Gut Serotonin Modulates Tmj Pain Via Cgrp And Microglia Activation

Serotonin as a key neurotransmitter in the gut-brain axis, plays a significant role in chronic pain.This study aims to investigate how gut-derived serotonin regulates temporomandibular joint osteoarthritis (TMJOA)-related pain by modulating calcitonin gene-related peptide (CGRP) expression in trigeminal ganglion (TG). TMJOA patients(Approved by the ethics committee) were stratified into enteritis and non-enteritis groups based intestinal inflammation. The orofacial pain threshold was measured by quantitative sensory testing. In C57BL/6 mice (8 weeks, male), intestinal inflammation was induced by administering 2% dextran sulfate sodiumin drinking water, TMJOA was modeled by injecting complete Freund’s adjuvant. The orofacial pain threshold were evaluated using von Frey filaments. Serum and central nervous system levels of serotonin and tryptophan were measured by ELISA. Immunohistochemistry detected serotonin, CGRP, and Iba1 in the gut, TG, and central nervous system. Polymerase chain reaction was used to evaluate microglial activation in BV2 cells after CGRP stimulation, while Western blotting evaluated CGRP expression in cultured neurons after serotonin treatment. TMJOA patients with enteritis (19/43) and TMJOA mice exhibited significantly lower orofacial pain thresholds. Compared to the TMJOA group, mice with enteritis showed elevated gut-derived serotonin levels, reduced central serotonin synthesis and expression, and suppressed CGRP expression and microglial activation in the TG. In vitro, serotonin induced neuronal CGRP release, inhibiting CGRP-mediated microglial activation. Gut-derived serotonin modulates TMJ pain via the CGRP/microglia pathway in the CNS, highlighting its role in pain regulation through the gut-brain axis.