PACAP induces light aversion in mice by an inheritable mechanism independent of CGRP

Abstract

The neuropeptides CGRP and PACAP have emerged as mediators of migraine, yet the potential overlap of their mechanisms remains unknown. Infusion of PACAP, like CGRP, can cause migraine in people, and both peptides share similar vasodilatory and nociceptive functions. 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. Similar to CGRP, PACAP induced light aversion in outbred CD-1 mice. The light aversion was accompanied by increased resting in the dark, but not anxiety in a light-independent open field assay. Unexpectedly, about a third of the CD-1 mice did not respond to PACAP, which was not seen with CGRP. The responder and nonresponder phenotypes were stable, inheritable, and not sex-linked, although there was generally a trend for greater responses among male mice. RNA-seq analysis of trigeminal ganglia yielded hieriechial clustering of responder and nonresponder mice and revealed a number of candidate genes, including greater expression of pituitary hormones and receptors in a subset of responder mice. Importantly, an anti-PACAP monoclonal antibody could block PACAP-induced light aversion but not CGRP-induced light aversion. Conversely, an anti-CGRP antibody could not block PACAP-induced light aversion. Thus, we propose that CGRP and PACAP act by independent convergent pathways that cause a migraine-like symptom in mice.

From CGRP to PACAP: Unraveling the Next Chapter in Migraine Treatment

“…They play a role in vasodilation, neurogenic inflammation, and nociception. While CGRP plays an integral role in migraine, PACAP is likely to play a similar but distinct role as CGRP based on similarities and differences observed in both clinical and preclinical studies [107]. In rodent models, the PACAP pathway appears to be independent of the CGRP pathway, suggesting that CGRP and PACAP act in parallel ways that cause a migraine-like symptom [108].…”

PACAP-PAC1 Receptor Inhibition is Effective in Models of Opioid-Induced Medication Overuse Headache

“…The copyright holder for this preprint this version posted December 7, 2021. ; https://doi.org/10.1101/2021.12.05.471295 doi: bioRxiv preprint Preclinical work also shows that PACAP produces migraine like phenotypes as infusion in rodents causes light aversive behavior [25,26], meningeal dilation, and increased cfos expression in the trigeminal nucleus caudalis (TNC) [25]. PACAP knockout mice also have reduced susceptibility to the effects of nitroglycerin (NTG), a known human migraine trigger commonly used to model migraine in rodents [25].…”