Traumatic Brain Injury and Endogenous Pain Modulation

创伤性脑损伤和内源性疼痛调节

• 批准号: 10329882
• 负责人: DAVID J. CLARK
• 金额: --
• 依托单位: VETERANS ADMIN PALO ALTO HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10329882
• 关键词: Acute; Adrenergic Agents; Affect; Animal Model; Animals; Anxiety; Area; Brain Injuries; Brain Stem; Cells; Chronic; Chronic Brain Injury; Clinical; Cognitive deficits; Complement; Data; Degenerative polyarthritis; Development; Diabetic Neuropathies; Dorsal; Emotional; Equipment; Evaluation; Fiber; Fibromyalgia; Functional disorder; Gene Expression; General Population; Genes; Goals; Grant; Hindlimb; Histologic; Human; Human Resources; Immunohistochemistry; Injury; Laboratories; Lateral; Link; Liquid substance; Measures; Medical; Memory; Microinjections; Modeling; Molecular; Molecular Biology; Multiple Trauma; Neuronal Plasticity; Neurons; Neuropsychology; Neurotoxins; Nociception; Non-Steroidal Anti-Inflammatory Agents; Norepinephrine; Opioid; Outcome; Pain; Pain Clinics; Pain management; Pathway interactions; Patients; Percussion; Peripheral; Persistent pain; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Population; Positioning Attribute; Preclinical Testing; Process; Rattus; Reagent; Regulation; Regulatory Pathway; Resources; Rodent; Role; Sensory; Serotonin; Signal Transduction; Soft Tissue Injuries; Source; Spinal; Spinal Cord; Spinal cord posterior horn; Structure; Surgical incisions; System; TBI Patients; Testing; Tibial Fractures; Time; Tissues; Toxin; Translating; Trauma; Trauma patient; Traumatic Brain Injury; Veterans; War; behavior test; behavioral outcome; chronic pain; cognitive change; combat; design; designer receptors exclusively activated by designer drugs; disability; experience; healing; human model; inhibitor; insight; locus ceruleus structure; member; midbrain central gray substance; neural circuit; neuroinflammation; noradrenergic; pain inhibition; pre-clinical; preclinical study; prevent; receptor; reuptake; serotonin 7 receptor; soft tissue; synaptic function; targeted treatment; tool; translational study

Chronic pain and disability after war-related injuries and after trauma sustained in civilian settings are unexpectedly common. Chronic pain related to traumatic brain injury (TBI) in combination with peripheral injuries is particularly problematic, and we have no well-validated treatments. Potentially explaining the TBI- chronic pain relationship, data from both humans and animal models suggest that descending pain modulation is disrupted after TBI. Recently collected data using laboratory models of brain injury and TBI patients demonstrate the vulnerability of brainstem centers governing endogenous pain modulation. Histopathological and functional TBI studies suggest damage to the periaqueductal gray matter (PAG), a major endogenous pain control center, and the locus coeruleus (LC), a key structure providing descending noradrenergic inhibition to the spinal cord. Moreover, TBI alters the function of the rostral ventromedial medulla (RVM), a structure that provides both descending pain-facilitating and pain-inhibiting serotonergic fibers. Our main objective is, therefore, to evaluate endogenous pain regulatory mechanisms after TBI and pre-clinically test translatable approaches to pain control in this setting. In the first aim we evaluate the hypothesis that TBI disrupts descending pain modulation by altering descending noradrenergic and serotonergic circuits. The experimental approach uses a well-validated rat fluid percussion model of TBI studied along a broad time course to mimic sub-acute and chronic injuries. Highly selective and clinically available pharmacological tools targeting noradrenalin release, serotonergic tone and the stimulation of α2-adrenergic, as well as 5-HT3 and 5-HT7 receptors will be employed. Outcomes will focus on the regulation of nociceptive thresholds and the efficiency of descending pain modulation circuits. In the second aim we evaluate the hypothesis that TBI injures neurons and promotes sustained neuro- inflammation in the LC and RVM as well as giving rise to functional changes in descending pain modulation. In addition to neuropathological evaluations of brainstem and spinal tissues, we will use the microinjection of selective neurotoxins and chemogenetic DREADDs to study the function of brainstem pain regulatory centers after TBI. In the final aim we use two models of polytrauma combining TBI with soft tissue incision and, separately, tibial fracture. We hypothesize that clinically available modulators of noradrenergic and serotonergic signaling will reduce nociceptive sensitization, enhance descending pain modulation and reduce the interaction of peripheral trauma and TBI on neuroinflammation and the expression of several pain-related spinal genes. By reducing chronic pain-related changes we further hypothesize that functional measures, anxiety and cognitive changes will all be less affected after the injuries. At the time of completion of the project we expect to understand better how TBI, peripheral injury and the combination of injuries cause chronic pain. In the process of this evaluation we will delineate the roles of dysfunction in specific brainstem pain modulating centers. We anticipate being in position to plan translational human studies using some of the same agents and approaches employed preclinically.

在平民环境中遭受战争伤害和创伤后的慢性疼痛和残疾是 出乎意料的常见。创伤性脑损伤合并外周慢性疼痛 受伤问题尤其严重，我们没有经过充分验证的治疗方法。潜在地解释了TBI- 慢性疼痛关系，来自人类和动物模型的数据表明，下行疼痛 TBI后调制中断。最近使用脑损伤和脑外伤的实验室模型收集的数据 患者证明了脑干中枢支配内源性疼痛调制的脆弱性。 组织病理学和功能脑损伤研究提示中脑导水管周围灰质(PAG)受损， 主要的内源性疼痛控制中心，以及蓝斑(LC)，一个提供下行的关键结构 去甲肾上腺素对脊髓的抑制作用。此外，颅脑损伤还改变了吻侧腹内侧部的功能 延髓(RVM)，一种既提供下行疼痛便利又提供疼痛抑制的5-羟色胺能 纤维。因此，我们的主要目标是评估脑外伤后的内源性疼痛调节机制和 在这种情况下，对可翻译的疼痛控制方法进行临床前测试。 在第一个目标中，我们评估了以下假设：脑损伤通过改变 去甲肾上腺素能和5-羟色胺能神经回路。实验方法使用经过充分验证的大鼠 液压冲击伤模型模拟亚急性和慢性颅脑损伤的时间进程进行研究。 针对去甲肾上腺素释放和5-羟色胺能的高度选择性和临床可用的药理工具 Tone和刺激α2-肾上腺素能，以及5-HT3和5-HT7受体将被使用。 结果将集中在伤害性阈值的调节和下行疼痛的效率上。 调制电路。 在第二个目标中，我们评估了脑外伤损伤神经元并促进持续神经损伤的假说。 炎症在LC和RVM以及引起下行疼痛调制的功能改变。 除了对脑干和脊髓组织进行神经病理学评估外，我们还将使用显微注射 选择性神经毒素和化学致病DREADDS研究脑干疼痛调节功能 在TBI之后的中心。 在最终目标中，我们使用了两种多发伤合并软组织切开的模型，分别是： 胫骨骨折。我们假设临床上可用的去甲肾上腺素能和5-羟色胺能调节剂 信号将减少伤害性敏感化，增强下行疼痛调制，并减少 外周创伤与颅脑损伤相互作用对神经炎症及几种疼痛相关基因表达的影响 脊椎基因。通过减少慢性疼痛相关变化，我们进一步假设功能性措施， 在受伤后，焦虑和认知变化都会受到较小的影响。 在项目完成时，我们希望更好地了解创伤性脑损伤、周围损伤和 这些伤害的组合会导致慢性疼痛。在这一评估过程中，我们将界定 特定脑干疼痛调节中心的功能障碍。我们期待着能够做好计划 使用一些临床前使用的相同试剂和方法进行的转化性人体研究。