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微震荡事件， 摔倒了频繁的福尔斯跌倒和相关的轻微头部损伤是老年退伍军人的一个主要问题， 男性，往往会导致记忆力受损，抑郁，焦虑和慢性疼痛。许多研究表明 慢性疼痛状态伴随着神经炎症，尽管区域和纵向轮廓 这种创伤诱导的过程对长期慢性疼痛神经生物学的贡献在很大程度上是未知的。 Nod样受体蛋白3可能调节脑损伤后神经炎症的失调 （NLRP 3）半胱天冬酶-1的炎性体活化，半胱天冬酶-1是切割许多下游的半胱氨酸蛋白酶， 靶点，包括pro-IL-1β和pro-IL-18转化为其生物活性形式。这些细胞因子的持续增加 中枢神经系统中的神经元，反过来，促进慢性广泛疼痛，可以影响多个身体部位。到 为了更好地了解由于轻微脑震荡事件导致慢性疼痛的过程，我们将使用 组成型表达半胱天冬酶-1激活的荧光素酶报告基因的转基因小鼠。利用这种 转基因小鼠与鼠闭头脑震荡事件的组合与体内成像相容 并将使我们在第一个目标，以监测时空动态的神经炎症信号级联 在年轻和年老的雄性和雌性小鼠的大脑中的变化。这些观察结果可能与 慢性疼痛状态的发作。在第二个目标中，我们将确定是否药理学抑制 NLRP 3炎性小体组装改善慢性神经炎症和疼痛的行为相关性 小鼠总之，这些目标将提供关于神经炎症调节剂在神经系统中的功能的重要信息。 体内随时间的变化以及NLRP 3靶向可能是头部损伤中可行的治疗策略的程度- 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.