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

• 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
• 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

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.

与颞下颌关节紊乱 (TMJD) 相关的咀嚼痛和自发性疼痛是一种 口面部疼痛的普遍且重要的因素。颞下颌关节紊乱病 (TMJD) 疼痛对太多患者来说是一种 使人衰弱的慢性三叉神经痛极大地影响了他们的生活。颞下颌关节病的疼痛无疑 严重的未满足的医疗需求。不幸的是，目前治疗颞下颌关节紊乱病疼痛的方法缺乏有效性， 主要是由于：1）当前TMJD临床前模型在忠实模拟患者基本情况方面存在缺陷 投诉； 2) TMJD 背后的分子、细胞和神经回路机制的难以捉摸 疼痛。我们的提案旨在解决这两个关键问题。与疼痛相关的 TRP 通道、表达的疼痛 TRP 由三叉神经节 (TG) 感觉神经元产生，与急性和慢性疼痛密切相关 并代表制定合理指导的抗疼痛策略的可能的真正目标。然而， 它们在 TMJD 咀嚼痛和自发痛中的直接机制作用尚不清楚，需要进一步研究 澄清。在我们之前发表的初步研究中，我们开发并验证了咬合力和 条件性位置偏好测定，用于测量由以下因素引起的咀嚼疼痛和自发疼痛： 颞下颌关节炎症损伤或咬肌腱结扎，这两种方法都会引起长期 持久的疼痛行为。使用咬合力指标，我们发现颞下颌关节炎症引起的咀嚼痛是 在 Trpv4 敲除 (KO) 小鼠中，这种效应显着减弱，但并未完全逆转，这表明残余疼痛 可能是由其他疼痛 TRP 介导的。我们的基因表达研究表明 TRPV1 和 TRPA1 此外，TG 在 TMJ 炎症反应中上调，而且以 Trpv4 依赖性方式上调。 因此，我们假设 TRPV1 和 TRPA1 与 TRPV4 一样，会导致 TMJD 疼痛，特别是通过 他们的信号集合。我们将使用我们的两种颞下颌关节损伤模型来检验这一假设。疼痛- 行为读出指标将是咬合力和条件位置偏好。我们将采用组合 针对目标基因以及选择性神经元的药理学和遗传功能丧失方法 使用特定的 TRP 激动剂与带正电荷的利多卡因衍生物 (QX314) 结合进行沉默。另外，我们 将针对 TMEM100，一种最近发现的 TRPV1-TRPA1 功能相互作用的适配器，通过使用 用于局部注射的TMEM100抑制肽和感觉神经元-TMEM100条件敲除小鼠。我们的 三个具体目标将检查 TRPV1、TRPV4、TRPA1 和 TMEM100 对疾病发病机制的贡献 TMJD 病理性疼痛，包括神经源性炎症的评估，这是一种致病机制 我们收集了令人兴奋的试点数据，揭示了其对颞下颌关节病疼痛的关键作用。成功解决了我们的 雄心勃勃但可行的目标将提供大量新的基本见解，并且易于翻译 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 通过应用理性指导的新策略，应对“阿片类药物流行病”（即慢性颞下颌关节紊乱病疼痛）的时代。