Cytokine pathways and orofacial pain

描述(申请人提供)：颞下颌关节紊乱病(TMJD)，影响肌肉骨骼和关节组织，起源不同，通常没有成功的治疗。这些疾病的病因和病理仍不清楚。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和白细胞介素2-Lβ(IL-Lβ)在损伤部位被释放，并有助于增加外周伤害性感受器的敏感性。重要的是，细胞因子在持续性疼痛中的作用似乎并不局限于外周敏化。Lβ诱导中枢环氧合酶-2(COX-2)的表达。环氧合酶-2的激活导致中枢前列腺素的产生，并可能是中枢介导的肌肉和关节疼痛机制的基础。有趣的是，炎性痛敏显然是通过内源性疼痛易化通路介导的，该通路涉及头端腹内侧延髓(RVM)，RVM是下行疼痛调制的关键结构。很少有研究直接讨论促炎细胞因子在口面部疼痛机制中的作用，尽管有研究发现在关节炎患者的滑液中发现了一些细胞因子，但在健康的TMJ中没有发现。在这里，我们建议使用刺激性痛觉过敏的大鼠模型来研究外周和中枢细胞因子通路在持续性口面部疼痛中的作用。我们的主要假设是：1)细胞因子及相关通路在口腔面部炎症后被激活，并在持续性痛觉过敏/痛觉过敏的发生发展中起关键作用；2)细胞因子的痛敏效应涉及与中枢痛觉下行调制回路的相互作用。目的1研究炎性刺激引起的口面部痛觉过敏/超敏的发展过程。目的研究咬肌内注射炎性刺激物后中枢神经系统细胞因子的激活及其相关途径。目的3评价细胞因子抑制剂及其相关的环氧合酶通路在咬肌痛觉过敏/痛敏中的作用。目的4研究细胞因子诱导的口腔面部炎症超敏反应中疼痛下行调制通路和三叉神经通路的相互作用。综上所述，我们提出了一系列实验来检验细胞因子级联反应在持续性口面部疼痛机制中的作用。这些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，并有助于寻找新的和有效的方法来治疗持续性口面部疼痛。

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.