title: Trigeminal Pain Molecules, Allodynia, and Photosensitivity Are Pharmacologically and Genetically Modulated in a Model of Traumatic Brain Injury.
abstract: The pain-signaling molecules, nitric oxide synthase (NOS) and calcitonin gene-related peptide (CGRP), are implicated in the pathophysiology of post-traumatic headache (PTH) as they are for migraine. This study assessed the changes of inducible NOS (iNOS) and its cellular source in the trigeminal pain circuit, as well as the relationship between iNOS and CGRP after controlled cortical impact (CCI) injury in mice. The effects of a CGRP antagonist (MK8825) and sumatriptan on iNOS messenger RNA (mRNA) and protein were compared to vehicle at 2 weeks postinjury. Changes in CGRP levels in the trigeminal nucleus caudalis (TNC) in iNOS knockouts with CCI were compared to wild-type (WT) mice at 3 days and 2 weeks post injury. Trigeminal allodynia and photosensitivity were measured. MK8825 and sumatriptan increased allodynic thresholds in CCI groups compared to vehicle (p < 0.01), whereas iNOS knockouts were not different from WT. Photosensitivity was attenuated in MK8825 mice and iNOS knockouts compared to WT (p < 0.05). MK8825 and sumatriptan reduced levels of iNOS mRNA and iNOS immunoreactivity in the TNC and ganglia (p < 0.01). Differences in iNOS cellular localization were found between the trigeminal ganglia and TNC. Although the knockout of iNOS attenuated CGRP at 3 days (p < 0.05), it did not reduce CGRP at 2 weeks. CGRP immunoreactivity was found in the meningeal layers post-CCI, while negligible in controls. Findings support the importance of interactions between CGRP and iNOS in mediating allodynia, as well as the individual roles in photosensitivity. Mitigating prolonged increases in CGRP may be a promising intervention for treating acute PTH.
authors.affiliation: Department of Neurological Surgery, Thomas Jefferson University , Philadelphia, Pennsylvania.
authors.forename: Brittany V
authors.initials: BV
authors.lastname: Daiutolo
authors.affiliation: Department of Neurological Surgery, Thomas Jefferson University , Philadelphia, Pennsylvania.
authors.forename: Ashley
authors.initials: A
authors.lastname: Tyburski
authors.affiliation: Department of Neurological Surgery, Thomas Jefferson University , Philadelphia, Pennsylvania.
authors.forename: Shannon W
authors.initials: SW
authors.lastname: Clark
authors.affiliation: Department of Neurological Surgery, Thomas Jefferson University , Philadelphia, Pennsylvania.
authors.forename: Melanie B
authors.initials: MB
authors.lastname: Elliott
mesh_terms: D000818:Animals; D000070642:Brain Injuries, Traumatic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D015740:Calcitonin Gene-Related Peptide / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D006930:Hyperalgesia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency* / Q000235:genetics; D010775:Photic Stimulation / Q000379:methods; D010787:Photosensitivity Disorders / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D011897:Random Allocation; D013141:Spiro Compounds / Q000494:pharmacology / Q000627:therapeutic use; D018170:Sumatriptan / Q000494:pharmacology / Q000627:therapeutic use; D014276:Trigeminal Nerve / Q000378:metabolism / Q000473:pathology
chemical_list: C575097:MK-8825; D011725:Pyridines; D013141:Spiro Compounds; D018170:Sumatriptan; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D015740:Calcitonin Gene-Related Peptide
keywords: pain; post-traumatic headache; post-traumatic migraine; traumatic brain injury; trigeminovascular system