Mapping Orofacial Nociceptive Pathways and Alterations Due to Inflammation

绘制口面部伤害感受通路和炎症引起的改变

• 批准号: 8991918
• 负责人: Joshua James Emrick
• 金额: $ 2.25万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8991918
• 关键词: Address; Afferent Neurons; Analgesics; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Arthritis; Attenuated; Bradykinin; Brain; C Fiber; Cells; Characteristics; Chemicals; Connective Tissue; Dental; Dental Pulp; Dental Pulp Necrosis; Dentition; Development; Disease; FOS gene; Fiber; Genes; Genetic; Gingivitis; Goals; Health; Heating; Herpesvirus 1; Hyperalgesia; Hypersensitivity; Immunohistochemistry; Infection; Inflammation; Inflammation Mediators; Inflammatory; Injury; Ion Channel; Irritants; Joints; Knock-in; Label; Lead; Light; Maps; Mastication; Masticatory muscles; Mechanics; Methods; Modality; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Mus; Muscle; Myofascial Pain Syndromes; Myositis; Neuraxis; Neurogenic Inflammation; Neurons; Nociception; Nociceptors; Non-Steroidal Anti-Inflammatory Agents; Oral cavity; Output; Pain; Pathway interactions; Patients; Pattern; Periodontitis; Peripheral; Population; Process; Production; Protons; Pulp Canals; Pulpitis; Redness; Reporter; Research; Signal Transduction; Site; Source; Spinal Cord; Staining method; Stains; Stimulus; Structure; Subgroup; Substance P; Swelling; Symptoms; Synapses; System; TRPV1 gene; Temporomandibular Joint; Temporomandibular Joint Disorders; Temporomandibular joint arthritis; Tissues; Tooth Loss; Tracer; Trigeminal Nuclei; Trigeminal System; Viral; Virus; Work; allodynia; anterograde transport; base; differential expression; extracellular; fluorescence imaging; inflammatory pain; molecular marker; mouse model; nerve supply; neurochemistry; novel; orofacial; peripherin; receptive field; somatosensory; targeted treatment

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.

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）、支持牙列的结缔组织（牙龈炎和牙周炎）、参与咀嚼的肌肉（肌炎）或颞下颌关节（关节炎或颞下颌关节紊乱病/TMD）。涉及上述部位的炎症会产生特征性症状：肿胀、发红、发热和疼痛。为了解决炎症性疼痛，这是一个主要的来源，病人的发病率，这是至关重要的，以了解潜在的病理生理过程。伤害感受是伤害性刺激激活初级传入感觉神经元（伤害感受器）的过程，其经由向中枢神经系统（CNS）的信号传导产生疼痛，并通过在损伤部位释放炎性介质而促成炎症。伤害感受器是一个异质组;分子的差异表达（例如，离子通道）用于描绘伤害感受器亚组（例如，TRPV 1/热、TRPM 8/冷和TRPA 1/化学刺激物）（Basbaum、Bautista等人，2009）。已经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，使用小鼠报告细胞系的更强大和灵敏的方法尚未被用于研究三叉神经网络中由伤害感受器亚型启动的通路，三叉神经网络支配口腔组织。此外，一些证据表明，描绘和启动伤害性感受的特征性离子通道的表达， 因此，炎症和炎症环境改变了发炎组织中伤害感受器的亚群分布（Ji，Samad等，2002）。为了绘制支配口面组织的伤害感受器亚型的表达谱和转导途径，我们将采用遗传修饰的、Cre依赖性的、跨突触转运的单纯疱疹病毒1型HSV 129 <$TK-TT报告菌株，连同可用的报告小鼠品系（TRPV 1-Cre、TRPM 8-Cre、TRPA 1-Cre、外周蛋白-Cre和Nav1.8-Cre）。病毒/小鼠报告系统将荧光标记选择性靶向的伤害感受器亚型及其突触配偶体。为了探索炎症是否诱导伤害感受器亚型的表达谱和转导途径的任何改变，我们将开发牙髓炎、牙周炎、肌炎和关节炎/TMD的小鼠模型，并再次利用病毒/小鼠报告系统和荧光成像来鉴定伤害感受器表达和突触伴侣的任何改变。同样，我们将确定非甾体类抗炎药（NSAID）的管理是否减弱炎症诱导的变化，如果观察到。我们的工作将是至关重要的，更好地了解伤害感受器的途径和过程的基础过敏性疼痛，并可能最终导致新的目标，其治疗。