The neuropeptides pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) play roles in vasodilation, the immune response and neuronal signaling, with recent links to headache disorders. This association has resulted in considerable interest in targeting this family of peptides and their receptors for drug development, and, notably, an anti-PACAP antibody has reported clinical efficacy in reducing migraine frequency. The PACAP/VIP ligands act at G protein-coupled receptors (GPCRs). PAC₁, VPAC₁ and VPAC₂ are the officially-recognized canonical receptors. Each of these has the potential to generate receptor variants through exon splicing. These variants may exhibit altered function, significantly increasing the diversity of PACAP-responsive receptors. In addition to these canonical receptors, PACAP is proposed to activate other unrelated receptors, GPR55 and MRGPRX2. Altogether, any of these canonical and proposed receptors may mediate the biological actions of PACAP, including migraine-relevant behaviors. However, we have a limited understanding of how these receptors function, such as their capacity to activate downstream signaling, the cellular and subcellular location of that signaling, and whether accessory protein interactions may alter these responses, especially in migraine-relevant contexts. The complex nature of the PACAP/VIP system therefore provides not only numerous considerations for target design and validation, but also unique opportunities for "designer" drugs. This narrative review provides an overview of the complex PACAP/VIP system, exploring peptide, receptor and downstream signaling behaviors that may be potential targets for the treatment of headache disorders and beyond.

Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: ZT has no conflict of interest. DLH is or has been a consultant or speaker for AbbVie, Nxera Pharma, Lilly, Lundbeck and Teva in the past three years. DLH has received research funding from Pfizer, Abbvie and Solros Therapeutics in the past three years.