Modeling temporomandibular joint disorders pain: role of transient receptor potential ion channels

颞下颌关节疾病疼痛建模：瞬时受体电位离子通道的作用

基本信息

批准号：
9595624
负责人：
Yong Chen
金额：
$ 37.72万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9595624
关键词：
Acute Pain Address Affect Afferent Neurons Age Agonist American Animal Model Arthritis Attenuated Biological Assay Bite Force Calcitonin Gene-Related Peptide Calcitonin-Gene Related Peptide Receptor Cells Charge Chronic Data Dependence Development Diagnosis Disease model Economic Burden Effectiveness Face Gene Expression Gene Targeting Genetic Goals Hypersensitivity Individual Inflammatory Injections Injury Integral Membrane Protein Ion Channel Jaw Knock-out Knockout Mice Knowledge Lidocaine Ligation Masseter Muscle Masticatory muscles Measures Mediating Medical Messenger RNA Methods Modeling Molecular Mus Neurobiology Neurogenic Inflammation Neurons Nociception Orofacial Pain Pain Pain Assessment Tool Pathogenesis Pathogenicity Pathologic Patients Peptides Permeability Pharmacology Plant Roots Play Pre-Clinical Model Publishing Quality of life Reporting Research Residual state Role Signal Transduction Signaling Molecule Societies Stimulus Structure of trigeminal ganglion Syndrome TRPV1 gene Temporomandibular Joint Temporomandibular Joint Disorders Temporomandibular joint disorder pain Tendon structure Testing Therapeutic Time Tissues Trigeminal Pain Up-Regulation Vertebrates base chronic pain chronic painful condition clinically relevant combat disability experience innovation insight joint injury loss of function member mouse model mutant neural circuit novel novel diagnostics opioid epidemic pain behavior preference receptor response selective expression spontaneous pain therapeutic target tool

项目摘要

Masticatory and spontaneous pain associated with temporomandibular joint disorders (TMJD) is a prevalent and significant contributor to orofacial pain. TMJD pain presents for too many patients as a debilitating chronic trigeminal pain condition that impacts their lives overwhelmingly. TMJD pain is undoubtedly a serious unmet medical need. Unfortunately, current treatments for TMJD pain are lacking in effectiveness, primarily due to: 1) shortcomings of current TMJD preclinical models to faithfully model patients’ cardinal complaints; 2) the elusiveness of the molecular, cellular and neural-circuit mechanisms that underlie TMJD pain. Our proposal seeks to address both key issues. TRP channels relevant for pain, pain-TRPs, expressed by trigeminal ganglion (TG) sensory neurons, have been critically implicated in both acute and chronic pain and represent possible bona-fide targets for development of rationally-guided anti-pain strategies. However, their direct-mechanistic roles in masticatory and spontaneous pain of TMJD are elusive and in need of clarification. In our previously published and preliminary studies, we developed and validated bite force and conditioned place preference assays for measuring masticatory and spontaneous pain, induced by inflammatory injury to the TMJ or ligation of the tendon of the masseter muscle, both methods evoking long- lasting pain-behavior. Using bite force metrics, we found TMJ inflammation-induced masticatory pain to be significantly attenuated, but not fully reversed in Trpv4 knockout (KO) mice, suggesting that the residual pain might be mediated by other pain-TRPs. Our gene expression studies demonstrated that TRPV1 and TRPA1 were up-regulated in the TG in response to TMJ inflammation, moreover, in a Trpv4-dependent manner. Therefore, we hypothesize that TRPV1 and TRPA1, like TRPV4, contribute to TMJD pain, in particular via the ensemble of their signaling. This hypothesis will be examined using our two models of TMJ injury. Pain- behavior read-out metrics will be bite force and conditioned place preference. We will employ a combination of pharmacologic and genetic loss-of-function approaches for the targeted genes as well as selective neuronal silencing using specific TRP agonists combined with positively charged lidocaine derivative (QX314). Also, we will target TMEM100, a recently discovered adaptor of TRPV1-TRPA1 functional interactions, by using a TMEM100-inhibitory peptide for local injections and sensory neuron-TMEM100 conditional knockout mice. Our three Specific Aims will examine the contribution of TRPV1, TRPV4, TRPA1 and TMEM100 to pathogenesis of TMJD pathologic pain including assessment of neurogenic inflammation, a pathogenic mechanism for which we have collected exciting pilot data revealing its key contribution to TMJD pain. Successfully addressing our ambitious, yet feasible Aims will provide a rich yield of new fundamental insights and also readily translatable new knowledge. These will empower us to overcome a serious unmet medical need that our society faces in the age of the “opioid epidemic”, namely chronic TMJD pain, by applying a rationally-guided new strategy.

与颞下颌关节疾病（TMJD）有关的咀嚼性和赞助疼痛是一个流行而重要的是口服疼痛。 TMJD疼痛为太多患者带来了使慢性三叉神经疼痛状况衰弱，这绝大多数会影响他们的生活。 TMJD疼痛无疑是严重未满足的医疗需求。不幸的是，目前对TMJD疼痛的治疗缺乏有效性，主要由于：1）当前TMJD临床前模型的缺点，以忠实地对患者的红衣主教建模投诉； 2）分子，细胞和神经电路机制的弹性，这些机制是TMJD的基础疼痛。我们的建议旨在解决这两个关键问题。与疼痛，疼痛TRP相关的TRP通道表达通过三叉神经节（TG）感觉神经元，与急性和慢性疼痛有关并代表可能的善意目标，用于制定理性引导的反潘恩策略。然而，它们在TMJD的咀嚼和赞助商中的直接机械角色是难以捉摸的，需要澄清。在我们先前发表的初步研究中，我们开发并验证了咬合力，有条件地点偏好测定测量咀嚼性和赞助疼痛的测定法咬伤肌肉肌肉的TMJ炎症损伤或结扎，两种方法都引起了长期持久的疼痛行为。使用咬合力指标，我们发现TMJ炎症引起的咀嚼性疼痛为显着减弱，但在TRPV4敲除（KO）小鼠中没有完全逆转，表明残留疼痛可能是由其他疼痛trps介导的。我们的基因表达研究表明TRPV1和TRPA1 此外，在TMJ注入的情况下，在TG中以TRPV4依赖性方式被上调。因此，我们假设TRPV1和TRPA1（如TRPV4）尤其会导致TMJD疼痛，特别是通过信号的合奏。该假设将使用我们的TMJ损伤模型进行检查。疼痛- 行为读出的指标将是咬合力和条件的地点偏好。我们将采用组合针对靶向基因以及选择性神经元的药理和遗传丧失方法使用特定的TRP激动剂结合带正电的利多卡因衍生物（QX314）的沉默。另外，我们将通过使用A靶标TMEM100，这是最近发现的TRPV1-TRPA1功能相互作用的适配器 TMEM100抑制性肽用于局部注射和感觉神经元-TMEM100条件敲除小鼠。我们的三个具体目的将研究TRPV1，TRPV4，TRPA1和TMEM100对发病机理的贡献 TMJD病理疼痛，包括评估神经源性感染，一种致病机制我们收集了令人兴奋的试点数据，揭示了其对TMJD疼痛的关键贡献。成功地解决了我们的问题雄心勃勃但可行的目标将提供丰富的新基本见解，并且很容易翻译新知识。这些将使我们能够克服我们社会面临的严重未满足的医疗需求通过采用合理引导的新策略，“阿片类流行病”的年龄，即慢性TMJD疼痛。