In recent years, vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptides (PACAPs) have gained special interest in headache science. VIP and PACAPs (two isoforms, PACAP27 and PACAP38) are related in structure and function, as are their receptors, but they show differences in vasodilating- and headache-inducing properties. Intravenous infusion of PACAP27 or PACAP38, but not VIP, induces a long-lasting dilation of cranial arteries and delayed headache. The relationship between the long-lasting cranial vasodilation and headache development is not fully clarified.
In a double-blinded, placebo-controlled, crossover study in 12 healthy volunteers, diameter changes of cranial arteries, occurrence of headache and the parasympathetic system were examined before, during and after a 2-hour continuous intravenous infusion of VIP and placebo. Primary endpoints were the differences in area under the curve for the superficial temporal artery diameter and headache intensity scores, as well as in headache incidence, between VIP and placebo.
The superficial temporal artery diameter was significantly larger on the VIP day compared to placebo ( < 0.001) and the dilation lasted for more than 2 h. The incidence of headache was higher ( = 0.003) on the VIP day compared to the placebo day. The difference in headache intensity scores was more evident in the post-infusion period (120-200 min,  = 0.034) and in the post-hospital phase (4-12 h,  = 0.025). Cranial parasympathetic activity, measured through the production of tears, was higher during VIP compared to placebo ( = 0.033).
Continuous intravenous infusion of VIP over 2 h induced a long-lasting cranial vasodilation, activation of the cranial parasympathetic system, and delayed mild headaches in healthy volunteers. The study is registered at (NCT03989817).