Fig. 1.

Neurogenic vasodilation in migraine. Activation of peptidergic trigeminal sensory neurons results in the release of calcitonin gene-related peptide (CGRP), which acting at the CGRP-like receptor (CLR) coupled to receptor activity-modifying protein-1 (RAMP1), relaxes smooth muscle cells of intra- and extracranial arteries. Exogenous or endogenous agonists of transient receptor potential vanilloid 1 (TRPV1) or ankyrin 1 (TRPA1) promote the release of CGRP. Prostaglandins (PGs), bradykinin (BK) or other proalgesic agents, either directly via activation of their specific G protein coupled receptors (GPCR) or indirectly (through channel activation) also contribute to neuropeptide release. Nitric oxide (NO) generated from glyceryl trinitrate (GTN) acts downstream to CGRP to evoke vasodilatation and probably headache. Neurogenic vasodilatation in addition to cause the headache may also contribute to neuronal sensitization. Sumatriptan and other triptans inhibit CGRP release acting at prejunctional serotonin 5-HT1D receptors or evoke arterial vasoconstriction via stimulation of 5-HT1B receptors on vascular smooth muscle. Botulinum neurotoxin type A (BoNTA) has also been shown to inhibit CGRP release