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

Adrienn Markovics, Viktoria Kormos, Balazs Gaszner, Arvin Lashgarara, Eva Szoke, Katalin Sandor, Krisztina Szabadfi, Bernadett Tuka, Janos Tajti, Janos Szolcsanyi, Erika Pinter, Hitoshi Hashimoto, Jozsef Kun, Dora Reglodi, Zsuzsanna Helyes

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77 Citations (Scopus)

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 10mg/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 (0-30min) and late phases (90-120min) due to direct vasodilation and trigeminal sensitization, respectively, was significantly reduced in PACAP -/- mice. Meningeal blood flow increased by 30-35% during 4h 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 4h after NTG in PACAP +/+, but not in PACAP -/- animals. Similar PAC1 receptor immunostaining was detected in both groups, which did not change 4h after NTG treatment. PACAP-38 (300μg/kg, i.p.) produced photophobia similarly to NTG and 30% meningeal vasodilatation for 30min in PACAP +/+, but not in PACAP -/- mice. It significantly increased neural activation 4h 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.

Original languageEnglish
Pages (from-to)633-644
Number of pages12
JournalNeurobiology of Disease
Volume45
Issue number1
DOIs
Publication statusPublished - Jan 1 2012

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Keywords

  • C-Fos immunohistochemistry
  • Laser Doppler blood perfusion scanning
  • Light-aversive behavior
  • Light-dark box
  • Meningeal microcirculation
  • PAC1 receptor immunohistochemistry

ASJC Scopus subject areas

  • Neurology

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