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Headache pain from migraine affects approximately 15% of the global population. However, the identity of any putative threat that migraine or headache warns us to avoid is unknown because migraine pathogenesis is poorly understood. Here, we show that a stress-induced increase in pituitary adenylate cyclase-activating polypeptide-38 (PACAP38), known as an initiator of allosteric load inducing unbalanced homeostasis, causes headache-like behaviour in male mice via mas-related G protein-coupled receptor B2 (MrgprB2) in mast cells.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>The repetitive stress model and dural injection of PACAP38 were performed to induce headache behaviours. We assessed headache behaviours using the facial von Frey test and the grimace scale in wild-type and MrgprB2-deficient mice. We further examined the activities of trigeminal ganglion neurons using in vivo <jats:italic>Pirt<\/jats:italic>-GCaMP Ca<jats:sup>2+<\/jats:sup> imaging of intact trigeminal ganglion (TG).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Repetitive stress and dural injection of PACAP38 induced MrgprB2-dependent headache behaviours. Blood levels of PACAP38 were increased after repetitive stress. PACAP38\/MrgprB2-induced mast cell degranulation sensitizes the trigeminovascular system in dura mater. Moreover, using in vivo intact TG <jats:italic>Pirt<\/jats:italic>-GCaMP Ca<jats:sup>2+<\/jats:sup> imaging, we show that stress or\/and elevation of PACAP38 sensitized the TG neurons via MrgprB2. MrgprB2-deficient mice showed no sensitization of TG neurons or mast cell activation. We found that repetitive stress and dural injection of PACAP38 induced headache behaviour through TNF-a and TRPV1 pathways.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Our findings highlight the PACAP38-MrgprB2 pathway as a new target for the treatment of stress-related migraine headache. Furthermore, our results pertaining to stress interoception via the MrgprB2\/PACAP38 axis suggests that migraine headache warns us of stress-induced homeostatic imbalance.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s10194-024-01786-3","type":"journal-article","created":{"date-parts":[[2024,5,27]],"date-time":"2024-05-27T23:02:22Z","timestamp":1716850942000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["PACAP38\/mast-cell-specific receptor axis mediates repetitive stress-induced headache in mice"],"prefix":"10.1186","volume":"25","author":[{"given":"Hyeonwi","family":"Son","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Shannonhouse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruben","family":"Gomez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu Shin","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,5,28]]},"reference":[{"key":"1786_CR1","doi-asserted-by":"publisher","first-page":"954","DOI":"10.1016\/S1474-4422(18)30322-3","volume":"17","author":"GBD 2016 Headache Collaborators","year":"2018","unstructured":"GBD 2016 Headache Collaborators (2018) Global, regional, and national burden of migraine and tension-type headache, 1990\u20132016: a systematic analysis for the global burden of Disease Study 2016. 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Representative in vivo TG imaging of spontaneous activity from WT control mice, related to Fig.\u00a03c.Movie S2. Representative in vivo TG imaging of spontaneous activity from WT stressed mice, related to Fig.\u00a03c.Movie S3. Representative in vivo TG imaging of spontaneous activity from KO stressed mice, related to Fig.\u00a03c.Movie S4. Representative in vivo TG imaging of spontaneous activity from WT vehicle mice, related to Fig.\u00a03e.Movie S5. Representative in vivo TG imaging of spontaneous activity from WT PACAP38-injected mice, related to Fig.\u00a03e.Movie S6. Representative in vivo TG imaging of spontaneous activity from KO PACAP38-injected mice, related to Fig.\u00a03e.Movie S7. Representative in vivo TG imaging of activated neurons in response to 0.4\u00a0g filament stimulus from WT control mice, related to Fig.\u00a04b.Movie S8. Representative in vivo TG imaging of activated neurons in response to 0.4\u00a0g filament stimulus from WT stressed mice, related to Fig.\u00a04b.Movie S9. Representative in vivo TG imaging of activated neurons in response to 0.4\u00a0g filament stimulus from KO stressed mice, related to Fig.\u00a04b.Movie S10. Representative in vivo TG imaging of activated neurons in response to capsaicin from WT control mice, related to Fig.\u00a04c.Movie S11. Representative in vivo TG imaging of activated neurons in response to capsaicin from WT stressed mice, related to Fig.\u00a04c.Movie S12. Representative in vivo TG imaging of activated neurons in response to capsaicin from KO stressed mice, related to Fig.\u00a04c.Movie S13. Representative in vivo TG imaging of activated neurons in response to 0.4\u00a0g filament stimulus from WT vehicle mice, related to Fig.\u00a04d.Movie S14. Representative in vivo TG imaging of activated neurons in response to 0.4\u00a0g filament stimulus from WT PACAP38-injected mice, related to Fig.\u00a04d.Movie S15. Representative in vivo TG imaging of activated neurons in response to 0.4\u00a0g filament stimulus from KO PACAP38-injected mice, related to Fig.\u00a04d.Movie S16. Representative in vivo TG imaging of activated neurons in response to capsaicin from WT vehicle mice, related to Fig.\u00a04e.Movie S17. Representative in vivo TG imaging of activated neurons in response to capsaicin from WT PACAP38-injected mice, related to Fig.\u00a04e.Movie S18. Representative in vivo TG imaging of activated neurons in response to capsaicin from KO PACAP38-injected mice, related to Fig.\u00a04e.","order":6,"name":"Ethics","group":{"name":"EthicsHeading","label":"Supplemental information"}}],"article-number":"87"}}