Two-hour infusion of vasoactive intestinal polypeptide induces delayed headache and extracranial vasodilation in healthy volunteers

Abstract

Background 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. Methods 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. Results The superficial temporal artery diameter was significantly larger on the VIP day compared to placebo ( p < 0.001) and the dilation lasted for more than 2 h. The incidence of headache was higher ( p = 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, p = 0.034) and in the post-hospital phase (4–12 h, p = 0.025). Cranial parasympathetic activity, measured through the production of tears, was higher during VIP compared to placebo ( p = 0.033). Conclusion 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. Trial Registration: The study is registered at ClinicalTrials.gov (NCT03989817).

Nocebo response in human models of migraine: A systematic review and meta-analysis of randomized, double-blind, placebo-controlled, two-way crossover trials in migraine without aura and healthy volunteers

“…A total of 943 articles were screened by title and abstract. Of these, 27 studies met the inclusion criteria (1994 and 2020) and were included in the qualitative and quantitative analysis (9–35) (Figure 1). Twelve studies (10 published and two studies under review) reported data on the incidence of migraine attacks after placebo in individuals with migraine without aura (9–17,31,33), whereas 10 studies did so in healthy volunteers (18,19,22,23,25,27,29,30,32,34).…”

“…Twelve studies (10 published and two studies under review) reported data on the incidence of migraine attacks after placebo in individuals with migraine without aura (9-17,31,33), whereas 10 studies did so in healthy volunteers (18,19,22,23,25,27,29,30,32,34). Furthermore, 16 studies reported data on the incidence of delayed headache after placebo in healthy volunteers (13,(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)32,34). A summary of the included studies is presented in Table 1 and Table 2.…”

“…Seventeen studies were included in the primary analysis, comprising a total of 210 healthy volunteers (13,(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)32,34). The random effects meta-analysis showed that the incidence of delayed headache after placebo was 10.5% (95% CI ¼ 4.8-17.6%, I 2 ¼ 45.2%).…”

Plasma levels of vasoactive neuropeptides in pediatric patients with migraine during attack and attack-free periods

“…Our plasma VIP findings are consistent with these previous reports, although our results were observed in pediatric migraineurs. Another clinical study recently demonstrated that more prolonged VIP-mediated vasodilation provokes more headache than shorter vasodilation (34). Considered together, PACAP-38 and VIP may contribute to migraine pain through both vasodilation and dural mast cell degranulation.…”

PACAP induces light aversion in mice by an inheritable mechanism independent of CGRP

“…We have shown that, similar to our results when testing PACAP-27, VIP can also induce light aversive behavior in mice if measured immediately after administration, consistent with its shorter half-life compared to PACAP (Mason et al, 2020). This suggests that the VPAC receptors are capable of inducing migraine-like phenotypes in mice, which has recently been validated by prolonged VIP infusion causing delayed headache in people (Pellesi et al, 2020). Alternatively, it is possible that PACAP-38 involvement in migraine may be independent of the VPAC or PAC1 receptors.…”