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.

缺乏对神经生物学基础的理解， 创伤后脑损伤（TBI）引起的急性和慢性疼痛的可能性目前尚不清楚，这进一步限制了我们的能力。 开发合适的治疗方法电针（EA）是一种已经使用多年的治疗方式。 然而，它的作用方式在很大程度上是未知的，尽管有越来越多的证据表明，大脑和脊髓 脊髓主要参与针刺刺激的处理。针灸的镇痛作用是 有据可查此外，针灸在急性和慢性炎症过程中调节全身炎症的强大能力， 最近在多种疾病状况中记录了慢性事件。然而， 临床前数据使用程序启动TBI的临床试验。该提案的主要目的是测试 电针治疗缓解疼痛/头痛样的剂量依赖性有效性和作用机制 在闭合性头部创伤性脑损伤（CH-TBI）的临床相关啮齿动物模型中的行为。该模型密切 类似于在涉及汽车头部撞击的人体损伤情况中看到的钝性创伤头部损伤 碰撞、运动和在战场上受到的爆炸伤害。该CH-TBI啮齿动物模型表现出 进行性和持久性口面部和躯体疼痛/头痛样症状的综合证据 由无痛性刺激引起。这些疼痛/头痛样症状与几种 已知沿着三叉神经和脊髓丘脑神经元疼痛通路的疼痛信号传导受体和分子沿着。 由于创伤性脑损伤后引起慢性疼痛和头痛是军人和文职人员的主要健康问题， 临床前研究旨在探索潜在的神经生物学和靶向治疗至关重要。因此，我们认为， 本提案中两个机制驱动的具体目标的目的是加强我们对 电针治疗的神经生物学影响TBI诱导的疼痛/头痛样行为的变化， 和躯体痛觉过敏/异常性疼痛。我们最近的研究使用一个温和的CH冲击加速度TBI模型在成人 Sprague道利大鼠显示出显著的和持久的三叉神经和足底痛觉过敏， 艺术操作性口面和爪子疼痛奖励/冲突测试范式。具体目标1将评估治疗 电针治疗对TBI诱导的口面和爪异常性疼痛/痛觉过敏进展的潜力 使用2种不同的持续时间（2周vs. 4周），在TBI后的时间点（TBI后即刻）和慢性时间点（2个月）进行比较。 周）的EA治疗。具体目标2将解决TBI和治疗引起的疼痛机制的变化 三叉神经和躯体疼痛通路的信号传导;这些研究将定量的变化， 一系列基于MRI的生物标志物，分子和受体与疼痛信号和炎症相关， 使用定量MRI和基于免疫组织化学（IHC）的三叉神经和躯体疼痛通路 技术.研究人员提出，EA治疗将产生一个安全的，显着减少口面 和躯体异常性疼痛/超敏反应;因此，这种疗法具有快速临床转化的潜力 作为治疗TBI引起的疼痛和头痛的重要的无药物疗法。研究人员进一步提出， 电针治疗引起的口面和躯体疼痛敏感性的显著降低将伴随着 显著减少炎症生物标志物和疼痛信号分子/受体在面部和 躯体疼痛通路MRI和IHC数据将进一步确定作用机制的细节。这些研究 有可能增加我们对TBI引起的疼痛/头痛的神经生物学的理解， 从EA受益的机制，治疗开始的适当时间，治疗持续时间，以及进一步 为开发两性TBI诱导的疼痛/头痛治疗提供平台。我们 我假设，如果在损伤后急性给药， 疼痛通路中的适应不良可塑性。而且，4周的治疗将产生明显更好的 与2周治疗相比，由于疼痛通路中基于刺激的持久引导可塑性，