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.

与战争有关的伤害和在平民环境中遭受的创伤后的慢性疼痛和残疾是 与外伤性脑损伤 (TBI) 相关的慢性疼痛与外周疼痛出乎意料地常见。 损伤尤其成问题，而且我们没有有效的治疗方法来解释 TBI。 慢性疼痛的关系，来自人类和动物模型的数据表明，下降的疼痛 最近使用脑损伤和 TBI 实验室模型收集的数据。 患者表现出控制内源性疼痛调节的脑干中心的脆弱性。 组织病理学和功能性 TBI 研究表明导水管周围灰质 (PAG) 受损，PAG 是一种 主要的内源性疼痛控制中心和蓝斑（LC），这是提供下行疼痛的关键结构 此外，TBI 改变了头侧腹内侧的功能。 髓质（RVM），一种提供下行促进疼痛和抑制疼痛的血清素能的结构 因此，我们的主要目标是评估 TBI 和 TBI 后的内源性疼痛调节机制。 在这种情况下进行临床前测试可转化的疼痛控制方法。 在第一个目标中，我们评估了 TBI 通过改变下行疼痛调节来破坏下行疼痛调节的假设。 去甲肾上腺素能和血清素能下行回路实验方法使用经过充分验证的大鼠。 TBI 的流体冲击模型在广泛的时间过程中进行了研究，以模拟亚急性和慢性损伤。 针对去甲肾上腺素释放、血清素能的高度选择性和临床可用的药理学工具 将采用音调和 α2-肾上腺素能以及 5-HT3 和 5-HT7 受体的刺激。 结果将集中于伤害性阈值的调节和疼痛下降的效率 调制电路。 在第二个目标中，我们评估了 TBI 损伤神经元并促进持续的神经元损伤的假设。 LC 和 RVM 的炎症以及引起下行疼痛调节的功能变化。 除了脑干和脊柱组织的神经病理学评估外，我们还将使用显微注射 选择性神经毒素和化学遗传学 DREADDs 研究脑干疼痛调节功能 TBI 后的中心。 在最终目标中，我们使用两种多发伤模型，将 TBI 与软组织切口相结合，并分别： 我们勇敢地使用临床上可用的去甲肾上腺素能和血清素能调节剂。 信号传导将减少伤害性敏化，增强下行疼痛调节并减少 周围创伤和 TBI 对神经炎症的相互作用以及几种与疼痛相关的表达 通过减少与慢性疼痛相关的变化，我们进一步阻碍了功能测量， 受伤后焦虑和认知变化的影响都会较小。 在项目完成时，我们希望更好地了解 TBI、外周损伤和 损伤的组合会导致慢性疼痛。在评估过程中，我们将描述以下因素的作用。 特定脑干疼痛调节中心的功能障碍我们预计能够制定计划。 使用一些与临床前相同的药物和方法进行的转化人体研究。