Traumatic Brain Injury, Stress, and Headache

创伤性脑损伤、压力和头痛

• 批准号: 9395336
• 负责人: Jane E. Hartung
• 金额: $ 5.63万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9395336
• 关键词: Acute; Adrenergic Receptor; Affect; Afferent Neurons; American; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Auras; B-Lymphocytes; Behavior; Behavioral; Behavioral Assay; Calcium; Cell Density; Cells; Chemosensitization; Chronic; Clinical; Cognitive deficits; Dendritic Cells; Dura Mater; Electrophysiology (science); Environment; Esthesia; Event; Face; Female; Flow Cytometry; Foundations; Genetic; Headache; Hypersensitivity; Image; Immune; Inflammation Mediators; Inflammatory; Injury; Interleukin-10; Interleukin-6; Link; Lymphoid; Maintenance; Measures; Messenger RNA; Microscopy; Migraine; Motor; Myelogenous; Natural Killer Cells; Nature; Neurons; Nociception; Nociceptors; Pain; Pain Disorder; Patients; Persistent pain; Pharmaceutical Preparations; Phenotype; Physiological; Population; Post-Traumatic Headaches; Pre-Clinical Model; Property; Proteins; Rattus; Recruitment Activity; Recurrence; Regulation; Reporting; Scientist; Secondary to; Site; Solid; Stimulus; Stress; Structure; Sumatriptan; Symptoms; T-Lymphocyte; TBI Patients; Tactile; Techniques; Tension Headache; Testing; Training; Traumatic Brain Injury; allodynia; awake; career; clinically relevant; cytokine; density; design; experience; experimental study; in vivo; inflammatory pain; insight; macrophage; male; mechanical allodynia; mild traumatic brain injury; novel; novel strategies; novel therapeutic intervention; patch clamp; patient population; relating to nervous system; response; sensory stimulus; stressor

The symptom most commonly experienced with patients with traumatic brain injury combined with and stress is recurrent post-­traumatic headache (PTH). While 35-­60% of patients with mild TBI experience headache, in combination with an intense stressor, the rate of headache in this patient population rises to 85%. PTH shares many features with migraine, including facial allodynia, aura, and sensitivity to sensory stimuli, suggesting that these two conditions may develop through overlapping mechanisms. A growing body of evidence now implicates that migraine, and potentially PTH, may arise from the dura that leads to activation/sensitization of dural afferent neurons. While we have previously demonstrated the effect of stress alone on dural afferent excitability and dural immune cell density, it is likely that TBI with stress potentiates these events, shifting the dural environment from inhibitory to excitatory to drive PTH, if not migraine. Therefore, this proposal will employ a clinically – relevant animal model to determine if immune molecules and adrenergic receptors are involved in the potentiation of PTH that results from TBI and stress. First, I will test headache-­linked behaviors, facial tactile allodynia and grimacing, paired with in vivo recordings of spontaneous and evoked calcium transients in dural afferents in animals with TBI with stress. Second, I will assess if dural afferent excitability is altered in animals with TBI and stress. Finally, I will measure the density and phenotype of dural immune cells and the cytokines they express in animals with TBI and stress. Results from these experiments will provide information in which dural afferents and the milieu of dural immune cells contribute to the maintenance of PTH. In the proposed experiments, I will employ an array of behavioral assays and in vivo microscopy paired with patch clamp electrophysiology and flow cytometry and cytokine expression. Thus, the successful completion of the proposed experiments will provide novel information regarding the function of a protein critical for Ca2+ regulation, suggest novel therapeutic approaches for the treatment of inflammatory pain, and provide a solid experimental foundation upon which to build a career as an independent scientist.

最常见的脑损伤患者和压力最常见的症状是创伤后的次数（PTH）。虽然35-60％的轻度TBI体验标头患者结合了强烈的压力源，但该患者人群的标头速率上升到85％。 PTH与偏头痛具有许多特征，包括面部异常性疾病，Aura和对感觉刺激的敏感性，这表明这两种情况可能通过重叠的机制发展。现在，越来越多的证据植入偏头痛和潜在的PTH可能是由于硬脑膜引起的，导致硬脑膜传入神经元的激活/敏化。尽管我们以前已经证明了仅压力对硬脑膜传入刺激和硬脑膜免疫细胞密度的影响，但具有压力潜力的TBI很可能会使这些事件的影响从抑制性转变为兴奋性，即使不是偏移，也可以将其转变为兴奋性。因此，该建议将采用临床上的相关动物模型来确定免疫分子和肾上腺素受体是否参与了PTH的潜力，这是TBI和压力引起的。首先，我将测试标头连接的行为，面部触觉异常性和悲剧性，并与具有压力的TBI动物的硬脑膜传入中赞助和诱发的钙瞬变的体内记录。其次，我将评估具有TBI和压力的动物中的硬脑膜传入兴奋性。最后，我将测量硬脑膜免疫细胞的密度和表型以及它们在具有TBI和压力的动物中表达的细胞因子。这些实验的结果将提供信息，在这些信息中，硬脑膜免疫细胞和沙发免疫细胞环境有助于维持PTH。在拟议的实验中，我将采用一系列行为评估和体内显微镜与斑块夹电生理学以及流式细胞仪和细胞因子表达配对。这是成功完成拟议的实验的成功完成，将提供有关CA2+调节至关重要的蛋白质功能的新信息，提出了用于治疗炎症性疼痛的新型治疗方法，并为建立作为独立科学家的职业提供了坚实的实验基础。