• Song Guo, Charlotte Ernstsen, Anders Hay-Schmidt, David Møbjerg Kristensen, Messoud Ashina, Jes Olesen, and Sarah Louise Christensen.
• Department of Neurology, Danish Headache Center, Research Institute, Copenhagen University Hospital-Rigshospitalet Glostrup, Nordstjernevej 42, Glostrup, 2600, Copenhagen, Denmark.
• J Headache Pain. 2022 Dec 5; 23 (1): 155155.

BackgroundCalcitonin gene-related peptide (CGRP) antagonizing drugs represents the most important advance in migraine therapy for decades. However, these new drugs are only effective in 50-60% of patients. Recent studies have shown that the pituitary adenylate cyclase-activating peptide (PACAP38) pathway is independent from the CGRP signaling pathway. Here, we investigate PACAP38 signaling pathways in relation to glyceryl trinitrate (GTN), levcromakalim and sumatriptan.MethodsIn vivo mouse models of PACAP38-, GTN-, and levcromakalim-induced migraine were applied using tactile sensitivity to von Frey filaments as measuring readout. Signaling pathways involved in the three models were dissected using PACAP-inhibiting antibodies (mAbs) and sumatriptan.ResultsWe showed that PACAP mAbs block PACAP38 induced hypersensitivity, but not via signaling pathways involved in GTN and levcromakalim. Also, sumatriptan has no effect on PACAP38-induced hypersensitivity relevant to migraine. This is the first study testing the effect of a PACAP-inhibiting drug on GTN- and levcromakalim-induced hypersensitivity.ConclusionsBased on the findings in our mouse model of migraine using migraine-inducing compounds and anti-migraine drugs, we suggest that PACAP acts via a distinct pathway. Using PACAP38 antagonism may be a novel therapeutic target of interest in a subgroup of migraine patients who do not respond to existing therapies.© 2022. The Author(s).

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