expression but also induces Piezo2 expression through Ca(2+)-dependent activation of ERK1/2 and p38 MAPK cascades, mediated by specific transcription factors. These findings reveal that peripheral sensitization in TN is mediated through a Ca(2+)-CGRP/SP-Piezo2 positive feedback loop, dependent on the neuroinflammatory response along the TG neuron–Merkel cell axis as a prerequisite condition. This discovery provides a novel insight into the pathogenesis of TN. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s11658-025-00831-6.