Development of CGRP-dependent pain and headache related behaviours in a rat model of concussion: Implications for mechanisms of post-traumatic headache

Abstract

Background and objective Posttraumatic headache (PTH) is one of the most common, debilitating and difficult symptoms to manage after a mild traumatic brain injury, or concussion. However, the mechanisms underlying PTH remain elusive, in part due to the lack of a clinically relevant animal model. Here, we characterized for the first time, headache and pain-related behaviours in a rat model of concussion evoked by a mild closed head injury (mCHI) - the major type of military and civilian related trauma associated with PTH - and tested responses to current and novel headache therapies. Methods Concussion was induced in adult male rats using a weight-drop device. Characterization of headache and pain related behaviours included assessment of cutaneous tactile pain sensitivity, using von Frey monofilaments, and ongoing pain using the conditioned place preference or aversion (CPP/CPA) paradigms. Sensitivity to headache/migraine triggers was tested by exposing rats to low-dose glyceryl trinitrate (GTN). Treatments included acute systemic administration of sumatriptan and chronic systemic administration of a mouse anti-CGRP monoclonal antibody. Results Concussed rats developed cephalic tactile pain hypersensitivity that was resolved by two weeks post-injury and was ameliorated by treatment with sumatriptan or anti-CGRP monoclonal antibody. Sumatriptan also produced CPP seven days post mCHI, but not in sham animals. Following the resolution of the concussion-evoked cephalic hypersensitivity, administration of GTN produced a renewed and pronounced cephalic pain hypersensitivity that was inhibited by sumatriptan or anti-CGRP antibody treatment as well as a CGRP-dependent CPA. GTN had no effect in sham animals. Conclusions Concussion leads to the development of headache and pain-related behaviours, in particular sustained enhanced responses to GTN, that are mediated through a CGRP-dependent mechanism. Treatment with anti-CGRP antibodies may be a useful approach to treat PTH.

Symptoms of Autonomic Dysfunction Among Those With Persistent Posttraumatic Headache Attributed to Mild Traumatic Brain Injury: A Comparison to Migraine and Healthy Controls

“…Migraine is the phenotype observed in the majority of individuals with PTH . Investigations into mechanisms of PTH have used brain imaging, measurement of pain modulatory systems and cranial sensitization with thermal and pressure stimulation, and animal models . At present, it is unknown if PTH is a unique headache type with separate pathophysiology and clinical features from migraine and there have been few studies investigating this possibility .…”

“…[2][3][4][5][6][7][8] Investigations into mechanisms of PTH have used brain imaging, [9][10][11] measurement of pain modulatory systems and cranial sensitization with thermal and pressure stimulation, 12 and animal models. [13][14][15] At present, it is unknown if PTH is a unique headache type with separate pathophysiology and clinical features from migraine and there have been few studies investigating this possibility. 16,17 Investigations that deeply phenotype individuals with PTH and compare the PTH phenotype to migraine might lead to identification of features that are more representative of PTH compared to migraine.…”

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.…”

Increased severity of closed head injury or repetitive subconcussive head impacts enhances post-traumatic headache-like behaviors in a rat model

“…Yet, many cases of PTH arise de novo following a concussive head trauma (8). We have recently characterized a rat model of de novo PTH that displays numerous headache/migraine-like pain behaviors following a single mild closed head injury (CHI) (9). In particular, we observed the development of cephalic mechanical allodynia that could be ameliorated by systemic treatment with a blocking monoclonal antibody that targets calcitonin-gene-related peptide (Anti-CGRP mAb) (9), suggesting the involvement of peripheral CGRP signaling.…”