PACAP: Lessons From A Potent Migraine Inducer?

Another topic important to our understanding of the pathophysiology of migraine was presented at AAN 2015 by Henrik Schytz, MD.* Dr Schytz has recently been involved in the investigation of pituitary adenylate cyclase-activating peptide (PACAP)--a potent migraine inducer, which offers potential insight into a new therapeutic target for migraine. PACAP is present in the trigeminocervical complex and is elevated acutely during a migraine attack. Recent work has also confirmed that when migraine is effectively treated with sumatriptan, PACAP levels return to baseline.¹

PACAP has been the subject of a number of recent studies. Dr Schytz has been involved in current efforts to better characterize its physiological, biochemical, and migraine-inducing effects.²

This double-blind crossover study recruited 24 females who had episodic migraine without aura and randomly allocated them to receive either PACAP38 or vasoactive intestinal peptide (VIP). Subjects were monitored closely for development of migraine symptoms over the next 24 hours. Serum levels of PACAP, VIP, and tryptase were measured at baseline and at 60 min, and 300 min. If migraine was triggered, subcutaneous sumatriptan was administered. MRA of selected intra- and extracranial arteries of the head was also conducted at baseline, 2 hours post-infusion, at onset of migraine, and 30 min after resolution of migraine (or at 5 hours if migraine did not occur). The goal was to characterize PACAP38 with regard to its potential migraine-inducing effects, associated plasma levels, and evidence of mast cell degranulation as an associated mechanism (elevated tryptase) as well as the peptide's potential vascular effects.

The results demonstrated that PACAP38 was a potent aggravator of migraine. 73% of patients reported migraine-like attacks with a median onset of 4h 15 min after infusion compared with 18% after VIP infusion (p=0.0020). Measured PACAP38 serum concentration was significantly higher at 60 min than expected from infusion alone in those with migraine attacks compared with those who were headache free, suggesting potential de novo release. Arterial imaging of intracranial vessels showed no change in circumference at any time point. However dilation of the extracranial arteries was demonstrated in both infusion groups: greater dilation was seen in the superficial temporal arteries and middle meningeal arteries in the PACAP38 group. This dilation subsequently reversed after sumatriptan administration. There was no significant change in tryptase levels in any group, which suggests that widespread mast cell degranulation did not occur.

Overall, this study supports the hypothesis that PACAP38 is involved in the migraine pathway via mechanisms similar to those of CGRP. Not only do levels of the peptide rise and fall with the onset and treatment of the attack, but now it has now been demonstrated that administration of PACAP38 induces attacks in migraineurs. This provides several new potential therapeutic targets --  most prominently a specific PACAP receptor PAC1. With additional study, the development of a PAC1 antagonist may potentially lead to a new class of migraine treatment.

*Dr Schytz was the winner of the Harold Wolff-John Graham Award, an annual award sponsored by the AAN for outstanding research in the area of Headache and Facial Pain Research.

References:

1. Zagami AS, Edvinsson L, Goadbsy PJ. Pituitary adenylate cyclase activating polypeptide and migraine. Ann Clin Transl Neurol. 2014;1:1036-1040.
2. Amin FM, Hougaard A, Schytz HW, et al. Investigation of the pathophysiological mechanisms of migraine attacks induced by pituitary adenylate cyclase-activating polypeptide-38. Brain.2014:137;779-794.