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- Title
Investigation of the pathophysiological mechanisms of migraine attacks induced by pituitary adenylate cyclase-activating polypeptide-38.
- Authors
Amin, Faisal Mohammad; Hougaard, Anders; Schytz, Henrik W.; Asghar, Mohammad S.; Lundholm, Elisabet; Parvaiz, Arushma I.; de Koning, Patrick J. H.; Andersen, Malene R.; Larsson, Henrik B. W.; Fahrenkrug, Jan; Olesen, Jes; Ashina, Messoud
- Abstract
A better understanding of migraine mechanisms is necessary to develop new treatments for this common and disabling condition. Amin et al. show that pituitary adenylate cyclase-activating peptide-38 (PACAP38) has greater migraine-inducing ability than vasoactive intestinal peptide. PACAP38 has higher affinity for the PAC1 receptor, which may represent a therapeutic target.Pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) and vasoactive intestinal polypeptide are structurally and functionally closely related but show differences in migraine-inducing properties. Mechanisms responsible for the difference in migraine induction are unknown. Here, for the first time, we present a head-to-head comparison study of the immediate and long-lasting observations of the migraine-inducing, arterial, physiological and biochemical responses comparing PACAP38 and vasoactive intestinal polypeptide. In a double-blind crossover study 24 female migraine patients without aura were randomly allocated to intravenous infusion of PACAP38 (10 pmol/kg/min) or vasoactive intestinal polypeptide (8 pmol/kg/min) over 20 min. We recorded incidence of migraine during and after infusion (0–24 h). Magnetic resonance angiography of selected extra- and intracranial arteries, blood samples (plasma PACAP38 and vasoactive intestinal polypeptide and serum tryptase), and vital signs (blood pressure, heart rate, respiratory frequency, and end-tidal pressure of CO2) was recorded before and up to 5 h after infusion. Twenty-two patients [mean age 24 years (range 19–36)] completed the study on both days. Sixteen patients (73%) reported migraine-like attacks after PACAP38 and four after vasoactive intestinal polypeptide (18%) infusion (P = 0.002). Three of four patients, who reported migraine-like attacks after vasoactive intestinal polypeptide, also reported attacks after PACAP38. Both peptides induced marked dilatation of the extracranial (P < 0.05), but not intracranial arteries (P > 0.05). PACAP38-induced vasodilatation was longer lasting (>2 h), whereas vasoactive intestinal polypeptide-induced dilatation was normalized after 2 h. We recorded elevated plasma PACAP38 at 1 h after the start of PACAP38 infusion only in those patients who later reported migraine attacks. Blood levels of vasoactive intestinal polypeptide and tryptase were unchanged after PACAP38 infusion. In conclusion, PACAP38-induced migraine was associated with sustained dilatation of extracranial arteries and elevated plasma PACAP38 before onset of migraine-like attacks. PACAP38 has a much higher affinity for the PAC1 receptor and we therefore suggest that migraine induction by PACAP38 may be because of activation of the PAC1 receptor, which may be a future anti-migraine drug target.
- Subjects
PATHOLOGICAL physiology; MIGRAINE; PITUITARY adenylate cyclase activating polypeptide; BLOOD sampling; CHEMICAL affinity; MAGNETIC resonance angiography; COMPARATIVE studies
- Publication
Brain: A Journal of Neurology, 2014, Vol 137, Issue 3, p779
- ISSN
0006-8950
- Publication type
Article
- DOI
10.1093/brain/awt369