Abstract
Posttraumatic 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 headache and pain behaviors using a recently developed rat model of mild closed head injury (mCHI). We initially employed a monoclonal antibody against CGRP and used histological methods and 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 PTH-related 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 trinitrate (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.
Highlights
Ongoing activation of meningeal mast cells (MCs) following a mild closed head injury (mCHI) is independent of peripheral CGRP signaling.
Prophylactic depletion of meningeal MC content prior to mCHI does not affect the development of acute posttraumatic headache-like behavior.
Prophylactic depletion of meningeal MC content prior to mCHI induction blocks the establishment of chronic latent sensitization to glyceryl trinitrate (GTN), a major headache trigger.
Latent sensitization to GTN post-mCHI does not involve acute activation of meningeal MCs.
Footnotes
Disclosures: The study was funded by NIH grants NS086830, NS078263, NS101405 to DL and in part by Teva Pharmaceuticals, through a grant to DL. DB has no conflict of interest to declare.
Authorship: Authorship has been granted only to those individuals who have contributed substantially to the research or manuscript.