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This strong association suggests the involvement of the cranial parasympathetic efferent pathway. To investigate its contribution, we studied the role of pituitary adenylate cyclase activating polypeptide\u201038 (PACAP\u201038), a potent sensory and parasympathetic neuropeptide, in modulating pre\u2010 and post\u2010ganglionic cranial parasympathetic projection\u00a0neurons, and their influence on headache\u2010related trigeminal\u2010autonomic responses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Using PACAP\u201038 and PACAP\u201038 responsive receptor antagonists, electrophysiological, behavioural and facial neurovascular\u2010blood flow was measured in rats to probe trigeminal\u2010 and parasympathetic\u2010neuronal, periorbital thresholds and cranial\u2010autonomic outcomes, as they relate to primary headaches.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Sumatriptan attenuated the development of PACAP\u201038 mediated activation and sensitization of trigeminocervical neurons and related periorbital allodynia. PACAP\u201038 also caused activation and enhanced responses of dural\u2010responsive pre\u2010ganglionic pontine\u2010superior salivatory parasympathetic neurons. Further, the PACAP\u201038 responsive receptor antagonists dissected a role of VPAC<jats:sub>1<\/jats:sub> and PAC<jats:sub>1<\/jats:sub> receptors in attenuating cranial\u2010autonomic and trigeminal\u2010neuronal responses to activation of the cranial parasympathetic projection, which requires post\u2010ganglionic parasympathetic neurotransmission.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Given the prevailing view that sumatriptan acts to some degree via a peripheral mechanism, our data support that PACAP\u201038 mediated receptor activation modulates headache\u2010related cranial\u2010autonomic and trigeminovascular responses via peripheral and central components of the cranial parasympathetic projection. This provides a mechanistic rationale for the association of CAS with more severe headache phenotypes in cluster headache and migraine, and supports the cranial parasympathetic projection as a potential novel locus for treatment by selectively targeting PACAP\u201038 or PACAP\u201038 responsive VPAC<jats:sub>1<\/jats:sub>\/PAC<jats:sub>1<\/jats:sub> receptors.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.16242","type":"journal-article","created":{"date-parts":[[2023,9,14]],"date-time":"2023-09-14T15:17:48Z","timestamp":1694704668000},"page":"480-494","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["PACAP\u201038 related modulation of the cranial parasympathetic projection: A novel mechanism and therapeutic target in severe primary headache"],"prefix":"10.1111","volume":"181","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6577-6825","authenticated-orcid":false,"given":"Simon","family":"Akerman","sequence":"first","affiliation":[{"name":"Department of Neural and Pain Sciences University of Maryland Baltimore  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Goadsby","sequence":"additional","affiliation":[{"name":"Headache Group, Wolfson Sensory, Pain and Regeneration Research Centre (SPaRRC) Institute of Psychology, Psychiatry and Neuroscience, King's College London  London UK"},{"name":"Department of Neurology University of California Los Angeles  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0503-0527","authenticated-orcid":false,"given":"Marcela","family":"Romero\u2010Reyes","sequence":"additional","affiliation":[{"name":"Department of Neural and Pain Sciences University of Maryland Baltimore  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,10,4]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaa7557"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1526-4610.2009.01501.x"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2010.06.028"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/aws249"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awy313"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15538"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awt369"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/s10194-018-0861-3"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1177\/0333102420970889"},{"key":"e_1_2_12_11_1","first-page":"690","article-title":"Passage of pituitary adenylate cyclase activating polypeptide1\u201027 and pituitary adenylate cyclase activating polypeptide1\u201038 across the blood\u2010brain barrier","volume":"267","author":"Banks W. 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