PACAP versus CGRP in migraine: From mouse models to clinical translation

Migraine 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 that 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.