Mapping Orofacial Nociceptive Pathways and Alterations Due to Inflammation

描述（由申请人提供）：损伤或感染的标志之一是炎症，这在口腔和相关组织中很常见。例如，炎症可能发生在牙髓（牙髓炎）、支撑牙列的结缔组织（牙龈炎和牙周炎）、咀嚼肌肉（肌炎）或颞下颌关节（关节炎或颞下颌关节紊乱/TMD）。涉及上述部位的炎症产生特征性症状：肿胀、发红、发热和疼痛。为了解决炎症性疼痛，这代表了患者发病率的主要来源，了解潜在的病理生理过程是至关重要的。伤害感觉是指有害刺激激活初级传入感觉神经元（伤害感受器），通过向中枢神经系统（CNS）发送信号产生疼痛，并通过在损伤部位释放炎症介质导致炎症的过程。痛觉感受器是一个异质性群体；分子（如离子通道）的差异表达有助于划分伤害感受器亚群（如TRPV1/热、TRPM8/冷和TRPA1/化学刺激物）（Basbaum, Bautista et al. 2009）。使用逆行标记和免疫组织化学研究了伤害感受器纤维的外周和中央投射模式（Gibbs， Melnyk等人，2011;Kim， Chung等人，2011）。然而，使用小鼠报告系的更强大和敏感的方法尚未被用于研究三叉神经网络中伤害感受器亚型所启动的途径，三叉神经网络支配口腔组织。此外，一些证据表明，描述和启动痛觉的特征离子通道的表达，

DESCRIPTION (provided by applicant): One of the hallmarks of injury or infection is inflammation, which is common in the oral cavity and associated tissues. For example, inflammation may arise in the dental pulp (pulpitis), connective tissues supporting the dentition (gingivitis and periodontitis), muscles involved in mastication (myositis), or temporomandibular joint (arthritis or temporomandibular disorder/TMD). Inflammation involving the aforementioned sites produces characteristic symptoms: swelling, redness, heat, and pain. To address inflammatory pain, which represents a major source of patient morbidity, it is critical to understand the underlying pathophysiological processes. Nociception is the process whereby noxious stimuli activate primary afferent sensory neurons (nociceptors) producing pain via signaling to the central nervous system (CNS) and contributing to inflammation by releasing inflammatory mediators at the site of injury. Nociceptors are a heterogeneous group; the differential expression of molecules (e.g., ion channels) serves to delineate nociceptor subgroups (e.g., TRPV1/heat, TRPM8/cold, and TRPA1/chemical irritants) (Basbaum, Bautista et al. 2009). The peripheral and central projection patterns of nociceptor fibers have been studied using retrograde labeling and immunohistochemistry (Gibbs, Melnyk et al. 2011; Kim, Chung et al. 2011). However, more powerful and sensitive methods using mouse reporter lines have not been employed to study the pathways initiated by nociceptor subtypes in the trigeminal network, which innervates oral cavity tissues. Furthermore, several lines of evidence suggest that the expression of the characteristic ion channels that delineate and initiate nociception and, consequently, the subpopulation profile of nociceptors in the inflamed tissue are altered by inflammation and the inflammatory milieu (Ji, Samad et al. 2002). In order to map of the expression profile and transduction pathway of nociceptor subtypes innervating the orofacial tissues we will employ a genetically modified, Cre-dependent, transsynaptically transported reporter strain of herpes simplex virus type 1, HSV129¿TK-TT, in conjunction with available strains of reporter mice (TRPV1-Cre, TRPM8-Cre, TRPA1-Cre, peripherin-Cre, and Nav1.8-Cre). The virus/mouse reporter system will fluorescently label selectively targeted nociceptor sub-types and their synaptic partners. To explore whether inflammation induces any alterations in the expression profile and transduction pathway of nociceptor subtypes we will develop mouse models of pulpitis, periodontitis, myositis, and arthritis/TMD and again utilize the virus/mouse reporter system and fluorescent imaging to identify any alterations in nociceptor expression and synaptic partners. Similarly, we will determine if administration of non-steroidal anti-inflammatory (NSAIDs) agents attenuates inflammation-induced alterations, if observed. Our work will be critical for a better understanding nociceptor pathways and processes underlying hypersensitivity pain and may ultimately lead to novel targets for its treatment.