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

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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.