Investigators at Danish Headache Centre, University of Copenhagen, Glostrup, Denmark, studied the incidence of migraine during and after intravenous infusion of pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) and vasoactive intestinal polypeptide (VIP) in 22 female migraine patients without aura (mean age 24 years [range 19-36]). Sixteen patients (73%) reported migraine-like attacks after PACAP38 and 4 after VIP (18%) infusion (P=0.002). Three of 4 patients who reported migraine-like attacks after VIP also reported attacks after PACAP38. Both peptides induced dilatation of extracranial (P<0.05) but not intracranial arteries (P>0.05). PACAP38-induced vasodilatation lasted >2 h whereas VIP-induced dilatation was normalized after 2 h. Plasma PACAP38 levels were elevated at 1 h after starting infusion only in patients who reported migraine attacks. PACAP38 has a high affinity for the PAC1 receptor. Activation of the PAC1 receptor may explain the mechanism of migraine and offer a target for development of anti-migraine drugs. 
COMMENTARY. A commentary from the Department of Neurology, University of Szeged, Hungary, discusses the trigemino-vascular theory of migraine and the pain- transmission link between the vascular and neuronal regions . PACAP and other neuropeptides have essential roles in activation of the trigemino-vascular system. PACAP38 is present in the trigeminal ganglion and caudal trigeminal nucleus. The effects of PACAP38 are mediated through G-protein-linked receptors, including PAC1. The clinical study by Amin et al  is consistent with previous laboratory animal studies comparing the effects of nitroglycerol and PACAP on the trigemino-vascular system .