Figure 3.

CGRP actions on dural mast cells. Compounds such as CGRP, substance P or inflammatory cytokines can bind to mast cells via a diverse array of receptors (66, 108). Following activation, the mast cell releases granules that contain compounds such as histamine, heparin, enzymes like tryptase, many different cytokines and serotonin (68, 72, 113). The effect of these compounds is diverse. Among the most prominent are histamine and serotonin. Histamine can cause vasodilation and immune activation. Serotonin has mixed vascular activity depending on the site of action. It has been found to dilate middle meningeal arteries (114). It can also modulate cytokine release from monocytes (115). Tryptase is a protease that can cleave other proteins, such as protease-activated receptor (PAR) 2. PAR-2 activation is thought to sensitize transient receptor potential channels present on sensory afferents, so downstream protease activity could possibly result in TG sensitization (116). The cytokines found in mast cells are incredibly diverse, and both pro- and anti-inflammatory cytokines have been found but degranulation is believed to drive further inflammation and sensitization of afferents (117).