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是导致颌骨，咀嚼性肌肉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有限的下颌运动的影响，导致生活质量降低，高 经济负担。尽管这些成本是生物标志物或生物标志物签名的确切机制 在TMD患者中发生的情况尚不清楚，也不清楚主要分子在初级水平上 感觉神经元或周围TMJ区域介导向慢性，持续下颌关节和肌肉疼痛的过渡。 结果，这些患者的治疗选择受到严重限制。在此提案中，我们将执行单元格 与颞下颌关节（TMJ）的组织RNA序列分析和shot弹枪脂质分析 TMD疼痛的转导，传递和调节。我们的目标是描述生物标志物和 生物标志物特征并确定非阿片类药物治疗剂的新靶标，以改善 TMD疼痛的患者。在我们对TMD疼痛中的生物标志物和/生物标志物签名的分析中，我们将考虑 TMJ和Orofacial区域的独特神经生物学。首先，包括不同的种族组织和区域，包括 TMJ，可能会导致TMD疼痛差异。由于回流组织被周围高度支配 与其他区域相比，神经和高度血管化，这种不正确增加会增加直接的机械 关节功能期间的曲面组织的刺激，这会导致炎症变化，进一步变化 病理。此外，口面区域，尤其是咬合肌肉，将下颌骨连接到 TMJ损伤也可能会损坏和/或发炎。咬肌用于咀嚼和 下巴紧握。肌肉过度使用牙齿磨牙和下巴缝隙会导致肌肉变得紧张， 发炎，痛苦。因此，回旋术组织和咬肌可能为非阿片类药物提供理想的靶标 疼痛治疗的治疗剂。其次，性是重要的生物学变量。由于TMD疼痛非常普遍 在女性中，我们将主要关注该人群以及性激素调节的作用和 疼痛调节中的受体。我们认为伤害会导致TMJ神经生物学和 分子签名，尤其是在年轻女性中。第三，除了本地化的伤害感受感官传入外 三叉神经节（TG），TMJ也被迷走神经传入所支配。我们的初步数据表明TMJ迷走神经 传入可以抑制TMJ损伤引起的痛觉过敏，这表明它们可以调节TMD疼痛的严重程度。 因此，我们将对投射到TMJ的迷走神经节进行遗传和脂肪分子测定。在AIM 1中，我们将 描述周围TMJ组织中TMD疼痛的生物标志物和/或生物标志物特征，TG和迷走神经 在小鼠中投射到TMJ（RNA测序和脂质组学）的神经元（VG）神经元。生物标志物和/或生物标志物 使用TMJ组织和 口面组织。我们将通过识别和定量单个脂质来确定脂质的景观 物种（可能是数千种）和多磷酸肌醇类别，将确定改变的代谢途径 使用基于多维质谱法的受伤和控制小鼠的TMJ传入以及TG和VG的TG和VG shot弹枪脂质组学（MDMS-SL）。在AIM 2中，我们将确定在发炎的TMJ和 人类的口面区域。我们的RNA测序和脂肪组学分析有望提供遗传和 健康和发炎的TMJ中TMJ和Orofacial组织动力学的脂质组信息和洞察力 来自老鼠和人类。我们希望这些发现将有助于确定新的目标以开发 用于TMD疼痛的非阿片类药物疗法。