{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T18:56:50Z","timestamp":1770490610426,"version":"3.49.0"},"reference-count":14,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,4,18]],"date-time":"2023-04-18T00:00:00Z","timestamp":1681776000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003554","name":"Lundbeckfonden","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003554","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP) provoked cluster headache attacks in individuals with episodic cluster headache during their active phase and individuals with chronic cluster headache. In this study, we investigated whether infusions of PACAP and VIP caused alterations in plasma levels of VIP and their potential contribution to induced cluster headache attacks.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Participants received either PACAP or VIP infusion for 20 min on 2 separate days with an interval of at least 7 days in between. Blood collection was performed at T<jats:sub>0<\/jats:sub>, T<jats:sub>20<\/jats:sub>, T<jats:sub>30<\/jats:sub>, and T<jats:sub>90<\/jats:sub>. Plasma levels of VIP were measured using a validated radioimmunoassay method.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Blood samples were collected from participants with episodic cluster headache in the active phase (eCHA, <jats:italic>n<\/jats:italic> = 14), remission (eCHR, <jats:italic>n<\/jats:italic> = 15), and from participants with chronic cluster headache (cCH, <jats:italic>n<\/jats:italic> = 15). Baseline levels of VIP did not differ among the three groups (<jats:italic>p<\/jats:italic> = 0.1161). During PACAP infusion, mixed-effects analysis revealed a significant increase in plasma levels of VIP in eCHA (<jats:italic>p<\/jats:italic> = 0.0300) and eCHR (<jats:italic>p<\/jats:italic> = 0.0058) but not in cCH (<jats:italic>p<\/jats:italic> = 0.2930). We found no difference in the increase of plasma VIP levels between patients who developed PACAP38- or VIP-induced attacks.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Cluster headache attacks induced by PACAP38 or VIP infusion are not associated with changes in plasma levels of VIP. Further studies are needed to investigate the role of VIP and the parasympathetic system in cluster headache.<\/jats:p><\/jats:sec><jats:sec><jats:title>Clinical trial registration<\/jats:title><jats:p>The parent study is registered at <jats:ext-link>ClinicalTrials.gov<\/jats:ext-link> (NCT03814226).<\/jats:p><\/jats:sec>","DOI":"10.3389\/fneur.2023.1135246","type":"journal-article","created":{"date-parts":[[2023,4,18]],"date-time":"2023-04-18T05:42:10Z","timestamp":1681796530000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Plasma levels of VIP are not elevated during PACAP- and VIP-induced cluster headache attacks: an exploratory study"],"prefix":"10.3389","volume":"14","author":[{"given":"Christina","family":"Deligianni","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lanfranco","family":"Pellesi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Basit Ali","family":"Chaudhry","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne Luise","family":"Haulund Vollesen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Agneta Henriette","family":"Snoer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jens","family":"Hannibal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rigmor H\u00f8jland","family":"Jensen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Messoud","family":"Ashina","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,4,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1177\/0333102413485658","article-title":"The international classification of headache disorders, 3rd edition (beta version)","volume":"33","author":"Zhang","year":"2013","journal-title":"Cephalalgia."},{"key":"B2","doi-asserted-by":"publisher","first-page":"18006","DOI":"10.1038\/nrdp.2018.6","article-title":"Cluster headache","volume":"4","author":"Hoffmann","year":"2018","journal-title":"Nat Rev Dis Primers."},{"key":"B3","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1186\/s10194-018-0852-4","article-title":"PACAP and its role in primary headaches","volume":"19","author":"Edvinsson","year":"2018","journal-title":"J Headache Pain."},{"key":"B4","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1016\/B978-0-444-53491-0.00016-X","article-title":"Autonomic nervous system control of the cerebral circulation","volume":"117","author":"Goadsby","year":"2013","journal-title":"Handb Clin Neurol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1016\/0306-4522(94)90025-6","article-title":"Pituitary adenylate cyclase activating polypeptide expression in sensory neurons","volume":"63","author":"Mulder","year":"1994","journal-title":"Neuroscience."},{"key":"B6","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1016\/j.neuroscience.2015.08.043","article-title":"Stimulatory effect of pituitary adenylate cyclase-activating polypeptide 6-38, M65 and vasoactive intestinal polypeptide 6-28 on trigeminal sensory neurons","volume":"308","author":"S\u00e1ghy","year":"2015","journal-title":"Neuroscience."},{"key":"B7","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1093\/brain\/117.3.427","article-title":"Human in vivo evidence for trigeminovascular activation in cluster headache Neuropeptide changes and effects of acute attacks therapies","volume":"117","author":"Goadsby","year":"1994","journal-title":"Brain."},{"key":"B8","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1177\/0333102419837154","article-title":"Calcitonin-gene related peptide and disease activity in cluster headache","volume":"39","author":"Snoer","year":"2019","journal-title":"Cephalalgia."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1474","DOI":"10.1177\/0333102420940689","article-title":"The effect of pituitary adenylate cyclase-activating peptide-38 and vasoactive intestinal peptide in cluster headache","volume":"40","author":"Vollesen","year":"2020","journal-title":"Cephalalgia."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1766","DOI":"10.1021\/es00082a001","article-title":"Less than obvious. Statistical treatment of data below the detection limit","volume":"24","author":"Helsel","year":"1990","journal-title":"Environ Sci Technol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"871176","DOI":"10.3389\/fneur.2022.871176","article-title":"Plasma levels of CGRP during a 2-h infusion of VIP in healthy volunteers and patients with migraine: an exploratory study","volume":"13","author":"Pellesi","year":"2022","journal-title":"Front Neurol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1016\/j.sjpain.2013.04.002","article-title":"Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) in the circulation after sumatriptan","volume":"4","author":"Hansen","year":"2013","journal-title":"Scand J Pain"},{"key":"B13","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/S0169-328X(00)00101-7","article-title":"Pituitary adenylate cyclase-activating peptide is an activator of vasoactive intestinal polypeptide gene transcription in human neuroblastoma cells","volume":"79","author":"Georg","year":"2000","journal-title":"Brain Res Mol Brain Res."},{"key":"B14","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1177\/0333102416639517","article-title":"Part II: Biochemical changes after pituitary adenylate cyclase-activating polypeptide-38 infusion in migraine patients","volume":"37","author":"Guo","year":"2017","journal-title":"Cephalalgia."}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2023.1135246\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,18]],"date-time":"2023-04-18T05:42:13Z","timestamp":1681796533000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2023.1135246\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,18]]},"references-count":14,"alternative-id":["10.3389\/fneur.2023.1135246"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2023.1135246","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,18]]},"article-number":"1135246"}}