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Anika Hunfeld, Daniel Segelcke, Ingo Bäcker, Badreddine Mecheri, Kathrin Hemmer, Elisabeth Dlugosch, Michael Andriske, Frank Paris, Xinran Zhu, Hermann Lübbert

• 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-HT\(_{2B}\) receptors. This model has predictive value for antimigraine drugs but cannot explain the delayed onset of efficacy of 5-HT\(_{2B}\) receptor antagonists when clinically used for migraine prophylaxis. We found that mCPP failed to induce dural PPE in mice. Considering the role 5-HT\(_{2B}\) 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-HT\(_{2B}\) 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-HT\(_{2B}\) receptors under hypoxia. It seems striking, that chronic endogenous activation of 5-HT\(_{2B}\) receptors is crucial for the sensitization since 5-HT\(_{2B}\) receptor antagonists have strong, albeit delayed migraine prophylactic efficacy.