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.
Background Chronic post-traumatic headache (PTH) is one of the most common symptoms of mild traumatic brain injury (mTBI) but its underlying mechanisms remain unknown. Inflammatory degranulation of dural mast cells (MCs) is thought to promote headache, and may play a role in PTH. Whether mTBI is associated with persistent degranulation of dural MCs is yet to be determined. Methods Histochemistry was used to evaluate time course changes in dural MC density and degranulation level in concussive head trauma and blast mouse models of mTBI. The effects of sumatriptan and the MC stabilizer cromolyn sodium on concussion-evoked dural MC degranulation were also investigated. Results Concussive head injury evoked persistent MC degranulation for at least 30 days. Blast trauma gave rise to a delayed MC degranulation response commencing at seven days that also persisted for at least 30 days. Neither sumatriptan nor cromolyn treatment reduced concussion-evoked persistent MC degranulation. Conclusions mTBI evoked by closed head injury or blast exposure is associated with persistent dural MC degranulation. Such a response in mTBI patients may contribute to PTH. Amelioration of PTH by sumatriptan may not involve inhibition of dural MC degranulation. If persistent dural MC degranulation contributes to PTH, then cromolyn treatment may not be effective.
Acute pain following inguinal hernia repair can be difficult to treat. Here we report, for the first time, the development of a novel, anatomically relevant rat model to facilitate improved understanding and treatment of acute postoperative pain following inguinal hernia repair.
Highlights• Administration of an anti-CGRP mAb does not block ongoing meningeal mast cells (MCs) degranulation following a mild closed head injury (mCHI).• mCHI-evoked cephalic mechanical hyperalgesia does not involve acute degranulation of MCs.• Depletion of meningeal MCs content prior to mCHI blocks the development of chronic latent sensitization to the headache trigger glyceryl trintrate (GTN) following recovery from the initial mCHI-evoked acute cranial hyperalgesia• GTN-evoked delayed cephalic and extracephalic mechanical pain hypersensitivity is associated with the latent sensitization is not mediated by GTN-evoked meningeal MC degranulation.. CC-BY-NC-ND 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/392928 doi: bioRxiv preprint first posted online Aug. 16, 2018; AbstractPosttraumatic headache (PTH) is one of the most common, debilitating and difficult symptoms to manage after a mild traumatic brain injury, or concussion. While the mechanisms underlying PTH remain elusive, recent studies suggest the potential involvement of calcitonin gene-related peptide (CGRP), a mediator of neurogenic inflammation, and the ensuing activation of meningeal mast cells (MCs), key pro-algesic resident immune cells that can lead to the activation of the headache pain pathway. The following study investigated the relative contribution of MCs to the development of PTH-like pain behaviors using a recently developed rat model of mild closed head injury (mCHI). We initially employed histological methods and a monoclonal antibody against CGRP to test the relative contribution of peripheral CGRP signaling to the activation of meningeal MCs following mCHI. We then used a prophylactic, pharmacological MC granule depletion protocol, combined with behavioral nociceptive testing, to address the hypotheses that intact meningeal MC granule content is necessary for the development of PTHrelated acute and persistent headache and pain-like behaviors following mCHI. The data suggest that following mCHI, ongoing meningeal MC degranulation does not involve peripheral CGRP signaling, and that the cephalic mechanical pain hypersensitivity that develops following mCHI does not depend upon acute meningeal MC degranulation. Our data, however, also reveals that the development of latent sensitization, a key chronic pain-like phenomenon, manifested as persistent hypersensitivity upon the recovery from mCHI-evoked acute cranial hyperalgesia to the headache trigger glyceryl trinitate (GTN) requires intact MC content during and immediately after mCHI. Collectively, our data implicate the acute activation of meningeal MCs as mediator of chronic pain hypersensitivity following a concussion or mCHI. Targeting MCs may be explored for early prophylactic treatment of PTH.
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