Abstract
BackgroundTo review the role of PACAP38 in human models of primary headaches, discuss possible mechanisms of PACAP38-induced migraine, and outline future directions.DiscussionExperimental studies have established PACAP38 as a potent pharmacological “trigger” molecule of migraine-like attacks. These studies have also revealed a heterogeneous PACAP38 migraine response in migraine without aura patients. In addition, findings from brain imaging studies have demonstrated neuronal and vascular changes in migraine patients both ictally and interictally after PACAP38 infusion.ConclusionHuman migraine models have shed light on the importance of PACAP38 in the pathophysiology of primary headaches. These studies have also pointed to the PAC1 receptor and the PACAP38 molecule itself as target sites for drug testing. Future research should seek to understand the mechanisms underlying PACAP38-induced migraine. The results from an ongoing proof of concept randomized clinical trial may reveal the therapeutic potential of anti-PAC1 receptor antibodies for migraine prevention.
Highlights
To review the role of PACAP38 in human models of primary headaches, discuss possible mechanisms of PACAP38-induced migraine, and outline future directions
Human migraine models have shed light on the importance of PACAP38 in the pathophysiology of primary headaches. These studies have pointed to the PAC1 receptor and the PACAP38 molecule itself as target sites for drug testing
The results from an ongoing proof of concept randomized clinical trial may reveal the therapeutic potential of anti-PAC1 receptor antibodies for migraine prevention
Summary
To review the role of PACAP38 in human models of primary headaches, discuss possible mechanisms of PACAP38-induced migraine, and outline future directions. Much research effort has been devoted to studying the pathophysiology of primary headaches using human experimental models, which have led to the discovery of novel headache-eliciting signaling pathways and new drug targets [1]. In this context, pituitary adenylate cyclase-activating polypeptide (PACAP) has over the past decade emerged as a key signaling molecule implicated in migraine [2] and possibly in cluster headache [3]. Studies have reported that the VPAC1–2 receptors play a role in vasodilation and mast cell degranulation [16,17,18,19,20], whereas one study in rats implicated the PAC1 receptor in pro-nociceptive transmission [21]
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