PACAP38 induces migraine-like attacks in patients with migraine without aura

• Published in: Brain (London, England : 1878) Vol. 132; no. 1; pp. 16 - 25
• Main Authors: Schytz, Henrik Winther, Birk, Steffen, Wienecke, Troels, Kruuse, Christina, Olesen, Jes, Ashina, Messoud
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.01.2009; Oxford Publishing Limited (England)
• Subjects: Adult; Biological and medical sciences; Blood Flow Velocity - drug effects; Blood Pressure - drug effects; cerebral vessels; Cross-Over Studies; Double-Blind Method; Female; Flushing - chemically induced; Headache - chemically induced; Headache - physiopathology; Heart Rate - drug effects; Humans; Male; Medical sciences; Middle Aged; Middle Cerebral Artery - drug effects; Middle Cerebral Artery - physiopathology; migraine without aura; Migraine without Aura - chemically induced; Migraine without Aura - physiopathology; Neurology; PACAP38; parasympathetic nervous system; Pituitary Adenylate Cyclase-Activating Polypeptide - pharmacology; Pituitary Adenylate Cyclase-Activating Polypeptide - toxicity; Temporal Arteries - diagnostic imaging; Temporal Arteries - drug effects; transcranial Doppler; Ultrasonography; Vascular diseases and vascular malformations of the nervous system; Vasodilation - drug effects; Vasodilator Agents - pharmacology; Vasodilator Agents - toxicity; Young Adult; PACAP38; transcranial Doppler; parasympathetic nervous system; migraine without aura; cerebral vessels; Sonography; Doppler ultrasound study; Human; Nervous system diseases; Migraine; Central nervous system; Cardiovascular disease; Cerebral disorder; Encephalon; Vascular disease; Pain; Autonomic nervous system; Central nervous system disease; Aura; Cerebrovascular disease; Parasympathetic nervous system
• ISSN: 0006-8950; 1460-2156; 1460-2156
• DOI: 10.1093/brain/awn307

Experimental studies have shown that infusion of vasoactive neurotransmitters may trigger headache or migraine-like attacks in man. Pituitary adenylate cyclase activating peptide-38 (PACAP38) is a strong vasodilator found in trigeminal sensory and parasympathetic perivascular nerve fibers. We therefore hypothesized that infusion of PACAP38 would cause headache in healthy subjects and migraine-like attacks in migraine patients. Twelve healthy subjects and 12 migraine patients were examined in two separate studies. All subjects were allocated to receive 10 pmol/kg/min PACAP38 and placebo in a randomized, double-blind crossover study design. Headache was scored on a verbal rating scale (VRS) during hospital (0–2 h) and post-hospital (2–12 h) phases. Mean blood flow velocity in the middle cerebral artery (VMCA) by transcranial Doppler (TCD) and diameter of the superficial temporal artery (STA) by high resolution ultrasonography were recorded during hospital phase in migraineurs. PACAP38 infusion caused headache in all healthy subjects and 11 out of 12 migraine patients. Seven migraine patients experienced migraine-like attacks after PACAP38 and none after placebo (P = 0.016). Most of attacks (6 out of 7) occurred during the post-hospital phase [mean time 6 h (range 2–11)]. Two healthy subjects reported migraine-like attacks after PACAP38 during the hospital phase and none during the post-hospital phase. In the hospital phase, the area under the curve (AUC) for headache score was larger during PACAP38 infusion compared to placebo in healthy subjects (P = 0.005) and tended to be larger in migraineurs (P = 0.066). In the post-hospital phase, the AUC for headache was larger after PACAP38 infusion compared to placebo in both healthy subjects (P = 0.005) and migraine patients (P = 0.013). In migraine patients, PACAP38 caused a peak decrease of 16.1% in VMCA and a 37.5% increase in STA diameter at 20 min after start of infusion. In conclusion, PACAP38 infusion caused headache and vasodilatation in both healthy subjects and migraine patients. In migraine sufferers, PACAP38 caused delayed migraine-like attacks. The findings stimulate further investigation of the neuronal and vascular mechanisms of PACAP38.