• Dara Bree and Dan Levy.
• Departments of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States.
• Pain. 2019 May 1; 160 (5): 1050-1058.

AbstractPost-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.

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