PACAP-38 Migraine Model

Pituitary adenylate-cyclase-activating polypeptide-38 (PACAP-38) is a neuropeptide with strong clinical validity as a migraine trigger: intravenous infusion provokes delayed migraine-like attacks in the majority of migraine patients, with sumatriptan able to abort the response. Acting via PAC1/VPAC receptors (Gs–adenylate cyclase–cAMP/PKA and MAPK/ERK signaling) as well as mast cell–expressed Mrgpr receptors, PACAP-38 triggers dural mast cell degranulation and neurogenic inflammation, sensitizing the trigeminovascular system.

In rats, subcutaneous administration of PACAP-38 reproduces this phenotype, inducing mechanical allodynia (periorbital and hindpaw, assessed by von Frey), light aversion, and other migraine-like behaviors.

Notably, PACAP-induced hypersensitivity persists despite pharmacological or genetic blockade of CGRP signaling, indicating a pathway that is largely independent of — and complementary to — the CGRP axis. This distinguishes the PACAP-38 model from CGRP- or GTN-based paradigms and positions it as a valuable tool for characterizing candidates targeting the PAC1 receptor or downstream PACAP signaling, an emerging class of migraine therapeutics.