PACAP and its receptors in migraine pathophysiology: Commentary on Walker et al., Br J Pharmacol 171: 1521–1533

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This article is a Commentary on Walker CS, Sundrum T and Hay DL (2014). PACAP receptor pharmacology and agonist bias: analysis in primary neurons and glia from the trigeminal ganglia and transfected cells. Br J Pharmacol 171: 1521–1553. doi: 10.1111/bph.12541

This is a Commentary on an article in BJP by Walker, Sundrum & Hay, Br J Pharmacol 2014; 171: 1521–1533. Walker et al. (2014) examined the action of pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38), PACAP-27 and vasoactive intestinal peptide (VIP) on primary cultures of trigeminal ganglia neurons and glial cells derived from 3- to 5-day-old rat pups. They showed PACAP-responsive receptors that resemble transfected PAC_1B receptors. A complex PACAP receptor pharmacology was uncovered that should facilitate understanding of the role that PACAP receptors have in clinical conditions, particularly migraine headaches.

PACAP belongs to the VIP-glucagon growth hormone-releasing factor-secretin superfamily of signalling peptides (Vaudry et al., 2000) and this peptide is encoded by the ADCYAP1 gene, resulting in a pro-peptide of 175 amino acids. Following truncation, PACAP is expressed in one of the two forms containing either 27 or 38 amino acids, PACAP-27 and PACAP-38 respectively. PACAP-38 is more prevalent, representing about 90% of the PACAP forms in mammalian tissues (Bourgault et al., 2008). PACAP is expressed throughout the CNS, as well as in peripheral organs and glands (Fahrenkrug and Hannibal, 2004). The peptide has been implicated in a wide range of biological functions but I will limit the present discussion to its relevance in migraine pathophysiology (Edvinsson and Uddman, 2005). A role for PACAP in migraine has been suggested by three observations: (i) PACAP levels are increased in the cranial circulation of the cat upon stimulation of the superior sagittal sinus (Zagami et al., 1995); (ii) plasma levels of PACAP are increased during migraine attacks in humans (Tuka et al., 2013); and (iii) infusion of PACAP in those known to have migraine results in migraine-like headache (Schytz et al., 2009). The obvious, but unanswered, questions are; what are the sources of endogenous PACAP and how can systemic PACAP induce migraine? The peptide is a large molecule that does not pass the blood–brain barrier (BBB) (Erdling et al., 2013), which suggests that the relevant targets are outside the BBB. Recently, it was observed that infusion of PACAP-38 resulted in marked dilatation of extracranial, but not intracranial, arteries. This response preceded the onset of migraine-like headache and was sensitive to triptan administration (Amin et al., 2014).

Migraine is a complex disorder that is influenced by genetics and environmental factors. Evidence indicates that a genuine migraine attack originates in the CNS. Brainstem regions, as well as the trigeminal and parasympathetic systems, are considered important for the expression of various symptoms in primary headache attacks (Akerman et al., 2011). Cell bodies in the otic and sphenopalatine ganglia co-store VIP/PACAP and NOS, and a small population of cells also contain ChAT, the enzyme that synthesizes ACh (Edvinsson and Uddman, 2005). The trigeminal ganglion and trigeminal nucleus caudalis contain a subpopulation of neurons that store PACAP, but not VIP (Csati et al., 2012a). Interestingly, sensory nerve fibres containing calcitonin gene-related peptide (CGRP), probably originating from the trigeminal ganglion, project to the cranial parasympathetic ganglia and there are CGRP receptors on satellite glial cells in the sphenopalatine ganglion (Csati et al., 2012b). These findings provide morphological evidence for an interaction between the parasympathetic and sensory systems.

When released, PACAP may bind to three different GPCRs, which also can bind VIP as well. VIP, PACAP-38 and PACAP-27 all have equal affinity in binding to the VIP/PACAP receptors VPAC₁ and VPAC₂. The third receptor, PAC₁, has high affinity for both forms of PACAP, but has 100- to 1000-fold lower affinity for VIP (Dickson and Finlayson, 2009; receptor nomenclature follows Alexander et al., 2013). The principal effect of VPAC₁/VPAC₂ or PAC₁ receptor stimulation is an increase in cAMP through AC activation. Activation of other second messenger systems, including PLC and PLD, has been demonstrated and may occur along with AC activation. Clinical experiments have shown that PACAP, but not VIP, elicits a migraine-like headache, suggesting the PAC₁ receptor as a putative anti-migraine target. Systemic administration of nitroglycerol or PACAP-38 produced photophobia and meningeal vasodilatation in wild-type, but in PACAP-knockout, mice (Markovics et al., 2012). Those effects and an increased activation 4 h later in the trigeminal ganglion and in the trigeminal nucleus caudalis were attributed to stimulation of the peripheral terminals of PACAP-ergic trigeminal sensory nerves in the meningeal region in the wild-type, but not in the PACAP-knockout, mice.

All three PACAP receptors have been found in the migraine-related sphenopalatine and trigeminal ganglia and on intracranial blood vessels (Knutsson and Edvinsson, 2002; Erdling et al., 2013). In their study, Walker and colleagues quantified PACAP-related signalling in primary cell cultures from trigeminal ganglion (neurons and glia) and showed that PACAP, but not VIP, induced cAMP production (Walker et al., 2014). The response was antagonized by PACAP(6–38), which is consistent with PAC₁ receptor pharmacology (Harmar et al., 2012). Interestingly, PACAP-38, but not PACAP-27 or VIP, also caused ERK1/2 activation in cultured glial cells but not in neurons. The task of in-depth analysis of PAC₁ receptors and development of receptor antagonists has not been easy because as many as 10 splice variants, displaying different intracellular coupling, have been reported (Blechman and Levkowitz, 2013). The research on PACAP and its receptors is still in its infancy. A critical unanswered question is similar to that for CGRP receptor antagonists – do PAC₁ receptor antagonists have to pass through the BBB in order to be effective? Current research points to the promise of PAC₁ receptor antagonists for migraine treatment, which gives impetus to the development of such antagonists for clinical studies.

Glossary

BBB

blood–brain barrier

CGRP

calcitonin gene-related peptide

PACAP

pituitary adenylate cyclase-activating peptide

VIP

vasoactive intestinal peptide

Conflict of interest

The author declares no competing interests.