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.

创伤性脑损伤合并精神压力的患者最常见的症状是复发性脑外伤后头痛（PTH）。虽然35- 60%的轻度TBI患者经历头痛，但结合强烈的应激源，该患者人群中头痛的发生率上升至85%。PTH与偏头痛有许多共同特征，包括面部异常性疼痛、先兆和对感觉刺激的敏感性，这表明这两种情况可能通过重叠机制发展。越来越多的证据表明，偏头痛和潜在的甲状旁腺激素可能源于硬脑膜，导致硬脑膜传入神经元的激活/敏化。虽然我们以前已经证明了压力单独对硬脑膜传入兴奋性和硬脑膜免疫细胞密度的影响，但很可能是TBI与压力加强了这些事件，将硬脑膜环境从抑制性转变为兴奋性以驱动PTH，如果不是偏头痛的话。因此，该提议将采用临床相关的动物模型来确定免疫分子和肾上腺素能受体是否参与由TBI和应激引起的PTH增强。首先，我将测试与头痛相关的行为，面部触觉异常性疼痛和鬼脸，并结合TBI动物在应激条件下硬脑膜传入神经中自发和诱发钙瞬变的体内记录。第二，我将评估是否硬脑膜传入兴奋性改变与创伤性脑损伤和压力的动物。最后，我将测量硬脑膜免疫细胞的密度和表型以及它们在TBI和应激动物中表达的细胞因子。这些实验的结果将提供信息，其中硬膜传入和硬膜免疫细胞的环境有助于PTH的维持。在拟议的实验中，我将采用一系列的行为测定和在体内显微镜配对膜片钳电生理和流式细胞术和细胞因子的表达。因此，拟议的实验的成功完成将提供新的信息有关的蛋白质的功能的钙离子调节的关键，建议新的治疗方法治疗炎症性疼痛，并提供一个坚实的实验基础上，建立一个职业生涯作为一个独立的科学家。