Figure 2.

Neurogenic inflammation and its main features. (A) Stimulation of the trigeminal nerve causes the release of neuropeptides, including CGRP, SP, NO, VIP, and 5-HT, leading to neurogenic inflammation, which has four main features: the increased vascular permeability, leukocyte infiltration, glial cell activation, and increased production of inflammatory mediators, such as cytokines and chemokines. (B) Vasoactive peptides, such as CGRP and SP, bind their receptors on smooth muscle of dural vessels and cause vasodilation. The released neuropeptides induce mast cell degranulation, resulting in the release of histamine, which leads endothelium-dependent vasodilation. (C) Binding of the released SP to the NK1 receptors expressed on the microvascular blood vessels disrupts the membrane and causes plasma protein leakage and leukocyte extravasation. (D) Mast cells are in close association with neurons, especially in the dura, where they can be activated following trigeminal nerve and cervical or sphenopalatine ganglion stimulation. Release of neuropeptides causes mast cell degranulation, which leads to release of histamine and serotonin and selectively can cause the release of pro-inflammatory cytokines, such as TNF-α, IL-1, and IL-6. (E) Under the influence of inflammatory stimuli, microglia can become reactive microglia. Microglia activation leads to the production of inflammatory mediators and cytotoxic mediators.