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: 8526099
• 负责人: Joshua James Emrick
• 金额: $ 3.95万
• 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 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8526099
• 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; Heating; Herpesvirus 1; Hyperalgesia; Hypersensitivity; Image; Immunohistochemistry; Infection; Inflammation; Inflammation Mediators; Inflammatory; Injury; Ion Channel; Irritants; Joints; Knock-in Mouse; 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; extracellular; inflammatory pain; molecular marker; mouse model; nerve supply; neurochemistry; novel; orofacial; peripherin; public health relevance; receptive field; somatosensory; therapeutic target

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，牙髓（牙髓炎）、支持牙列的结缔组织（牙龈炎）中可能出现炎症。 ）牙周炎）、参与咀嚼的肌肉（肌炎）或颞下颌关节（关节炎或颞下颌疾病/TMD）。疼痛部位会产生特征性症状：肿胀、发红、发热和疼痛。为了解决患者发病的主要根源，了解伤害性刺激激活初级传入感觉神经元的潜在病理生理过程至关重要。 （伤害感受器）通过向中枢神经系统 (CNS) 发出信号产生疼痛，并通过在损伤部位释放炎症介质来促进炎症。伤害感受器是分子的差异表达组。 （例如，离子通道）用于描绘伤害感受器亚组（例如，TRPV1/热、TRPM8/冷和 TRPA1/化学刺激物）（Basbaum、Bautista 等人，2009）。伤害感受器纤维的外周和中央投射模式已被研究。使用逆行标记和免疫组织化学（Gibbs、Melnyk 等人，2011 年；Kim， Chung 等人，2011）然而，尚未采用使用小鼠报告系的更强大和更灵敏的方法来研究由三叉神经网络中的伤害感受器亚型启动的通路，此外，一些证据表明，描述和引发伤害感受的特征离子通道的表达， 因此，发炎组织中伤害感受器的亚群谱会因炎症和炎症环境而改变（Ji，Samad 等，2002）为了绘制支配口面部组织的伤害感受器亚型的表达谱和转导途径。一种经过基因改造、Cre 依赖性、跨突触转运的 1 型单纯疱疹病毒 HSV129 报告菌株TK-TT 与可用的报告小鼠品系（TRPV1-Cre、TRPM8-Cre、TRPA1-Cre、外周蛋白-Cre 和 Nav1.8-Cre）结合，病毒/小鼠报告系统将选择性地标记目标伤害感受器亚群。 -类型及其突触伙伴。为了探索炎症是否会引起伤害感受器亚型的表达谱和转导途径的任何改变，我们将开发牙髓炎的小鼠模型，牙周炎、肌炎和关节炎/TMD，并再次利用病毒/小鼠报告系统和荧光成像来识别伤害感受器表达和突触伙伴的任何变化，类似地，我们将确定非甾体抗炎 (NSAID) 药物的施用是否会减弱。如果观察到炎症引起的改变，我们的工作对于更好地了解过敏性疼痛背后的伤害感受器通路和过程至关重要，并可能最终找到治疗其的新靶点。