Peripheral Mechanisms of Posttraumatic Headache

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DESCRIPTION (provided by applicant): Persistent headache is one of the most common symptoms following a mild traumatic head injury, but for many individuals with posttraumatic headache (PTH) overall pain management remains unsatisfactory, leading to suffering and poor quality of life. The inability to effectively control PTH pain can be attributed in part to the poo understanding of the pathophysiology underlying PTH. Preclinical research on PTH has been hampered by the lack of an animal model that mimics the most common type of head trauma and exhibits behaviors that can be linked to ongoing headache and persistent pain. The goal of following proposal is to examine key peripheral mechanisms that could contribute to the development of PTH pain. Based on exciting preliminary data, our working hypothesis is that mild head trauma leads to inflammatory-driven persistent activation and sensitization of primary afferent neurons that innervate the extracranial calvarial periosteum and intracranial dura mater, which in turn promote the development of sensory and affective changes that can be linked to PTH pain. We propose a series of studies that employ electrophysiology, behavioral testing, histology, pharmacology and mutant animals that lack immune cells to study our working hypothesis by addressing the following open questions: 1) Does head trauma lead to persistent activation and increased mechanical and chemical sensitivities of primary afferent neurons that innervate the calvarial periosteum and/or intracranial dura (Specific Aim 1)? 2) If so, do these neurophysiological changes correlate and contribute to the development of pericranial cutaneous allodynia, a sensory change linked to persistent headache, and suppression of burrowing, a change in innate behavior that reflects an affective (aversive) dimension of persistent pain (Specific Aim 2)? 3) Does a posttraumatic peripheral inflammatory response, in particular the recruitment and activation of immune cells within the skull's periosteum and intracranial dura, contribute to the posttraumatic neurophysiological changes and the ensuing behavioral changes linked to PTH pain. Results from this project will provide important insights into the pathogenesis of PTH, including the peripheral tissues from which PTH pain likely arise, the neurophysiological correlate of the headache and its underlying mechanisms. This novel information could lead to the expansion of the targets of interventions that can be used to alleviate this poorly understood trauma-related pain.