Trigeminal Pain Molecules, Allodynia, and Photosensitivity Are Pharmacologically and Genetically Modulated in a Model of Traumatic Brain Injury.

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.

Mechanical allodynia induced by traumatic brain injury is independent of restraint stress.

BACKGROUND: This study identifies the relationship between a test for post-traumatic headache and a marker for acute stress in rodent models of traumatic brain injury. NEW METHOD: C57BL/6 mice and Sprague Dawley rats were divided into Controlled Cortical Impact (CCI) injury, craniotomy (CR), and incision groups. Periorbital and paw allodynia were evaluated using the von Frey test prior to injury and up to four weeks post-operatively. Serum corticosterone was evaluated in groups with and without mild restraint. RESULTS: Periorbital and forepaw thresholds, but not hindpaw thresholds, were reduced in CCI and CR mice compared to incision (p<0.0001 and p<0.01). In contrast to mice, reduced periorbital and forepaw periorbital thresholds were found in CCI rats but not CR rats compared to incision (p<0.0001). Right periorbital thresholds were reduced compared to left thresholds for both rat and mouse at one week (p<0.01), but there were no side differences for forepaw thresholds. Hindpaw thresholds did not change from baseline values for any groups of mice or rats. In mice serum corticosterone levels were increased at one, two and four weeks post-CCI and CR, while the levels for rats were not different from incision (p<0.0001). Corticosterone levels were not different in mice subjected to restraint compared to no restraint. COMPARISON WITH EXISTING METHODS: This study presents novel data for allodynia in a rat model of TBI, and differences among mouse and rat species. CONCLUSIONS: Mechanical allodynia occurs independent of evoked restraint stress, while hypothalamic pituitary adrenal axis activity is dependent on head trauma and species.