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

Neurobiology of Disease

Balazs Gaszner¹  Hitoshi Hashimoto²  Dora Reglodi²  Arvin Lashgarara³  Bernadett Tuka⁴  Jozsef Kun⁵  Viktoria Kormos⁵  Eva Szoke⁵  Katalin Sandor⁵  Krisztina Szabadfi⁵  Erika Pinter⁵  Adrienn Markovics⁵  Zsuzsanna Helyes⁶  Janos Tajti⁷  Janos Szolcsanyi⁷ 

[1] Department of Anatomy, PTE-MTA Lendulet PACAP Research Group, University of Pecs, Faculty of Medicine, H-7624, Pecs, Szigeti u. 12., Hungary;PharmInVivo Ltd., H-7629, Pecs, Szondi Gy. u. 10., Hungary;Department of Anatomy, PTE-MTA Lendulet PACAP Research Group, University of Pecs, Faculty of Medicine, H-7624, Pecs, Szigeti u. 12., Hungary;Department of Experimental Zoology and Neurobiology, University of Pecs, H-7624 Pecs, Faculty of Natural Sciences, Ifjusag u. 6., Hungary;Department of Pharmacology and Pharmacotherapy, University of Pecs, Faculty of Medicine, H-7624, Pecs, Szigeti u. 12., Hungary;Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan;Neurology Department, University of Szeged, Faculty of Medicine, H-6725, Szeged, Semmelweis u. 6., Hungary;

关键词: Light-aversive behavior;    Light–dark box;    Laser Doppler blood perfusion scanning;    Meningeal microcirculation;    c-Fos immunohistochemistry;    PAC1 receptor immunohistochemistry;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown