Functional peripheral and central vagal neural circuits of interoception inhibiting pain

内感受抑制疼痛的功能性外周和中枢迷走神经回路

• 批准号: 10615995
• 负责人: Man-Kyo Chung
• 金额: $ 26.53万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10615995
• 关键词: Adult; Affect; Afferent Neurons; Anterior; Area; Arthralgia; Biological; Biological Assay; Biological Markers; Blood Vessels; Cells; Chronic; Clinical Data; Data; Development; Economic Burden; Excision; Female; Functional disorder; Ganglia; Gene Expression; Genetic; Gonadal Steroid Hormones; Head; Head and neck structure; Health; Hormone Receptor; Human; Hyperalgesia; Individual; Inflammatory; Injury; Interoception; Jaw; Label; Lipids; Mandible; Mass Spectrum Analysis; Masseter Muscle; Mastication; Masticatory muscles; Mechanics; Mediating; Metabolic Pathway; Modeling; Molecular Profiling; Motion; Mus; Muscle; Musculoskeletal structure; Myalgia; Nerve; Neurobiology; Neurons; Nociception; Oral cavity; Orofacial Pain; Outcome; Pain; Pain management; Pathology; Patients; Peripheral; Peripheral Nerves; Phenotype; Phosphatidylinositol Phosphates; Population; Prevalence; Quality of life; RNA Sequence Analysis; Regulation; Role; Sampling; Sensory; Severities; Shotguns; Structure of trigeminal ganglion; Temporomandibular Joint; Temporomandibular Joint Disorders; Temporomandibular joint disorder pain; Therapeutic; Tissues; aged; base; biomarker signature; comorbidity; cost; craniofacial; hormone regulation; improved; injured; insight; irritation; joint function; joint injury; lipidomics; male; mouse model; neural circuit; neurobiological mechanism; non-opioid analgesic; novel; orofacial; pain inhibition; sex; soft tissue; teeth clenching; therapeutic target; transcriptome sequencing; transmission process

TMDs are conditions that cause pain and dysfunction in the jaw, the masticatory muscles, and associated head and neck musculoskeletal structures. The prevalence among U.S. adults is 24%, and more than 15 million patients are affected by severe pain and limited mandibular motion, resulting in reduced quality of life and a high economic burden. Despite these costs, the exact mechanisms by which biomarkers or biomarker signatures occur in TMD patients are not well known, nor is it clear what specific molecules at the level of the primary sensory neuron or peripheral TMJ region mediate the transition to chronic, persistent jaw joint and muscle pain. As a result, treatment options for these patients are severely limited. In this proposal, we will perform single cell and tissue RNA sequence analysis and shotgun lipidomic analysis of temporomandibular joint (TMJ) relevant to the transduction, transmission, and regulation of TMD pain. Our objective is to delineate biomarkers and biomarker signatures and to identify novel targets of non-opioid therapeutics to improve the management of patients with TMD pain. In our analysis of biomarkers and/biomarker signatures in TMD pain, we will consider the unique neurobiology of TMJ and orofacial regions. First, different orofacial tissues and regions, including TMJ, likely contribute differentially to TMD pain. Since the retrodiscal tissues are highly innervated by peripheral nerves and are highly vascularized compared to other regions, such malpositioning increases direct mechanical irritation of the retrodiscal tissues during joint functions, which leads to inflammatory changes and further pathologies. In addition, the orofacial region, especially masseter muscle, which connects the mandible to the cheekbone may also be damaged and/or inflamed by TMJ injury. The masseter muscle is used for chewing and jaw clenching. Muscle overuse from tooth-grinding and jaw-clenching cause the muscle to become tense, inflamed, and painful. Thus, retrodiscal tissues and masseter muscle might provide ideal targets for non-opioid therapeutics for pain therapy. Second, sex is an important biological variable. Since TMD pain is highly prevalent in females, we will have a primary focus on this population and on the role of sex hormone regulation and receptors in pain regulation. We presume that injury induces substantial changes in TMJ neurobiology and molecular signature particularly in young females. Third, in addition to nociceptive sensory afferents localized in trigeminal ganglia (TG), TMJ is also innervated by vagal afferents. Our preliminary data suggest that TMJ vagal afferents can inhibit hyperalgesia induced by TMJ injury suggesting they can modulate severity of TMD pain. Therefore, we will undertake genetic and lipidomic assays of vagal ganglia projecting to TMJ. In Aim 1, we will delineate biomarkers and/or biomarker signatures of TMD pain in peripheral TMJ tissues and TG and vagal ganglia (VG) neurons projecting to TMJ (RNA sequencing and lipidomics) in mice. Biomarkers and/or biomarker signatures from TMD pain will be screened by RNA sequencing and lipidomics assays using TMJ tissue and orofacial tissue. We will determine the landscape of lipids by identification and quantification of individual lipid species (potentially thousands) and polyphosphoinositide classes and will identify altered metabolic pathways in TMJ afferents and TG and VG from injured and control mice using multi-dimensional mass spectrometry-based shotgun lipidomics (MDMS-SL). In Aim 2, we will Identify targets for non-opioid therapeutics in inflamed TMJ and orofacial regions in humans. Our RNA sequencing and lipidomics analysis promise to provide genetic and lipidomic information and insight into the dynamics of the TMJ and orofacial tissue in healthy and inflamed TMJ from mice and humans. We expect the findings will facilitate identification of novel targets for development of non-opioid therapeutics for TMD pain.

TMD 是导致下颌、咀嚼肌和相关头部疼痛和功能障碍的疾病 和颈部肌肉骨骼结构。美国成年人的患病率为 24%，超过 1500 万 患者受到严重疼痛和下颌运动受限的影响，导致生活质量下降和高 经济负担。尽管有这些成本，生物标志物或生物标志物签名的确切机制 TMD患者中发生的情况尚不清楚，也不清楚原发水平的具体分子是什么 感觉神经元或周围颞下颌关节区域介导向慢性、持续性下颌关节和肌肉疼痛的转变。 因此，这些患者的治疗选择受到严重限制。在这个提案中，我们将执行单细胞 以及与相关的颞下颌关节 (TMJ) 的组织 RNA 序列分析和鸟枪脂质组学分析 TMD 疼痛的转导、传播和调节。我们的目标是描绘生物标志物和 生物标志物特征并确定非阿片类药物治疗的新靶点，以改善对 TMD疼痛患者。在我们对 TMD 疼痛的生物标志物和/生物标志物特征的分析中，我们将考虑 颞下颌关节和口面部区域独特的神经生物学。首先，不同的口面部组织和区域，包括 颞下颌关节 (TMJ) 可能对 TMD 疼痛有不同的影响。由于椎间盘后组织高度受外周神经支配 与其他区域相比，神经和血管高度丰富，这种错位会增加直接机械损伤 在关节功能过程中刺激椎间盘后组织，导致炎症变化并进一步 病理学。此外，口面部区域，尤其是连接下颌骨和下颌骨的咬肌 颧骨也可能因颞下颌关节损伤而受损和/或发炎。咬肌用于咀嚼和 下巴咬紧。磨牙和咬紧牙关导致肌肉过度使用，导致肌肉紧张， 发炎了，而且很痛。因此，椎间盘后组织和咬肌可能为非阿片类药物提供理想的靶点 疼痛治疗的疗法。其次，性别是一个重要的生物学变量。由于 TMD 疼痛非常普遍 在女性中，我们将主要关注这一人群以及性激素调节和 疼痛调节受体。我们推测损伤会引起颞下颌关节神经生物学的实质性变化 分子特征，尤其是年轻女性。第三，除了位于局部的伤害性感觉传入之外 三叉神经节（TG）、颞下颌关节也受迷走神经传入神经支配。我们的初步数据表明 TMJ 迷走神经 传入神经可以抑制颞下颌关节损伤引起的痛觉过敏，表明它们可以调节TMD疼痛的严重程度。 因此，我们将对投射到颞下颌关节的迷走神经节进行遗传和脂质组学测定。在目标 1 中，我们将 描绘外周 TMJ 组织以及 TG 和迷走神经中 TMD 疼痛的生物标志物和/或生物标志物特征 小鼠中神经节 (VG) 神经元投射到 TMJ（RNA 测序和脂质组学）。生物标志物和/或生物标志物 TMD 疼痛的特征将通过 RNA 测序和脂质组学分析使用 TMJ 组织和 口面部组织。我们将通过识别和量化个体脂质来确定脂质的概况 物种（可能数千个）和多磷酸肌醇类别，并将识别改变的代谢途径 使用基于多维质谱法的受伤小鼠和对照小鼠的 TMJ 传入神经以及 TG 和 VG 鸟枪脂质组学 (MDMS-SL)。在目标 2 中，我们将确定非阿片类药物治疗颞下颌关节炎症和 人类的口面部区域。我们的 RNA 测序和脂质组学分析有望提供遗传和 脂质组学信息并深入了解健康和发炎的颞下颌关节和口面部组织的动态 来自老鼠和人类。我们期望这些发现将有助于确定新的开发目标 用于 TMD 疼痛的非阿片类药物疗法。