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.

Public Health Relevance

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 #
5R01DE018214-04
Application #
8119446
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Kusiak, John W
Project Start
2008-08-04
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
4
Fiscal Year
2011
Total Cost
$339,946
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Ding, Weihua; You, Zerong; Shen, Shiqian et al. (2017) An Improved Rodent Model of Trigeminal Neuropathic Pain by Unilateral Chronic Constriction Injury of Distal Infraorbital Nerve. J Pain 18:899-907
Mi, Wenli; Wang, Shuxing; You, Zerong et al. (2017) Nortriptyline Enhances Morphine-Conditioned Place Preference in Neuropathic Rats: Role of the Central Noradrenergic System. Anesth Analg 125:1032-1041
Zhang, Shuzhuo; You, Zerong; Wang, Shuxing et al. (2016) Neuropeptide S modulates the amygdaloidal HCN activities (Ih) in rats: Implication in chronic pain. Neuropharmacology 105:420-433
Rusanescu, Gabriel; Mao, Jianren (2014) Notch3 is necessary for neuronal differentiation and maturation in the adult spinal cord. J Cell Mol Med 18:2103-16
Zhang, Shuzhuo; Jin, Xu; You, Zerong et al. (2014) Persistent nociception induces anxiety-like behavior in rodents: role of endogenous neuropeptide S. Pain 155:1504-15
Song, Li; Wang, Shuxing; Zuo, Yunxia et al. (2014) Midazolam exacerbates morphine tolerance and morphine-induced hyperactive behaviors in young rats with burn injury. Brain Res 1564:52-61
Li, Na; Lim, Grewo; Chen, Lucy et al. (2013) Spinal expression of Hippo signaling components YAP and TAZ following peripheral nerve injury in rats. Brain Res 1535:137-47
Mao, Jianren (2012) Current challenges in translational pain research. Trends Pharmacol Sci 33:568-73
Wang, Shuxing; Song, Li; Tan, Yonghui et al. (2012) A functional relationship between trigeminal astroglial activation and NR1 expression in a rat model of temporomandibular joint inflammation. Pain Med 13:1590-600
Kim, Hyangin; Chen, Lucy; Lim, Grewo et al. (2012) Brain indoleamine 2,3-dioxygenase contributes to the comorbidity of pain and depression. J Clin Invest 122:2940-54

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