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Presented at National Neurotrauma Symposium 2015 in Santa Fe New Mexico.



Headache following traumatic brain injury (TBI) is highly prevalent, and it is also the most common and persistent symptom of post-concussion syndrome [1,2]. It could arise de novo or as a pre-existing headache disorder, in which migraine was the most frequent headache phenotype in both civilian and military patients with mild TBI [1,2]. Most post-traumatic headaches will resolve within a couple of weeks following injury; however, headache in a substantial subset of patients may last more than three months and contribute to a prolonged recovery from injury, disability, and a poor quality of living [2]. Headaches can persist well beyond the acute inflammatory period, necessitating intervention and preventative strategies for chronic post-traumatic headache as a time-sensitive problem to address.

Key pain signaling molecules, calcitonin gene-related peptide (CGRP) and nitric oxide synthase (NOS), play a role in post-traumatic headache pathophysiology as they do for migraine. CGRP and NO/NOS are proposed to have reciprocal feedback mechanisms in the trigeminovascular system. CGRP, a well-studied nociceptive neuropeptide in the fields od pain and migraine, increases in the trigeminal pain system after TBI [3]. A recent study by our laboratory noted significant iNOS (inducible nitric oxide synthase) positive cells from a microglial and/or macrophage source in the cortical area proximal to the injury [4]. Typically, iNOS is characterized locally at the injury site making the trigeminal pain circuit, an area remote from the injury site, a novel site to investigate. Nitric oxide triggers headache in migraineurs and animal models via abnormal activation of the trigeminovascular system. Nitric oxide is produced by different isoforms of the nitric oxide synthase (NOS) enzymes. Of the NOS isoforms, the inducible isoform was investigated as inflammation is a predominant feature of TBI and post-traumatic headache. Therefore, the goals of this research were threefold: (1) to investigate if iNOS gene and protein expression in the trigeminal ganglia and trigeminal nucleus caudalis (TNC) are altered in a murine model of controlled cortical impact (CCI) injury, (2) to identify the cellular source for changes in the expression of iNOS, and (3) to examine the proposed synergism between CGRP and iNOS in an in vivo model of TBI.