[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-449907-105":59,"doc-detail-449907-en":130},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":123,"head_meta":125,"extra_data":127,"updated_unix":129},105,"en","pacap-versus-cgrp-in-migraine-from-mouse-models-to-clinical-translation","PACAP versus CGRP in migraine - From mouse models to clinical translation","","Migraine is a complex neurological disorder involving multiple neuropeptides that shape nociceptive and sensory pathways. CGRP is the best-studied peptide and both a trigger and therapeutic target, while PACAP has emerged as an alternative target. This review compares PACAP and CGRP across preclinical mouse models, their regional expression patterns, receptor and signaling differences, and the largely independent behavioral outcomes they induce. It also addresses translational progress to the clinic, highlighting the exception of a PACAP type I receptor monoclonal antibody.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/pacap-versus-cgrp-in-migraine-from-mouse-models-to-clinical-translation/449907/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/pacap-versus-cgrp-in-migraine-from-mouse-models-to-clinical-translation/449907.png","ImageObject",300,407,{"name":92,"@type":93},"pixelkiddo","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-04","2026-09-30",true,{"@type":102,"interactionType":103,"userInteractionCount":44},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why are PACAP and CGRP both considered therapeutic targets for migraine?","Question",{"text":112,"@type":113},"They both modulate nociceptive and sensory pathways involved in migraine and act through receptor-mediated signaling. The review highlights their roles as peptide targets based on preclinical mouse evidence and mechanisms relevant to the disorder.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How do PACAP and CGRP differ in regional expression related to migraine?",{"text":117,"@type":113},"CGRP is more abundant in the trigeminal pain system, while PACAP is more prominent in parasympathetic ganglia that may contribute to migraine’s autonomic features. Both are expressed in peripheral and central migraine-relevant regions.",{"name":119,"@type":110,"acceptedAnswer":120},"Do PACAP- and CGRP-targeted therapies block the same migraine-like symptoms in mice?",{"text":121,"@type":113},"No. PACAP-mediated photophobia and mechanical allodynia are not blocked by CGRP-targeted therapies in mice, indicating largely independent pathways driving these behaviors.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},449907,1790925013,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":44,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145,"preview_page_count":4},962090883892,"https://ap-avatar.wpscdn.com/avatar/e00115db34f3e0f11b?x-image-process=image/resize,m_fixed,w_180,h_180&k=1790152879550218658","Author Manuscript Author Manuscript Author Manuscript Author Manuscript  \n\n| | HHS Public Access\u003Cbr>Author manuscript\u003Cbr>Cephalalgia. Author manuscript; available in PMC 2026 January 07. |\n| --- | --- |\n\nPublished in final edited form as:  \nCephalalgia. 2025 September ; 45(9): 3331024251364242. doi:10.1177/03331024251364242 .  \nPACAP versus CGRP in migraine: From mouse models to clinical translation  \nAdriana Della Pietra 1 , Adisa Kuburas 1 , Andrew F. Russo 1,2,3  \n1 Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, USA  \n2 Department of Neurology, University of Iowa, Iowa City, IA, USA  \n3Veterans Affairs Healthcare System, Iowa City, IA, USA  \nAbstract  \nMigraine is a complex neurological disorder involving multiple neuropeptides that modulate nociceptive and sensory pathways. The most studied peptide is calcitonin gene-related peptide (CGRP), which is a well-established migraine trigger and therapeutic target. Recently, another peptide, pituitary adenylate cyclase-activating polypeptide (PACAP), has emerged as an alternative target for migraine therapeutics. This review compares the roles of PACAP and CGRP in preclinical mouse models of migraine. PACAP shares similarities with CGRP, and both are expressed in peripheral and central migraine-relevant regions. However, CGRP is more abundant in the trigeminal pain system, whereas PACAP is more prominent in parasympathetic ganglia that may contribute to autonomic aspects of migraine. PACAP and CGRP act on receptors  \nthat can activate overlapping but distinct intracellular signaling pathways. While both peptides elevate cAMP levels to activate protein kinase A, PACAP is more effective than CGRP at engaging an alternative cAMP pathway involving small G proteins, as well as Gq-mediated calcium pathways. Moreover, PACAP and CGRP induce similar migraine-like behaviors in mice, including cephalic and plantar mechanical allodynia, photophobia and non-evoked pain, but they do so by largely independent pathways. Notably, PACAP-mediated photophobia and mechanical allodynia symptoms are not blocked by CGRP-targeted therapies in mice. Finally, we discuss how preclinical PACAP and CGRP studies have translated to the clinic, with the exception of a PACAP type I receptor monoclonal antibody. Overall, CGRP and PACAP are likely to act by parallel and non-redundant roles in migraine pathophysiology, which suggests that a combined targeting of CGRP and PACAP may offer a more effective strategy for treating migraine.  \nCreative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons AttributionNonCommercial 4.0 License ([https://creativecommons.org/licenses/by-nc/4.0/](https://creativecommons.org/licenses/by-nc/4.0/)) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page ([https://us.sagepub.com/en-us/nam/open-access-at-sage](https://us.sagepub.com/en-us/nam/open-access-at-sage)).  \nCorresponding author: Andrew F. Russo, Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, 52242, [USA. andrew-russo@uiowa.edu](USA. andrew-russo@uiowa.edu).  \nDeclaration of conflicting interests  \nAFR is a consultant for Lundbeck, Abbvie, Pfizer, Vedana Therapeutics, Arrowhead Pharmaceuticals, Omeros Corporation and Delphian Therapeutics, and holds patents on the CGRP monoclonal antibody for photophobia and diarrhea, on the PACAP monoclonal antibody for photophobia and on the CGRP HO enhancer element. ADP is a consultant for Delphian Therapeutics and AK is a consultant for Vedana Therapeutics. The contents do not represent the views of the US Department of Veterans Affairs or the United States Government.  \nAuthor Manuscript Author Manuscript Author Manuscript Author Manuscript  \nPietra et al. Page 2  \nKeywords  \nallodynia; neuropeptides; photophobia; preclinical model","cbCaihYqPMyyhKaN","https://ap.wps.com/l/cbCaihYqPMyyhKaN","pdf",1318729,25,"English","# Introduction\n## Peripheral and central distribution of PACAP and CGRP and their receptors\n### Peptide expression\n# PACAP versus CGRP signaling and receptor pathways\n# Migraine-like behaviors in mice and therapeutic implications\n# Clinical translation and therapeutic targets","[{\"question\":\"Why are PACAP and CGRP both considered therapeutic targets for migraine?\",\"answer\":\"They both modulate nociceptive and sensory pathways involved in migraine and act through receptor-mediated signaling. The review highlights their roles as peptide targets based on preclinical mouse evidence and mechanisms relevant to the disorder.\"},{\"question\":\"How do PACAP and CGRP differ in regional expression related to migraine?\",\"answer\":\"CGRP is more abundant in the trigeminal pain system, while PACAP is more prominent in parasympathetic ganglia that may contribute to migraine’s autonomic features. Both are expressed in peripheral and central migraine-relevant regions.\"},{\"question\":\"Do PACAP- and CGRP-targeted therapies block the same migraine-like symptoms in mice?\",\"answer\":\"No. PACAP-mediated photophobia and mechanical allodynia are not blocked by CGRP-targeted therapies in mice, indicating largely independent pathways driving these behaviors.\"}]","PACAP versus CGRP in migraine - From mouse models to clinical translation | PDF",1790731475,63]