LPA/LPAR signaling drives temporomandibular disorders–like pain through regulating the expression and sensitization of PIEZO2

Temporomandibular disorders (TMD) pain is the most common orofacial pain with limited effective treatments. Here, we observed elevated lysophosphatidic acid (LPA), a bioactive lipid, in blood, trigeminal ganglion (TG), and peri-temporomandibular joint (TMJ) tissues in mouse models of TMD-like pain induced by TMJ inflammation or masseter muscle injury. Notably, LPA levels were also elevated in TMD patients' blood and positively correlated with their pain intensity. LPA receptors (LPAR) 1 and 3 were expressed in mouse and human TG neurons and upregulated in TMD-like pain models. Inhibition or knockout of LPAR1 or LPAR3 attenuated TMD-like pain, while LPA injection into the TMJ or masseter muscle evoked pain. Furthermore, we demonstrated that LPA/LPAR signaling upregulates and sensitizes PIEZO2, a mechanosensitive ion channel, in TG neurons via extracellular signal-regulated kinase (ERK). Specific deletion or inhibition of PIEZO2 and suppression of ERK activation in TG neurons mitigated TMD-like pain. These findings suggest that LPA/LPAR signaling drives TMD-like pain via PIEZO2, offering potential therapeutic targets.