Skip to main content


  • Editorial
  • Open Access

Pituitary adenylate-cyclase-activating polypeptide (PACAP): another novel target for treatment of primary headaches?

The Journal of Headache and PainOfficial Journal of the "European Headache Federation" and of "Lifting The Burden - The Global Campaign against Headache"201819:33

  • Received: 18 April 2018
  • Accepted: 19 April 2018
  • Published:

Since its discovery in 1989 [1], pituitary adenylate cyclase activating peptide (PACAP) has emerged as a key molecule in primary headaches. New insights on the role of PACAP in migraine [2] have now been translated into interest in exploring the migraine preventative effect of monoclonal antibodies against PACAP and monoclonal antibodies against PAC1 receptor ( ;[3]).

Given that PACAP is a multifunctional peptide involved in various cellular and physiological responses, it is important to understand and further explore its function in non-headache mechanisms which might be relevant in context to primary headaches. This TJHP thematic series provide an overview of the history of the discovery of PACAP and its three receptors [4] and summarize PACAP and its receptor distribution in migraine relevant structures [5]. Furthermore, the readers will get insights on the role of PACAP in regulating the production of inflammatory mediators [6] and important role of degranulation of dural mast cells via a yet unknown receptor in migraine induction by PACAP38 [7]. The series also cover possible mechanisms of PACAP38-induced migraine, outline future directions [8] and discuss how PACAP may cross the blood brain barrier [9] and its implication for PACAP induced migraine. To further elucidate the role of PACAP in primary headaches it is important to study its role in regulation of sleep [10] and vascular tone [11] which are covered by excellent review articles in the special issue Both aspects are important in context of tolerability and safety of future anti PACAP drugs for prevention of primary headaches. Altogether our aim is to provide a comprehensive series of reviews focusing on PACAP as an emerging molecule in primary headache headaches.


Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Authors’ Affiliations

Department of Neurology, Danish Headache Center, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Department of Clinical and Molecular Medicine, Sapienza University, Rome, Italy
Regional Referral Headache Centre, Sant’Andrea Hospital, Rome, Italy


  1. Miyata A, Jiang L, Dahl RD et al (1990) Isolation of a neuropeptide corresponding to the N-terminal 27 residues of the pituitary adenylate cyclase activating polypeptide with 38 residues (PACAP38). Biochem Biophys Res Commun 170:643–648View ArticlePubMedGoogle Scholar
  2. Vollesen ALH, Amin FM, Ashina M. Targeted pituitary adenylate cyclase-activating peptide therapies for migraine. Neurotherapeutics 2018. [Epub ahead of print] Review. PubMed PMID: 29464574
  3. Robust development pipeline [Internet]. 2017 [cited 2017 Feb 27].
  4. Hirabayashi T, Nakamachi T, Shioda S (2018) Discovery of PACAP and its receptors in the brain. J Headache Pain 5:19. Google Scholar
  5. Edvinsson L, Tajti J, Szalárdy L, Vécsei L (2018) PACAP and its role in primary headaches. J Headache Pain. 9:19. Google Scholar
  6. Waschek JA, Baca SM, Akerman S (2018) PACAP and migraine headache: immunomodulation of neural circuits in autonomic ganglia and brain parenchyma. J Headache Pain. 13:19. Google Scholar
  7. Jansen-Olesen I, Hougaard PS (2018) PACAP and its receptors in cranial arteries and mast cells. J Headache Pain. 20:19. Google Scholar
  8. Ashina H, Guo S, Vollesen ALH, Ashina M (2017) PACAP38 in human models of primary headaches. J Headache Pain. 23:18. Google Scholar
  9. Amin FM, Winther Schytz H. Transport of the pituitary adenylate cyclase-activating polypeptide across the blood-brain barrier: implications for migraine.Google Scholar
  10. Holland PR, Barloese M, Fahrenkrug J (2018) PACAP in hypothalamic regulation of sleep and circadian rhythm: importance for headache. J Headache Pain. 5:19. Google Scholar
  11. Reglodi D, Vaczy A, Rubio-Beltran E et al. Protective effects of PACAP in ischemia. J Headache Pain. 2018; 19.


© The Author(s). 2018


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate. Please note that comments may be removed without notice if they are flagged by another user or do not comply with our community guidelines.