Pain related to temporomandibular disorders is a highly prevalent entity of orofacial pain, a debilitating chronic pain condition. Chronic orofacial pain is difficult to treat because its mechanisms remain largely unclear. Previous studies have indicated that both neuronal and non-neuronal (glial) elements play a critical role in the cellular mechanisms of pathological pain. It has been shown that peripheral nerve injury and inflammation can induce spinal glial activation and that proinflammatory cytokines can upregulate the expression of spinal N-methyl-D-aspartate receptors (NMDAR) mediated at least in part through activation of intracellular protein kinase C. Our preliminary data have demonstrated that the development of pain behavior induced by complete Freund's adjuvant injected into the temporomandibular joint (TMJ) in rats was associated with an increased expression of both interleukin-6 (IL-6) and NMDAR within the ipsilateral trigeminal subnucleus caudalis. These findings support the notion that interactions between neuronal and glial elements may also play a critical role in the cellular mechanisms of orofacial pain. In this grant, we propose to systematically examine the interaction between trigeminal glial activation and the expression of neuronal NMDAR and its role in the pathogenesis of TMJ pain behavior in rats. Our main hypothesis is that TMJ inflammation would induce glial activation and increases in proinflammatory cytokines such as IL-6 within trigeminal subnucleus caudalis, which would lead to the upregulation of neuronal NMDAR through a chain of cellular events including IL-6 receptor signaling, protein kinase C, and transcriptional nuclear factor-kappa B, contributing to TMJ pain behavior. This hypothesis will be examined using behavioral and pharmacological tools, immunohistochemistry, Western blot, in situ hybridization, real-time RT-PCR, protein kinase activity assay, electrophoretic mobility shift assay, and enzyme-linked immunosorbent assay to accomplish three specific aims: 1) to evaluate the functional role of glial-neuronal interactions in TMJ pain behavior;2) to examine trigeminal glial expression and its relationship to proinflammatory cytokine changes induced by TMJ inflammation;and 3) to investigate a cellular mechanism contributing to the expression of trigeminal neuronal NMDAR following glial activation. The anticipated results could suggest new therapeutic options for managing orofacial pain. Project Narrative The effectiveness of treating orofacial pain with non-steroidal anti-inflammatory drugs, tricyclic antidepressants, and opioid analgesics is often limited by these drugs'side effects and, in some cases, unwanted long-term consequences. The outcome of this study could lead to the development of new therapeutic tools to treat often intractable and debilitating clinical orofacial pain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE018214-05
Application #
8300030
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Kusiak, John W
Project Start
2008-08-04
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$346,955
Indirect Cost
$150,935
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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