Estrogen Effects on Signaling in Trigeminal Ganglion during TMJ Inflammation

During temporomandibular joint inflammation, release of neurotransmitters, cytokines and hormones modulate trigeminal neuronal output. Estrogen, for example, is known to alter gene transcription via a “genomic” response in which the hormone-receptor complex binds to a response element within the target gene's promoter. However, the extent to which estrogen activates second messenger cascades has not been fully characterized. OBJECTIVES: The objectives of our study were to investigate the activation of two important signaling pathways, AKT and MAPK, in the trigeminal ganglion after acute temporomandibular joint (TMJ) injury and to determine the influence of estrogen on their activation. METHODS: TMJ inflammation was induced via bilateral injection of complete Freund's adjuvant (CFA) into the TMJ of adult female ovariectomized (OVX) Sprague Dawley rats in the absence and presence of exogenous estrogen (low and high doses). Additional OVX animals were used as saline controls. The trigeminal ganglia were harvested 48 hours after CFA treatment and snap-frozen until analyzed. Western blot and enzymatic assays were used to assess changes in MAPK expression and phosphorylation. RESULTS: CFA stimulation induced p44/42 MAPK phosphorylation and activity, an effect which was enhanced by low estrogen treatment but not high estrogen. After 48 hours, AKT phosphorylation levels were comparable to controls. Pretreatment with both low and high doses of estrogen greatly enhanced AKT phosphorylation in CFA-stimulated animals when compared to saline controls and CFA alone. CONCLUSIONS: To our knowledge, this is the first report of AKT activation in the trigeminal ganglia during TMJ inflammation. Futhermore, our results suggest that estrogen has differential effects on the inflammatory response which may be mediated through a variety of intracellular mechanisms including multiple “nongenomic” signaling cascades.

This work was supported by the Baylor Oral Health Foundation.