Novel treatments of chronic pain due to repetitive mild traumatic brain injury

项目摘要 在退伍军人和平民人群中观察到的一种常见情况是头部轻度脑震荡，原因是 摔倒了。经常摔倒和伴随的轻微头部受伤是老年退伍军人的主要问题，特别是 男性，往往会导致记忆力受损、抑郁、焦虑和慢性疼痛。大量研究表明 慢性疼痛状态伴随着神经炎症，尽管局部和纵向特征 在这种创伤诱导的过程中，对长期慢性疼痛的神经生物学贡献在很大程度上是未知的。 颅脑损伤后神经炎症的调节失调可能受NOD样受体蛋白3的调节 (NLRP3)caspase-1的炎性小体激活，caspase-1是一种切割许多下游的半胱氨酸蛋白酶 靶点，包括前-IL-1β和前-IL-18进入其生物活性形式。这些细胞因子的持续增加 在中枢神经系统，反过来，促进慢性广泛性疼痛，可以影响身体的多个部位。至 为了更好地理解轻微脑震荡事件导致慢性疼痛的过程，我们将使用 构建表达caspase-1激活的荧光素酶报告基因的转基因小鼠。这一点的利用 转基因小鼠结合小鼠闭合性脑震荡事件与活体成像兼容 这将使我们第一个目标是监测神经炎症信号级联的时空动力学 在年轻和年长的雄性和雌性小鼠的大脑中。这些观察结果很可能与 慢性疼痛状态的发作。在第二个目标中，我们将确定药物抑制是否 NLRP3炎性小体组件改善慢性神经炎症和疼痛的行为相关性 老鼠。总之，这些目标将提供有关神经炎症调节因子在脑内的作用的关键信息。 跨时间的活体以及NLRP3靶向可能在多大程度上成为头部损伤的可行治疗策略- 诱发慢性疼痛状态。

PROJECT ABSTRACT A frequent condition observed in Veterans and civilian populations is a mild concussive event of the head due to a fall. Frequent falls and associated mild head injuries are a major problem among the older Veterans, especially males and can often lead to impaired memory, depression, anxiety and chronic pain. Numerous studies suggest that the chronic pain state is accompanied by neuroinflammation, though the regional and longitudinal profiles of this trauma-induced process contribution to long-term chronic pain neurobiology are largely unknown. Dysregulation of neuroinflammation following head injury may be modulated by Nod-like receptor protein 3 (NLRP3) inflammasome activation of caspase-1, the cysteine protease that cleaves numerous downstream targets, including pro-IL-1β and pro-IL-18 into their biologically active form. Sustained increase of these cytokines in the central nervous system, in turn, promotes chronic widespread pain that can affects multiple body sites. To better understand the processes which contribute to chronic pain due to a mild concussive event, we will use a transgenic mouse constitutively expressing a luciferase reporter of caspase-1 activation. Utilization of this transgenic mouse in combination with a murine closed-head concussive event is compatible with in vivo imaging and will allow us in the first aim to monitor the spatiotemporal dynamics of a neuroinflammation signaling cascade in the brain of younger and older male and female mice across time. These observations will likely correlate with the onset of chronic pain states. In the second aim, we will determine whether pharmacological inhibition of NLRP3 inflammasome assembly ameliorates chronic neuroinflammation and behavioral correlates of pain in mice. Together, these Aims will provide crucial information on the function of a regulator of neuroinflammation in vivo across time and the degree to which NLRP3 targeting may be a viable therapeutic strategy in head injury- induced chronic pain states.