期刊
NEUROBIOLOGY OF DISEASE
卷 45, 期 1, 页码 633-644出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2011.10.010
关键词
Light-aversive behavior; Light-dark box; Laser Doppler blood perfusion scanning; Meningeal microcirculation; c-Fos immunohistochemistry; PAC1 receptor immunohistochemistry
资金
- Hungarian Grants OTKA [K72592, K73044, NK78059, CNK78480, ETT 03-380/2009, ETT 04-364/2009, PTE KA-34039/10-8]
- Developing Competitiveness of Universities in the South Transdanubian Region [SROP-4.2.1.8-10/2/KONV-2010-0002]
- Hungarian Academy of Sciences
- Japan Society for the Promotion of Science (JSPS)
- Janos Bolyai Postdoctoral Research Fellowship
- Sanofi-Aventis
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 mu g/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. (C) 2011 Elsevier Inc. All rights reserved.
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