Objective: Review evidence supporting the role of mast cells in migraine pathophysiology. Background: Mast cells are known for their role in allergic reactions, but they are also important in immunity and inflammatory diseases, especially those precipitated or worsened by stress. Such are migraine headaches that are associated with spreading neuronal depression and neurogenic inflammation intracranially. Migraines are also comorbid with allergies and could precipitate acute coronary syndromes (ACS). Mast cells are located perivascularly, in close association with neurons, especially in the meninges. Mast cells can be activated by trigeminal nerve stimulation and by acute stress, leading to increased vascular permeability and neurogenic inflammation dependent on NK-1 receptors, but not necessarily on substance P (SP). Methods: We reviewed relevant literature and summarized our own findings. Results: Corticotropin-releasing hormone (CRH), a mediator of the stress response released from the hypothalamus, can activate CRH receptors either on the sensory nuclei of the trigeminal nerve or directly on the mast cells. They, then release proinflammatory, nociceptive and vasoactive mediators including histamine, tryptase and vascular endothelial growth factor (VEGF), thereby triggering migraine headaches. Conclusions: These results indicate that there are several novel points of intervention for the development of therapeutic agents to help alleviate migraines. Preliminary clinical studies with brain mast cell blockers and CRH receptor antagonists suggest that they could be useful prophylactically
