The adenylate cyclase activating polypeptide (PACAP) is a neuropeptide involved in migraine discovered in 1989, thanks to its ability to stimulate the formation of cAMP in rat pituitary cells (Miyata et al. 1989).
This neuropeptide exists in two functional isoforms: one of 38 amino acids (PACAP-38) having an internal cleavage site, and making it possible to generate a second isoform of 27 amino acids (PACAP-27). At the level of the central nervous system, the PACAP-38 form is predominant and acts as a neuromodulator (Vaudry et al. 2009). Since its discovery, PACAP has received significant attention due to its structural similarity to VIP. There is 68% homology between these two peptides (Segre et al. 1993). PACAP binds to three G-receptor-coupled proteins named PAC1, VPAC1, and VPAC2. These last two are recognized by both PACAP and VIP.
PACAP a neuromodulator and neurotransmitter
In the central nervous system, PACAP is known to act as a neuromodulator and neurotransmitter . This neuropeptide has been shown to be a potent local and systemic vasodilator , associated with hypertensive effects at high doses. Immunohistochemical analyzes revealed the presence of PACAP in anatomical structures related to the pathophysiology of migraine.
It has thus been found in the dura mater, the cerebral arteries (Sajedeh Eftekhari et al. 2013), the skin of the face (Moller et al. 1993), the trigeminal ganglion (Sajedeh Eftekhari et al. 2015; Jansen -Olesen et al. 2014, 38), Sp5C and in superficial layers I and II of C1–C2 (Uddman et al. 2002). In migraine patients, a high plasma level of PACAP during spontaneous attacks has been found (Tuka et al. 2013; Zagami et al. 2014).
Like VIP, it was also found in the parasympathetic system in the sphenopalatine and otic ganglion (Csati et al. 2012; Steinberg et al. 2016), however only PACAP was found in the trigeminal system (Tajti et al. 1999). In PAC1 receptor knockout mice, a decrease in chronic pain induced by chemical, mechanical or thermal stimuli has been shown (Jongsma et al. 2001; Mabuchi et al. 2004).
Similar results on these same mice showed a decrease in photophobia, as well as a decrease in the expression of the protein C-FOS in Sp5C, associated with a reduction in blood flow at the level of the meninges in an animal model of migraine (Markovics et al. 2012). These results show the interest of targeting the PAC1 receptor to prevent neurogenic inflammation induced by PACAP.
Like its counterpart CGRP , this neuropeptide has also been found in the higher integration centers of the pain response, such as the thalamus and the amygdala, playing a role in central sensitization (Martin et al. 2003). Intraventricular injection of PAC1 inhibitors has been reported to decrease the time to sensitization of second-order nociceptive neurons within the trigeminal sensory complex, following meningeal stimulation (Tuka et al. 2016 ).