Aims To investigate cellular changes in the spinal trigeminal nucleus (STN) and trigeminal ganglion associated with trigeminal nociception mediated by inflammation in the temporomandibular joint (TMJ) capsule. Methods Sprague Dawley rats (n=86) were utilized to investigate cellular and behavioral responses to prolonged TMJ inflammation caused by bilateral injection of complete Freund’s adjuvant (CFA) in the capsule. To investigate the cellular effects of protein kinase A (PKA) in the STN, rats were injected intrathecally with the selective PKA inhibitor KT5720 prior to injection of CFA into both TMJ capsules. Levels of calcitonin gene-related peptide (CGRP), active PKA, and ionized calcium-binding adapter molecule 1(Iba1) in the STN and expression of phosphorylated ERK (p-ERK) in the trigeminal ganglion were determined by immunohistochemistry (n ≥ 3). Nocifensive head withdrawal responses to mechanical stimulation of the cutaneous tissue over the TMJ were monitored following CFA injection in the absence or presence of KT5720 (n = 7). Statistical analysis was performed using parametric ANOVA tests. Results Intrathecal injection of KT5720 significantly inhibited the stimulatory effect of CFA on levels of CGRP, PKA, and the microglial protein Iba1 in the STN. In addition, administration of KT5720 decreased the average number of CFA-induced nocifensive withdrawal responses to mechanical stimulation and the CFA-mediated increase in p-ERK expression in the ganglion. Conclusion These findings provide evidence that elevated PKA activity in the STN promotes cellular events temporally associated with trigeminal nociception caused by prolonged TMJ inflammation.