Pituitary
adenylate cyclase-activating
peptide (
PACAP) is a
neuropeptide implicated in a wide range of functions, such as nociception and in primary
headaches. Regarding its localization,
PACAP has been observed in the sensory trigeminal ganglion (TG), in the parasympathetic sphenopalatine (SPG) and otic ganglia (OTG), and in the brainstem trigeminocervical complex. Immunohistochemistry has shown
PACAP-38 in numerous cell bodies of SPG/OTG, co-stored with
vasoactive intestinal peptide (VIP),
nitric oxide synthase (NOS) and, to a minor degree, with
choline acetyltransferase.
PACAP has in addition been found in a subpopulation of
calcitonin gene-related peptide (CGRP)-immunoreactive cells in the trigeminal system. The
PACAP/
VIP receptors (PAC1, VPAC1, and VPAC2) are present in sensory neurons and in vascular smooth muscle related to the trigeminovascular system. It is postulated that
PACAP is involved in nociception. In support, abolishment of
PACAP synthesis or reception leads to diminished
pain responses, whereas systemic
PACAP-38 infusion triggers
pain behavior in animals and delayed
migraine-like attacks in
migraine patients without marked vasodilatory effects. In addition, increased plasma levels have been documented in acute
migraine attacks and in
cluster headache, in accordance with findings in experimental models of trigeminal activation. This suggest that the activation of the trigeminal system may result in elevated venous levels of
PACAP, a change that can be reduced when
headache is treated. The data presented in this review indicate that
PACAP and its receptors may be promising targets for
migraine therapeutics.