PACAP38-related modulation of the cranial parasympathetic projection: a novel mechanism and therapeutic target in severe primary headache.

Given the prevailing view that sumatriptan acts to some degree via a peripheral mechanism, our data support that PACAP38-mediated receptor activation modulates headache-related cranial-autonomic and trigeminovascular responses via peripheral and central components of the cranial parasympathetic projection. This provides a mechanistic rationale for the association of CAS with more severe headache phenotypes in cluster headache and migraine and supports the cranial parasympathetic projection as a potential novel locus for treatment by selectively targeting PACAP38 or PACAP38-responsive VPAC1/PAC1 receptors.