Central Role Of CGRP And Protein Kinase A In Promoting Trigeminal Sensitization In An In Vivo Model Of Temporomandibular Joint Disorder

Temporomandibular joint disorder (TMJD) pathology involves activation of primary nociceptive neurons that promote peripheral sensitization and excitation of second order neurons implicated in the development of central sensitization and hyperalgesia. Elevated levels of the neuropeptide calcitonin gene-related peptide (CGRP) in the joint capsule and upper spinal cord are implicated in the underlying pathology of TMJD. The cellular effects of CGRP are mediated by increases in the activity of the protein kinase A (PKA), a protein known to cause neuronal sensitization. In my study, I tested the hypothesis that elevated levels of CGRP in the upper spinal cord promote both central and peripheral sensitization of trigeminal nociceptive neurons. To inhibit the cellular effects of CGRP, rats were injected intrathecally (i.t.) with CGRP8-37, a CGRP antagonist, or with KT 5720, a PKA inhibitor, before injection of CFA into both TMJ capsules. Treatment with CGRP8-37 or KT 5720 reduced CGRP, PKA, Iba1, and cytokine expression. Nocifensive withdrawal response to mechanical stimulation was reduced by KT 5720 treatment. In conclusion, results from my study provide evidence that CGRP and PKA are critical in promoting central and peripheral sensitization of trigeminal nociceptive neurons