Post-traumatic headache (PTH) is one of the most common, debilitating, and difficult symptoms to manage after a traumatic head injury. Although the mechanisms underlying PTH remain elusive, recent studies in rodent models suggest the potential involvement of calcitonin gene–related peptide (CGRP), a mediator of neurogenic inflammation, and the ensuing activation of meningeal mast cells (MCs), proalgesic resident immune cells that can lead to the activation of the headache pain pathway. Here, we investigated the relative contribution of MCs to the development of PTH-like pain behaviors in a model of mild closed-head injury (mCHI) in male rats. We initially tested the relative contribution of peripheral CGRP signaling to the activation of meningeal MCs after mCHI using a blocking anti-CGRP monoclonal antibody. We then used a prophylactic MC granule depletion approach to address the hypotheses that intact meningeal MC granule content is necessary for the development of PTH-related pain-like behaviors. The data suggest that after mCHI, ongoing activation of meningeal MCs is not mediated by peripheral CGRP signaling and does not contribute to the development of the mCHI-evoked cephalic mechanical pain hypersensitivity. Our data, however, also reveal that the development of latent sensitization, manifested as persistent hypersensitivity upon the recovery from mCHI-evoked acute cranial hyperalgesia to the headache trigger glyceryl trinitrate 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 after a concussion or mCHI. Targeting MCs may be explored for early prophylactic treatment of PTH.
Calcitonin gene–related peptide–independent activation of meningeal mast cells does not mediate acute post-traumatic headache-like behavior but contributes to the development of trauma-evoked chronic latent pain sensitization.
Departments of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States
Corresponding author. Address: Department of Anesthesia, Critical Care, and Pain Medicine, 330 Brookline Ave/DA 717, Boston, MA 02215, United States. Tel.: 617-667-0534. E-mail address: email@example.com (D. Levy).
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
Received October 31, 2018
Received in revised form December 20, 2018
Accepted December 26, 2018