Traumatic Brain Injury and Endogenous Pain Modulation

创伤性脑损伤和内源性疼痛调节

• 批准号: 10552600
• 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/10552600
• 关键词: 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; Genetic; 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; Population; Positioning Attribute; Preclinical Testing; Process; Productivity; Rattus; Reagent; Regulation; Regulatory Pathway; Resources; Rodent; Role; Selective Serotonin Reuptake Inhibitor; 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; Vertebral column; Veterans; War; antinociception; behavior test; behavioral outcome; chronic pain; cognitive change; combat; design; designer receptors exclusively activated by designer drugs; disability; efficacy evaluation; experience; healing; human model; inhibitor; insight; locus ceruleus structure; member; midbrain central gray substance; neural circuit; neuroinflammation; neuropathology; noradrenergic; pain inhibition; pharmacologic; 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.

战争伤害后和平民环境中遭受创伤后的慢性疼痛和残疾， 出乎意料的常见。与创伤性脑损伤（TBI）相关的慢性疼痛联合外周 受伤是特别成问题的，我们没有有效的治疗方法。可能解释了创伤性脑损伤- 慢性疼痛关系，来自人类和动物模型的数据表明， 在TBI之后，调制被破坏。最近使用脑损伤和TBI的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。 组织学和功能性TBI研究表明，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 去甲肾上腺素能抑制脊髓。此外，TBI改变了头端腹内侧核的功能， 延髓（RVM），一种提供下行疼痛促进和疼痛抑制的多巴胺能神经递质的结构， 纤维因此，我们的主要目标是评估TBI后的内源性疼痛调节机制， 在这种情况下，临床前测试可翻译的疼痛控制方法。 在第一个目标中，我们评估了TBI通过改变神经元的功能来破坏下行疼痛调制的假设。 去甲肾上腺素能和肾上腺素能下行回路。该实验方法使用经过充分验证的大鼠 沿着广泛的时间进程研究TBI的流体冲击模型以模拟亚急性和慢性损伤。 靶向去甲肾上腺素释放的高选择性和临床可用的药理学工具， 将使用α 2-肾上腺素能以及5-HT 3和5-HT 7受体的张力和刺激。 结果将集中在伤害性阈值的调节和降低疼痛的效率 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神经元损伤的假设。 LC和RVM中的炎症以及引起下行疼痛调制的功能变化。 除了脑干和脊髓组织的神经病理学评估外，我们还将使用显微注射技术， 选择性神经毒素和化学发生性DREADDs研究脑干疼痛调节功能 TBI后的中心 在最后的目的，我们使用两种模型的多发伤结合TBI与软组织切口，分别， 胫骨骨折我们假设临床上可获得的去甲肾上腺素能和肾上腺素能的调节剂 信号传导将减少伤害性敏感化，增强下行疼痛调节，并减少 外周创伤和TBI对神经炎症反应的相互作用及几种疼痛相关蛋白的表达 脊髓基因通过减少慢性疼痛相关的变化，我们进一步假设， 焦虑和认知变化在受伤后都不会受到太大影响。 在项目完成时，我们希望更好地了解TBI、外周损伤和 这些损伤的组合会导致慢性疼痛。在评估过程中，我们将描述以下方面的作用： 特定脑干疼痛调节中心的功能障碍。我们预计将在位置计划 使用临床前采用的一些相同试剂和方法的转化人类研究。