Provocation of attacks to discover migraine signaling mechanisms and new drug targets: early history and future perspectives - a narrative review.

Introduction: The development of several experimental migraine provocation models has significantly contributed to an understanding of the signaling mechanisms of migraine. The early history of this development and a view to the future are presented as viewed by the inventor of the models.

Methods: Extensive knowledge of the literature was supplemented by scrutiny of reference lists.

Results: Early studies used methodologies that were not blinded. They suggested that histamine and nitroglycerin (Glyceryl trinitrate, GTN) could induce headache and perhaps migraine. The development of a double blind, placebo-controlled model, and the use of explicit diagnostic criteria for induced migraine was a major step forward. GTN, donor of nitric oxide (NO), induced headache in people with- and without migraine as well as delayed migraine attacks in those with migraine. Calcitonin gene-related peptide (CGRP) did the same, supporting the development of CGRP antagonists now widely used in patients. Likewise, pituitary adenylate cyclase activating peptide (PACAP) provoked headache and migraine. Recently a PACAP antibody has shown anti migraine activity in a phase 2 trial. Increase of second messengers activated by NO, CGRP and PACAP effectively induced migraine. The experimental models have also been used in other types of headaches and have been combined with imaging and biochemical studies. They have also been used for drug testing and in genetic studies.

Conclusion: Conclusion. Human migraine provocation models have informed about signaling mechanisms of migraine leading to new drugs and drug targets. Future use of these models in imaging-, biochemistry- and genetic studies as well as in the further study of animal models is promising.