Cytokine pathways and orofacial pain

细胞因子途径和口面部疼痛

• 批准号: 7072268
• 负责人: KE REN
• 金额: $ 32.63万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7072268
• 关键词: Freund' s adjuvant; behavior test; cytokine; disease /disorder etiology; enzyme mechanism; gene expression; hyperalgesia; immunocytochemistry; inflammation; interleukin 1; interleukin 6; irritation /irritant; laboratory rat; neuroanatomy; neuropharmacology; oral facial pain; pathologic process; prostaglandin endoperoxide synthase; spinal trigeminal nucleus; striated muscles; temporomandibular joint syndrome; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Temporomandibular joint disorders (TMJDs), affect the musculoskeletal and joint tissues, are heterogeneous in origin, and are often not successfully treated. The etiology and pathology of these disorders remain unclear. Recent studies indicate that proinflammatory cytokines are associated with responses of the nervous system to tissue or nerve injury. Proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-l beta (IL-l beta) are released at the site of injury and contribute to an increased sensitivity of peripheral nociceptors. Importantly, the involvement of cytokines in persistent pain does not appear to be limited to peripheral sensitization. Intefleukin-l beta induces cyclooxygenase-2 (Cox-2) in the CNS. The activation of Cox-2 leads to central prostanoid production and may underlie the mechanisms of centrally mediated pain involving muscle and joint. Interestingly, inflammatory hyperalgesia is apparently mediated through an endogenous pain facilitatory pathway involving rostral ventromedial medulla (RVM), a pivotal structure in descending pain modulation. Few studies have directly addressed the role of proinflammatory cytokines in orofacial pain mechanisms, despite the findings that some cytokines are found in the synovial fluid of arthritic but not in healthy TMJs. Here we propose to use a rat model of irritant-induced hyperalgesiaJallodynia to investigate the contribution of peripheral and central cytokine pathways to persistent orofacial pain. Our major hypotheses are 1) cytokines and related pathways are activated after orofacial inflammation and play a critical role in the development of persistent hyperalgesia/allodynia and 2) the hyperalgesic effect of cytokines involves an interaction with central pain descending modulatory circuitry. Aim 1 will characterize the development of orofacial hyperaIgesia/allodynia induced by inflammatory irritants. Aim 2 will investigate the activation of cytokines and related pathways in the CNS after injection of inflammatory irritants into the masseter. Aim 3 will evaluate the effects of the inhibitors of cytokine and related Cox pathways on masseter hyperalgesia/allodynia. Aim 4 will examine the interaction of the pain descending modulatory circuitry and trigeminal pathways in cytokine-induced orofacial inflammatory hypersensitivity. In summary, we propose a set of experiments to examine the involvement of the cytokine cascade in persistent orofacial pain mechanisms. The findings will further our understanding of the etiology and pathology of muscle-related TMJDs and facilitate the search for novel and efficient I approaches for the management of persistent orofacial pain.

描述（由申请人提供）：颞下颌关节疾病（TMJDs），影响肌肉骨骼和关节组织，来源多样，通常无法成功治疗。这些疾病的病因和病理尚不清楚。最近的研究表明，促炎细胞因子与神经系统对组织或神经损伤的反应有关。促炎细胞因子如肿瘤坏死因子- α (tnf - α)和白细胞介素- 1 β (il - 1 β)在损伤部位释放，有助于外周伤害感受器的敏感性增加。重要的是，细胞因子在持续疼痛中的作用似乎并不局限于外周致敏。干扰素- 1 β在中枢神经系统诱导环氧化酶-2 （Cox-2）。Cox-2的激活导致中枢前列腺素的产生，可能是中枢介导的肌肉和关节疼痛机制的基础。有趣的是，炎症性痛觉过敏显然是通过内源性疼痛促进通路介导的，该通路涉及吻侧腹内侧髓质（RVM），这是下行疼痛调节的关键结构。很少有研究直接探讨促炎细胞因子在口面部疼痛机制中的作用，尽管发现一些细胞因子存在于关节炎患者的滑液中，而不在健康的颞下颌关节中。在这里，我们建议使用大鼠刺激性痛觉过敏模型来研究外周和中枢细胞因子通路对持续性口面部疼痛的贡献。我们的主要假设是：1)细胞因子和相关通路在口腔面部炎症后被激活，并在持续性痛觉过敏/异常性痛的发展中起关键作用；2)细胞因子的痛觉过敏作用涉及与中枢疼痛下降调节回路的相互作用。目的1将描述由炎症刺激引起的口面部消化亢进/异常性疼痛的发展。目的2将研究在咬肌注射炎症刺激物后，中枢神经系统中细胞因子的激活及其相关途径。目的3将评估细胞因子和相关Cox通路抑制剂对咬肌痛觉过敏/异常性痛的影响。目的4将研究疼痛下降调节回路和三叉神经通路在细胞因子诱导的口面部炎症超敏反应中的相互作用。总之，我们提出了一组实验来研究细胞因子级联在持续口面部疼痛机制中的参与。该发现将进一步加深我们对肌肉相关TMJDs的病因和病理的理解，并促进寻找新的有效的方法来治疗持续性口面部疼痛。