title: Hypoxia facilitates neurogenic dural plasma protein extravasation in mice: a novel animal model for migraine pathophysiology.
abstract: Migraine animal models generally mimic the onset of attacks and acute treatment processes. A guinea pig model used the application of meta-chlorophenylpiperazine (mCPP) to trigger immediate dural plasma protein extravasation (PPE) mediated by 5-HT2B receptors. This model has predictive value for antimigraine drugs but cannot explain the delayed onset of efficacy of 5-HT2B receptor antagonists when clinically used for migraine prophylaxis. We found that mCPP failed to induce dural PPE in mice. Considering the role 5-HT2B receptors play in hypoxia-induced pulmonary vessel muscularization, we were encouraged to keep mice under hypoxic conditions and tested whether this treatment will render them susceptible to mCPP-induced dural PPE. Following four-week of hypoxia, PPE, associated with increased transendothelial transport, was induced by mCPP. The effect was blocked by sumatriptan. Chronic application of 5-HT2B receptor or nitric oxide synthase blockers during hypoxia prevented the development of susceptibility. Here we present a migraine model that distinguishes between a migraine-like state (hypoxic mice) and normal, normoxic mice and mimics processes that are related to chronic activation of 5-HT2B receptors under hypoxia. It seems striking, that chronic endogenous activation of 5-HT2B receptors is crucial for the sensitization since 5-HT2B receptor antagonists have strong, albeit delayed migraine prophylactic efficacy.
authors.affiliation: Institute of Animal Physiology, Ruhr-University Bochum, 44780 Bochum, Germany.
authors.forename: Anika
authors.initials: A
authors.lastname: Hunfeld
authors.affiliation: Institute of Animal Physiology, Ruhr-University Bochum, 44780 Bochum, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Segelcke
authors.affiliation: Institute of Animal Physiology, Ruhr-University Bochum, 44780 Bochum, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Bäcker
authors.affiliation: Institute of Animal Physiology, Ruhr-University Bochum, 44780 Bochum, Germany.
authors.forename: Badreddine
authors.initials: B
authors.lastname: Mecheri
authors.affiliation: Institute of Animal Physiology, Ruhr-University Bochum, 44780 Bochum, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Hemmer
authors.affiliation: Institute of Animal Physiology, Ruhr-University Bochum, 44780 Bochum, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Dlugosch
authors.affiliation: Institute of Animal Physiology, Ruhr-University Bochum, 44780 Bochum, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Andriske
authors.affiliation: Institute of Animal Physiology, Ruhr-University Bochum, 44780 Bochum, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Paris
authors.affiliation: Institute of Animal Physiology, Ruhr-University Bochum, 44780 Bochum, Germany.
authors.forename: Xinran
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Institute of Animal Physiology, Ruhr-University Bochum, 44780 Bochum, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Lübbert
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D004388:Dura Mater / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006168:Guinea Pigs; D000860:Hypoxia / Q000378:metabolism*; D008297:Male; D051379:Mice; D008881:Migraine Disorders / Q000209:etiology* / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010879:Piperazines / Q000009:adverse effects; D044403:Receptor, Serotonin, 5-HT2B / Q000378:metabolism; D057900:Transcytosis; D066253:Vascular Remodeling
chemical_list: D001798:Blood Proteins; D010879:Piperazines; D044403:Receptor, Serotonin, 5-HT2B; D019001:Nitric Oxide Synthase; C015068:1-(3-chlorophenyl)piperazine