Pituitary adenylate cyclase-activating polypeptide plays a key role in nitroglycerol-induced trigeminovascular activation in mice

Abstract Pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptors (PAC1, VPAC) are present in sensory neurons and vascular smooth muscle. PACAP infusion was found to trigger migraine-like headache in humans and we showed its central pro-nociceptive function in several mouse pain models. Nitroglycerol (NTG)-induced pathophysiological changes were investigated in this study in PACAP gene-deleted (PACAP−/− ) and wildtype (PACAP+/+ ) mice. Chemical activation of the trigeminovascular system was induced by 10 mg/kg i.p. NTG. Light-aversive behavior was determined in a light–dark box, meningeal microcirculation by laser Doppler blood perfusion scanning and the early neuronal activation marker c-Fos with immunohistochemistry. NTG-induced photophobia both in the early (0–30 min) and late phases (90–120 min) due to direct vasodilation and trigeminal sensitization, respectively, was significantly reduced in PACAP−/− mice. Meningeal blood flow increased by 30–35% during 4 h in PACAP+/+ mice, but only a 5–10% elevation occurred from the second hour in PACAP−/− ones. The number of c-Fos expressing cells referring to neuronal activation in the trigeminal ganglia and nucleus caudalis significantly increased 4 h after NTG in PACAP+/+ , but not in PACAP−/− animals. Similar PAC1 receptor immunostaining was detected in both groups, which did not change 4 h after NTG treatment. PACAP-38 (300 μg/kg, i.p.) produced photophobia similarly to NTG and 30% meningeal vasodilatation for 30 min in PACAP+/+ , but not in PACAP−/− mice. It significantly increased neural activation 4 h later in the trigeminal ganglia of both groups, but in the nucleus caudalis of only the PACAP+/+ mice. We provide the first experimental results that PACAP is a pivotal mediator of trigeminovascular activation/sensitization and meningeal vasodilation related to migraine.