The long-term goals of the proposed studies are to understand the cellular/molecular mechanisms regulating neuronal-glial interactions during temporomandibular joint (TMJ) pathology and therapy. Neuronal-glial interactions play a key role during inflammation and pain yet the cellular mechanisms are not well understood. The proposed studies will focus on the roles of calcitonin gene-related peptide (CGRP), nitric oxide (NO), and mitogen-activated protein (MAP) kinases in initiating and maintaining TMJ inflammation. Elevated levels of the neuropeptide CGRP and multifunctional signaling molecule NO in synovial fluid of arthritic TMJs correlate with chronic inflammation and pain and contribute to TMJ degeneration. Recently, MAP kinases have been reported to be important in the underlying pathology of inflammatory diseases. We will test the hypothesis that neuronal release of CGRP activates trigeminal glial cells causing increases in secondary messengers and induction of specific MAP kinases and iNOS that stimulate production and release of NO. Importantly, we have shown that NO increases CGRP synthesis and release from trigeminal neurons. Thus, we will investigate the cellular mechanisms involved in neuronal-glial interactions that help to sustain a pathological inflammatory cycle central to chronic inflammation and pain associated with TMJ disorders (TMD). In addition, we will determine the role of MAP kinase phosphatases, which function to regulate MAP kinase activity and thus, reduce inflammation. To accomplish these goals, primary cultures of trigeminal ganglia and trigeminal ganglia organ cultures as well as in vivo studies in a model of TMJ inflammation will be utilized. Results from these studies will provide insight into the molecular mechanisms by which CGRP release from trigeminal neurons modulates iNOS gene expression in glial cells that is likely to facilitate identification of new molecular targets for treating TMD and other orofacial diseases. It is estimated that 11 million American adults now suffer from symptoms attributed to TMD. Since TMD predominantly affects women of childbearing age and can be associated with significant morbidity, these disorders have significant social and economic ramifications. In the search for new treatment modalities to treat acute inflammation and chronic pain, a thorough understanding of the signaling molecules and pathways involved in neuronal and glial cell activation within the trigeminal ganglion would be beneficial. ? ? ?

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Special Emphasis Panel (ZDE1-GH (50))
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Kusiak, John W
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Missouri State University
Schools of Arts and Sciences
United States
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Durham, Zachary L; Hawkins, Jordan L; Durham, Paul L (2017) Tumor necrosis factor-Alpha stimulates cytokine expression and transient sensitization of trigeminal nociceptive neurons. Arch Oral Biol 75:100-106
Hawkins, Jordan L; Durham, Paul L (2016) Prolonged Jaw Opening Promotes Nociception and Enhanced Cytokine Expression. J Oral Facial Pain Headache 30:34-41
Hawkins, J L; Denson, J E; Miley, D R et al. (2015) Nicotine stimulates expression of proteins implicated in peripheral and central sensitization. Neuroscience 290:115-25
Durham, Paul L; Masterson, Caleb G (2013) Two mechanisms involved in trigeminal CGRP release: implications for migraine treatment. Headache 53:67-80
Cady, Ryan J; Denson, Jennifer E; Durham, Paul L (2013) Inclusion of cocoa as a dietary supplement represses expression of inflammatory proteins in spinal trigeminal nucleus in response to chronic trigeminal nerve stimulation. Mol Nutr Food Res 57:996-1006
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Vause, Carrie V; Durham, Paul L (2012) Identification of cytokines and signaling proteins differentially regulated by sumatriptan/naproxen. Headache 52:80-9
Durham, Paul L; Cady, Roger (2011) Insights into the mechanism of onabotulinumtoxinA in chronic migraine. Headache 51:1573-7
Masterson, Caleb G; Durham, Paul L (2010) DHE repression of ATP-mediated sensitization of trigeminal ganglion neurons. Headache 50:1424-39
Cady, Ryan J; Durham, Paul L (2010) Cocoa-enriched diets enhance expression of phosphatases and decrease expression of inflammatory molecules in trigeminal ganglion neurons. Brain Res 1323:18-32

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