Involvement of trigeminal ganglionic Nav1.7 in hyperalgesia of inflamed temporomandibular joint is dependent on ERK1/2 phosphorylation of glial cells in rats

Background: Inflammation is a major cause of temporomandibular disorder-related pain. The Na(v)1.7 sodium channel has a critical function in pain perceptions. However, whether and how Na(v)1.7 in the trigeminal ganglion is involved in temporomandibular joint (TMJ) inflammatory pain remains to be examined. Methods: TMJ inflammation was induced by complete Freund's adjuvant in female rats. The expression of trigeminal ganglionic Na(v)1.7 and other sodium channels was examined using real-time polymerase chain reaction or Western blotting. Immunohistofluorescence with fluorescent retrograde neuronal tracer DiI was used to confirm Na(v)1.7 in the trigeminal neurons innervating TMJ. The functions of trigeminal ganglionic Na(v)1.7 and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation were blocked with the microinjection of the Na(v)1.7 antibody or U0126 into the trigeminal ganglion. Head withdrawal threshold and food intake was measured to evaluate TMJ nociceptive responses. Results: TMJ inflammation significantly up-regulated Na(v)1.7 mRNA and protein; however, the mRNA of Na(v)1.3 was not affected and those of Na(v)1.8 and Na(v)1.9 were only slightly up-regulated. TMJ inflammation specifically induced Na(v)1.7 in the neurons innervating TMJ. In addition, blocking the Na(v)1.7 function significantly attenuated the hyperalgesia of the inflamed TMJ. Moreover, TMJ inflammation up-regulated ERK1/2 phosphorylation only in the glials; blocking ERK1/2 phosphorylation in the glials blocked Na(v)1.7 up-regulation in the neurons and correspondingly attenuated the hyperalgesia of the inflamed TMJ. Conclusions: Trigeminal ganglionic Na(v)1.7 has an important function in the hyperalgesia of the inflamed TMJ, which is dependent on the communication with the satellite glials.