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.

Persistent Post-Traumatic Headache and Migraine: Pre-Clinical Comparisons

“…Human-induced migraine studies have determined that Calcitonin Gene Related Peptide (CGRP) upregulate cyclic Adenosine Monophosphate (cAMP) levels, playing a key role in the pathogenesis of both migraine and PPTH [36]. CGRP is a potent vasodilator [37,38], whose receptors are present both in nerve fibers and in trigeminal neurons and in many areas involved in nociception and pain processing [39,40]. The release of CGRP, following trigeminal stimulation, induces neurogenic inflammation with mast cell degranulation [41], the release of pro-inflammatory modulators and the alteration of the blood-brain barrier [42].…”

Posttraumatic Headache: Basic Mechanisms and Therapeutic Targets

“…76 CGRP is released in response to head trauma in animal models and has been shown to mediate migraine-related behaviors in this setting including hyperalgesia and light avoidance [77][78][79][80] These data from animal models of traumatic brain injury, in combination with the substantial data regarding the role of CGRP in migraine, indicate that CGRP may also play an important role in PTH. 76 CGRP is released in response to head trauma in animal models and has been shown to mediate migraine-related behaviors in this setting including hyperalgesia and light avoidance [77][78][79][80] These data from animal models of traumatic brain injury, in combination with the substantial data regarding the role of CGRP in migraine, indicate that CGRP may also play an important role in PTH.…”

“…Neuropeptides.-CGRP.-There is now substantial evidence that calcitonin gene related peptide plays a primary role in migraine, and existing basic and clinical evidence for this role has been confirmed by the efficacy of small molecule CGRP receptor antagonists or antibodies targeting CGRP or its receptor. 76 CGRP is released in response to head trauma in animal models and has been shown to mediate migraine-related behaviors in this setting including hyperalgesia and light avoidance [77][78][79][80] These data from animal models of traumatic brain injury, in combination with the substantial data regarding the role of CGRP in migraine, indicate that CGRP may also play an important role in PTH. Quantification of CGRP levels in the acute posttraumatic period, or in patients with chronic posttraumatic headache could represent a valuable biomarker.…”

From blast to bench: A translational mini‐review of posttraumatic headache

“…In these experiments, mice showed increased mechanical allodynia in the periorbital region, both ipsi‐ and contralateral to the site of injury. Although peak nociception was observed 14 days following injury, allodynia persisted for up to 28 days post TBI (Elliott et al, ; Daiutolo et al, ). To support that this nociception was associated with PTH, two migraine medications—sumatriptan and the calcitonin gene‐related peptide (CGRP) antagonist MK8825—blocked CCI‐induced periorbital allodynia (Daiutolo et al, ).…”

“…Although peak nociception was observed 14 days following injury, allodynia persisted for up to 28 days post TBI (Elliott et al, ; Daiutolo et al, ). To support that this nociception was associated with PTH, two migraine medications—sumatriptan and the calcitonin gene‐related peptide (CGRP) antagonist MK8825—blocked CCI‐induced periorbital allodynia (Daiutolo et al, ). Furthermore, CCI also produced photophobia (Daiutolo et al, ), another frequently observed symptom of migraine (Rossi and Recober, ).…”