Functional peripheral and central vagal neural circuits of interoception inhibiting pain

TMD是一种会导致颌骨、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1500万人 患者受到剧烈疼痛和下颌运动受限的影响，导致生活质量下降和 经济负担。尽管有这些成本，生物标记物或生物标记物签名的确切机制 发生在TMD患者身上还不是很清楚，也不清楚在原发水平上有哪些特定的分子 感觉神经元或外周TMJ区介导向慢性持续性颌骨关节和肌肉疼痛的过渡。 因此，这些患者的治疗选择严重有限。在这个方案中，我们将执行单细胞 以及与以下相关的组织RNA序列分析和TMJ的鸟枪脂组学分析 TMD痛的传导、传递和调节。我们的目标是描述生物标志物和 生物标记物特征和确定非阿片类药物的新靶点，以改善对 有TMD疼痛的患者。在我们对TMD疼痛的生物标志物和/或生物标志物签名的分析中，我们将考虑 TMJ和口面部独特的神经生物学。首先，不同的口腔面部组织和区域，包括 TMJ可能对TMD疼痛有不同的贡献。由于椎间盘后组织受到外周的高度支配 神经与其他区域相比血运丰富，这种错位增加了直接机械性 关节功能过程中对盘后组织的刺激，导致炎症变化，并进一步 病理学。此外，口面部，特别是咬肌，连接下颌和下颌骨 颧骨也可能因TMJ损伤而受损和/或发炎。咬肌用于咀嚼和 紧咬着下巴。磨牙和咬合的肌肉过度使用会导致肌肉紧张， 发炎了，而且很痛。因此，盘后组织和咬肌可能是非阿片类药物的理想靶点。 疼痛治疗的治疗学。其次，性别是一个重要的生物变量。由于TMD疼痛非常普遍 在女性中，我们将主要关注这一群体以及性激素调节和 痛觉调节中的受体。我们推测，损伤会导致TMJ神经生物学和 分子标记，特别是在年轻女性身上。第三，除了伤害性感觉神经传入在 三叉神经节(TG)、TMJ也由迷走神经传入支配。我们的初步数据显示TMJ迷走神经 传入神经可抑制TMJ损伤所致的痛敏反应，提示它们可调节TMD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学和脂组学分析。在目标1中，我们将 描述TMJ周围组织和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 小鼠的神经节(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疼痛的信号将通过使用TMJ组织和脂质组学的RNA测序和脂质组学分析来筛选 口腔面部组织。我们将通过对个体脂质的鉴定和量化来确定脂类的景观 物种(可能有数千种)和多磷肌醇类，并将确定改变的代谢途径 损伤小鼠和对照小鼠TMJ传入和TG、VG的多维质谱学研究 鸟枪式脂质组学(MDMS-SL)。在目标2中，我们将确定非阿片类药物治疗发炎的TMJ的靶点和 人类的口面部区域。我们的RNA测序和脂质组学分析承诺提供遗传和 健康和炎症TMJ的脂组信息和对TMJ和口面部组织动力学的洞察力 从老鼠和人类身上。我们预期研究结果将有助确定新的发展目标。 非阿片类药物治疗TMD疼痛。

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.