{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T13:24:31Z","timestamp":1790861071171,"version":"4.1.0"},"reference-count":55,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T00:00:00Z","timestamp":1754438400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003554","name":"Lundbeck Foundation","doi-asserted-by":"publisher","award":["R403-2022-1352"],"award-info":[{"award-number":["R403-2022-1352"]}],"id":[{"id":"10.13039\/501100003554","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"NINDS","doi-asserted-by":"publisher","award":["NS128045"],"award-info":[{"award-number":["NS128045"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,3,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Emerging evidence implicates pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38) in migraine and other headache disorders. Systemic infusion of PACAP-38 induces migraine headache in people with migraine and mild headache in healthy adults. However, the precise mechanism and site of action remain poorly characterized. To address this gap, we assessed whether PACAP-38 elicits headache by activating meningeal nociceptors.<\/jats:p>\n                  <jats:p>In vivo single-unit electrophysiological recordings were obtained from C- and A\u03b4-meningeal nociceptors in the trigeminal ganglion of anaesthetized male and female rats. Spontaneous firing rates and mechanical responses to dural indentation with von Frey filaments were recorded before and for 4\u2005h after a 20-min intracarotid infusion of PACAP-38 (1\u2005\u00b5g\/ml\/kg, 10\u2005\u00b5g\/ml\/kg and 100\u2005\u00b5g\/ml\/kg) or vehicle (isotonic saline).<\/jats:p>\n                  <jats:p>At the human-equivalent dose (10\u2005\u00b5g\/ml\/kg), PACAP-38 activated 15 of 30 (50%) neurons, compared with none after vehicle (P &amp;lt; 0.01). Activation rates did not differ between C-fibres (7 of 17; 41%) and A\u03b4-fibres (8 of 13; 61.5%). The lowest dose of PACAP-38 (1\u2005\u00b5g\/ml\/kg) activated 3 of 9 (33%) neurons, whereas the highest dose (100\u2005\u00b5g\/ml\/kg) activated all four tested neurons, including two C-fibres and two A\u03b4-fibres.<\/jats:p>\n                  <jats:p>These results suggest that PACAP-38 induces headache through peripheral activation of meningeal nociceptors rather than exerting direct central effects within the spinal trigeminal nucleus.<\/jats:p>","DOI":"10.1093\/brain\/awaf284","type":"journal-article","created":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T11:38:04Z","timestamp":1754393884000},"page":"897-907","source":"Crossref","is-referenced-by-count":9,"title":["Activation and sensitization of meningeal nociceptors by PACAP-38: implications for migraine headache"],"prefix":"10.1093","volume":"149","author":[{"given":"Rune H\u00e4ckert","family":"Christensen","sequence":"first","affiliation":[{"name":"Department of Neurology, Danish Headache Center, Copenhagen University Hospital - Rigshospitalet , Copenhagen 2100 ,","place":["Denmark"]},{"name":"Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen 2200 ,","place":["Denmark"]},{"name":"Harvard Medical School , Boston, MA 02115 ,","place":["USA"]},{"name":"Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center , Boston, MA 02215 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Strassman","sequence":"additional","affiliation":[{"name":"Harvard Medical School , Boston, MA 02115 ,","place":["USA"]},{"name":"Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center , Boston, MA 02215 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Messoud","family":"Ashina","sequence":"additional","affiliation":[{"name":"Department of Neurology, Danish Headache Center, Copenhagen University Hospital - Rigshospitalet , Copenhagen 2100 ,","place":["Denmark"]},{"name":"Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen 2200 ,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6268-727X","authenticated-orcid":false,"given":"H\u00e5kan","family":"Ashina","sequence":"additional","affiliation":[{"name":"Department of Neurology, Danish Headache Center, Copenhagen University Hospital - Rigshospitalet , Copenhagen 2100 ,","place":["Denmark"]},{"name":"Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen 2200 ,","place":["Denmark"]},{"name":"Harvard Medical School , Boston, MA 02115 ,","place":["USA"]},{"name":"Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center , Boston, MA 02215 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