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.

对发展和持久性背后的基本神经生物学缺乏了解 目前尚不清楚创伤后脑损伤 (TBI) 引起的急性和慢性疼痛的机制，这进一步限制了我们的能力 制定适当的治疗方法。电针（EA）是一种已经使用多年的治疗方式。 然而，尽管有越来越多的证据表明大脑和脊髓 脊髓主要参与针灸刺激的处理。针灸的镇痛作用是 有据可查。此外，针灸在急性和急性期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，还不够 使用该程序启动 TBI 临床试验的临床前数据。该提案的主要目的是测试 电针治疗缓解疼痛/头痛样症状的剂量依赖性有效性和作用机制 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。这个模型紧密 类似于在涉及汽车头部撞击的人体伤害情况中看到的钝性头部损伤 碰撞、运动以及在战场情况下受到的爆炸伤害。展出的CH-TBI啮齿动物模型 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 由无痛刺激引起。这些疼痛/头痛样症状与多种疾病的变化相关 沿着三叉神经和脊髓丘脑神经元疼痛通路的已知疼痛信号受体和分子。 由于 TBI 后引起的慢性疼痛和头痛是军事和文职人员的主要健康问题， 旨在探索神经生物学基础的临床前研究，靶向治疗至关重要。所以， 本提案中两个机制驱动的具体目标的目标是增强我们对 EA 治疗影响 TBI 诱发的疼痛/头痛样行为变化的神经生物学，测试为面部 和躯体痛觉过敏/异常性疼痛。我们最近的研究使用成人轻度 CH 冲击加速 TBI 模型 Sprague Dawley 大鼠使用以下状态显示出显着且持久的三叉神经和足底痛觉过敏： 艺术操作口面部和爪子疼痛奖励/冲突测试范例。具体目标 1 将评估治疗效果 电针治疗对 TBI 诱发的急性口面部和爪子异常疼痛/痛觉过敏进展的潜力 （TBI 后立即）和 TBI 后慢性（2 个月）时间点，使用 2 种不同的持续时间（2 周与 4 周） 周）的 EA 治疗。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通路中的信号传导；这些研究将量化全面的变化 一系列基于 MRI 的生物标志物、分子和受体，与疼痛信号传导和炎症相关 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，电针治疗将安全、显着地减少口面部畸形。 和躯体异常性疼痛/过敏；因此，该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无药疗法。调查人员进一步建议 电针治疗引起的口面部和躯体疼痛敏感性显着降低将伴随 面部和面部的炎症生物标志物和疼痛信号分子/受体显着减少 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/头痛的神经生物学和 EA 的获益机制、治疗开始的适当时间、治疗持续时间以及进一步 为开发 TBI 引起的男女疼痛/头痛治疗提供平台。我们做 假设如果在受伤后在严重伤害之前立即进行电针治疗，其效果将达到最大 疼痛通路中会出现适应不良的可塑性。此外，4周的治疗效果会明显好转 由于疼痛通路中基于刺激的持久引导可塑性，与两周治疗相比的结果。