lookiilove.blogg.se

PACAP-38 is the dominant form of the two PACAP peptides, representing ∼90% of the PACAP peptide found in circulation ( Arimura et al., 1991). Both forms have equivalent receptor binding affinities and biological activities ( Nilsson et al., 1994). It was first identified as a 38 aa form (PACAP-38 Miyata et al., 1989) and was later found to have a truncated isoform (PACAP-27 Miyata et al., 1990). PACAP belongs to the vasoactive intestinal polypeptide (VIP)-secretin-glucagon superfamily of neuropeptides ( Arimura, 1992). PACAP is a multifunctional neuropeptide involved in nociception, neurogenic inflammation, and neurovascular modulation ( Vaudry et al., 2000 Hashimoto et al., 2006). PACAP shares many functions with CGRP ( Kaiser and Russo, 2013). Notably, PACAP levels in plasma are increased during migraine attacks, and the infusion of either the PACAP-38 or PACAP-27 isoforms causes migraine in people ( Schytz et al., 2009 Tuka et al., 2013 Zagami et al., 2014 Ghanizada et al., 2020). In particular, the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) has been linked to migraine pathogenesis ( Tuka et al., 2013). While key, it is clear that CGRP is not the only player and other sensory peptides have been suggested as candidates ( Russo, 2017). CGRP is upregulated during migraine attacks ( Goadsby and Edvinsson, 1993 Ramón et al., 2017), infusion of CGRP can induce migraine in ∼70% of migraineurs ( Lassen et al., 2002), and antibodies that block CGRP or its canonical receptor can effectively prevent migraine in ∼50% of patients ( Scuteri et al., 2019 Tringali and Navarra, 2019). However, it is now accepted that migraine involves the neuropeptide calcitonin gene-related peptide (CGRP Russo, 2015 Ashina et al., 2019 Edvinsson, 2019). Despite the high prevalence of migraine and recent advances in treatments, the underlying mechanisms have yet to be fully defined. One diagnostic criterion for migraine is photophobia, an often debilitating response to normal levels of light ( Digre and Brennan, 2012). It is one of the most incapacitating neurologic disorders in the world ( GBD 2016 Headache Collaborators, 2018). Migraine is a sensory disorder that is more than just a severe headache. Our finding that CGRP and PACAP monoclonal antibodies do not cross-inhibit the other peptide indicates that CGRP and PACAP actions are independent and suggests that PACAP-targeted drugs may be effective in patients who do not respond to CGRP-based therapeutics. Using an outbred strain of mice, we were able to show that most, but not all, mice respond to PACAP in a preclinical photophobia assay. SIGNIFICANCE STATEMENT The relationship between the neuropeptides CGRP (calcitonin gene-related peptide) and PACAP (pituitary adenylate cyclase-activating polypeptide) in migraine is relevant given that both peptides can induce migraine in people, yet to date only drugs that target CGRP are available. Thus, we propose that CGRP and PACAP act by independent convergent pathways that cause a migraine-like symptom in mice. Conversely, an anti-CGRP antibody could not block PACAP-induced light aversion. Importantly, an anti-PACAP monoclonal antibody could block PACAP-induced light aversion but not CGRP-induced light aversion. RNA-sequencing analysis of trigeminal ganglia yielded hierarchical clustering of responder and nonresponder mice and revealed a number of candidate genes, including greater expression of the Trpc5 and Kcnk12 ion channels and glycoprotein hormones and receptors in a subset of male responder mice. The responder and nonresponder phenotypes were stable, inheritable, and not sex linked, although there was a trend for greater responses among male mice. Unexpectedly, about one-third of the CD-1 mice did not respond to PACAP, which was not seen with CGRP. The light aversion was accompanied by increased resting in the dark, but not anxiety in a light-independent open field assay.

Similar to CGRP, PACAP induced light aversion in outbred CD-1 mice. In this study, we have used light aversion in mice as a surrogate for migraine-like photophobia to compare CGRP and PACAP and ask whether CGRP or PACAP actions were dependent on each other. Infusion of PACAP, like CGRP, can cause migraine in people, and both peptides share similar vasodilatory and nociceptive functions. The neuropeptides CGRP (calcitonin gene-related peptide) and PACAP (pituitary adenylate cyclase-activating polypeptide) have emerged as mediators of migraine, yet the potential overlap of their mechanisms remains unknown.