A nonpharmacological therapeutic intervention of TBI-induced facial allodynia/hyperalgesias in a rodent model

啮齿动物模型中 TBI 引起的面部异常性疼痛/痛觉过敏的非药物治疗干预

• 批准号: 10611481
• 负责人: JIAMEI HOU
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10611481
• 关键词: Absence of pain sensation; Acceleration; Acupuncture Therapy; Acute; Acute Pain; Adult; Analgesics; Angiography; Apoptotic; Behavior; Biological Markers; Blast Injuries; Blood - brain barrier anatomy; Blood Vessels; Blunt Trauma; Brain; Chronic; Chronic Brain Injury; Chronic Headaches; Clinical Trials; Companions; Complication; Conflict (Psychology); Craniocerebral Trauma; Cutaneous; Data; Dependence; Development; Diagnosis; Diffuse Axonal Injury; Dilatation - action; Disease; Dose; Effectiveness; Electric Stimulation; Electroacupuncture; Encephalopathies; Enzymes; Evaluation; Event; Exhibits; Face; Functional Magnetic Resonance Imaging; Gender; Gene Expression; Genes; Head; Headache; Health; Healthcare; Human; Human Resources; Hyperalgesia; Hypersensitivity; Immune; Immunohistochemistry; Inflammation; Inflammatory; Injury; Intervention; Magnetic Resonance Imaging; Mechanics; Mediating; Medicine; Military Personnel; Modality; Modeling; NF-kappa B; Neurobiology; Neuromodulator; Neurons; Orofacial Pain; Outcome; Pain; Painless; Pathway interactions; Patients; Permeability; Pharmaceutical Preparations; Placebo Control; Placebos; Post-Traumatic Headaches; Preventive treatment; Procedures; Quality of life; Rattus; Receptor Signaling; Reperfusion Injury; Reporting; Research Personnel; Rewards; Risk Factors; Rodent Model; Sepsis; Signal Transduction; Signaling Molecule; Spinal Cord; Sports; Sprague-Dawley Rats; Stimulus; Surface; Symptoms; System; TBI treatment; Tactile; Techniques; Testing; Therapeutic; Therapeutic Intervention; Therapeutic Uses; Time; Translations; Traumatic Brain Injury; Treatment Effectiveness; Trigeminal Nuclei; Trigeminal System; Up-Regulation; Vasodilator Agents; Vehicle crash; Veterans; War; Work; addiction; allodynia; behavior test; chemokine; chronic pain; clinical translation; clinically relevant; cytokine; design; disability; effective therapy; efficacy testing; evidence base; head impact; healing; inflammatory marker; injury and repair; innovation; interest; multimodality; neuroinflammation; neuronal excitability; neuronal survival; neuroregulation; noradrenergic; novel; orofacial; pain reduction; pain sensitivity; pain signal; pre-clinical; pre-clinical research; receptor; response; systemic inflammatory response; targeted treatment; treatment duration

The lack of understanding of the fundamental neurobiology that underlies the development and persistence of post-traumatic brain injury (TBI)-induced acute and chronic pain is currently unknown, further limiting our ability to develop appropriate treatments. Electro-acupuncture (EA) is a healing modality that has been in use for years. It's modes of action, however, are largely unknown, although there is increasing evidence that brain and spinal cord are primarily involved in the processing of acupuncture stimuli. The analgesic effects of acupuncture are well documented. In addition, acupuncture's powerful ability to modulate systemic inflammation during acute and chronic events has recently been documented in multiple disease conditions. However, there is not enough preclinical data using the procedure to initiate a clinical trial for TBI. The main objective of this proposal is to test the dose-dependent effectiveness and mechanism of action of EA treatment to alleviate pain/headache-like behavior in a clinically relevant rodent model of closed head traumatic brain injury (CH-TBI). This model closely resembles blunt trauma head injury seen in human injury situations involving head impact from automobile crashes, sports, and from blast injury received in battlefield situations. This CH-TBI rodent model exhibited comprehensive evidence of progressive and enduring orofacial and somatic pain/headache-like symptoms induced by non-painful stimulation. These pain/headache-like symptoms correlated with changes in several known pain signaling receptors and molecules along the trigeminal and spinothalamic neuronal pain pathways. Since post-TBI induced chronic pain and headache are major health issue in both military and civilian personnel, preclinical research aiming at the exploration of underlying neurobiology, and targeted therapy is vital. Therefore, the objective of two mechanism driven Specific Aims in this proposal is to enhance our understanding of the neurobiology of EA therapy-influenced changes in TBI-induced pain/headache-like behaviors tested as facial and somatic hyperalgesia/allodynia. Our recent studies using a mild CH impact acceleration TBI model in adult Sprague Dawley rats revealed significant and enduring trigeminal and plantar hyperalgesia using a state of the art operant orofacial and paw pain reward/conflict testing paradigm. Specific Aim 1 will evaluate the therapeutic potential of EA therapy on the progression of TBI-induced orofacial and paw allodynia/hyperalgesias at acute (immediate after TBI) and chronic (2 months) time points after TBI using 2 different durations (2-week vs. 4- week) of EA therapy. Specific Aim 2 will address TBI and therapy-induced changes in mechanisms of pain signaling in trigeminal and somatic pain pathways; these studies will quantitate of changes in a comprehensive array of MRI-based biomarkers, molecules, and receptors related to pain signaling and inflammation in the trigeminal and somatic pain pathways using quantitative MRI, and immunohistochemistry (IHC) based techniques. The investigators propose that EA treatment will produce a safe, significant reduction of orofacial and somatic allodynia/hypersensitivities; accordingly, this therapy has the potential for rapid clinical translation as significant drug free therapy to treat TBI-induced pain and headache. Investigators further propose that the EA treatment-induced significant reduction in orofacial and somatic pain sensitivity will be accompanied by significant reduction of inflammatory biomarkers, and pain signaling molecules/receptors in the facial and somatic pain pathways. MRI and IHC data will further identify details of the mechanisms of action. These studies have the potential to increase our understanding of the neurobiology of TBI-induced pain/headache and the mechanisms of benefits from EA, appropriate time of treatment initiation, duration of treatment, and further provide a platform for the development of TBI-induced pain/headache treatment in both genders. We do hypothesize that the effectiveness of EA will be maximal if it is administered acutely after injury before significant maladaptive plasticity in pain pathways happen. Moreover, 4 weeks treatment will produce significantly better outcomes compared to 2-week treatment due to stimuli-based enduring guided plasticity in the pain pathways.

缺乏对发展和持久性基础的基本神经生物学的理解 目前未知创伤后脑损伤（TBI）诱导的急性和慢性疼痛，进一步限制了我们的能力 开发适当的治疗方法。电针（EA）是多年来一直使用的治疗方式。 然而，尽管有越来越多的证据表明大脑和脊柱 绳索主要参与针灸刺激的加工。针灸的镇痛作用是 据记录。此外，针灸在急性和 最近在多种疾病状况中记录了慢性事件。但是，还不够 使用该程序启动TBI的临床试验的临床前数据。该建议的主要目的是测试 剂量依赖性的有效性和EA治疗的作用机制减轻疼痛/头痛样 闭合脑外伤脑损伤（CH-TBI）的临床相关啮齿动物模型中的行为。这个模型紧密 类似于钝性创伤头部损伤，在人损伤情况下涉及汽车的头部撞击 在战场情况下，撞车，运动以及受到爆炸受伤。这种CH-TBI啮齿动物模型显示 进行性和持久的口面和躯体疼痛/类似于头痛的症状的全面证据 由非疼痛刺激诱导。这些疼痛/头痛的症状与几个变化有关 沿三叉神经和脊柱丘脑神经元疼痛途径的已知疼痛信号受体和分子。 由于TBI诱发的慢性疼痛和头痛是军事和平民人员的主要健康问题，因此 旨在探索潜在神经生物学和靶向疗法的临床前研究至关重要。所以， 该提案中有两个机制驱动的具体目的的目的是增强我们对 EA治疗受影响的TBI诱导疼痛/头痛样行为的神经生物学，被测试为面部 和躯体痛觉过敏/异性痛。我们最近在成人中使用轻度CH撞击加速度TBI模型的研究 Sprague Dawley大鼠使用一种状态显示出显着的三叉状和足底痛觉过敏 艺术作战者的口面和爪子奖励/冲突测试范式。特定目标1将评估治疗性 EA治疗在急性时TBI诱导的Orofacial和Paw Alrodynia/Hypergersias进展的潜力 （TBI之后立即）和TBI后使用2个不同的持续时间（2周与4-- EA治疗的一周。具体目标2将解决TBI和治疗引起的疼痛机制变化 三叉神经和躯体疼痛途径中的信号传导；这些研究将量化全面的变化 基于MRI的生物标志物，分子和受体阵列与疼痛信号传导和炎症有关 使用定量MRI和免疫组织化学（IHC）的三叉神经和体疼痛途径（IHC） 技术。研究人员建议EA治疗将产生安全，大幅度的口面减少 和体细胞性异常/超敏反应；因此，该疗法有可能快速临床翻译 作为治疗TBI引起的疼痛和头痛的重要无药治疗。调查人员进一步建议 EA治疗引起的口面和躯体疼痛敏感性的显着降低将伴随 面部炎症生物标志物的大幅降低以及面部疼痛信号分子/受体的显着降低 体疼痛途径。 MRI和IHC数据将进一步确定作用机理的细节。这些研究 有可能增加我们对TBI诱发疼痛/头痛的神经生物学的理解 EA受益的机制，适当的治疗开始，治疗持续时间以及进一步 为在两个性别中开发TBI引起的疼痛/头痛治疗的平台提供了一个平台。我们做 假设EA在受伤之前急性施用EA的有效性将是最大的 疼痛途径中的适应不良的可塑性发生。此外，4周的治疗将产生明显更好 与疼痛途径中基于刺激的持久可塑性相比，结局与2周的治疗相比。