Pituitary adenylate cyclase-activating polypeptide plays a key role in nitroglycerol-induced trigeminovascular activation in mice |
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Authors: | Markovics Adrienn Kormos Viktoria Gaszner Balazs Lashgarara Arvin Szoke Eva Sandor Katalin Szabadfi Krisztina Tuka Bernadett Tajti Janos Szolcsanyi Janos Pinter Erika Hashimoto Hitoshi Kun Jozsef Reglodi Dora Helyes Zsuzsanna |
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Institution: | a Department of Pharmacology and Pharmacotherapy, University of Pecs, Faculty of Medicine, H-7624, Pecs, Szigeti u. 12., Hungaryb Department of Anatomy, PTE-MTA Lendulet PACAP Research Group, University of Pecs, Faculty of Medicine, H-7624, Pecs, Szigeti u. 12., Hungaryc Department of Experimental Zoology and Neurobiology, University of Pecs, H-7624 Pecs, Faculty of Natural Sciences, Ifjusag u. 6., Hungaryd Neurology Department, University of Szeged, Faculty of Medicine, H-6725, Szeged, Semmelweis u. 6., Hungarye Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japanf Center for Child Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University and Hamamatsu University School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japang Department of Molecular Pharmaceutical Science, Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japanh PharmInVivo Ltd., H-7629, Pecs, Szondi Gy. u. 10., Hungary |
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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. |
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Keywords: | NTG nitroglycerol PACAP pituitary adenylate cyclase-activating polypeptide TNC trigeminal nucleus caudalis TRG trigeminal ganglia VIP vasoactive intestinal polypeptide i p intraperitoneal |
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