The Third Alarm Bell
A neuropeptide of the trigeminal nerve system. Infuse it and people who get migraines get one; healthy people get mild or no headache. An antibody against it showed efficacy for migraine prevention in phase II — the same strategy that worked for cgrp.
In depth
A trigeminal neuropeptide that provokes migraine on infusion and does nothing much to people who do not get them.
What drives it
Cortical spreading wave increases it.
Cortical spreading depression activates the trigeminovascular system, releasing the neuropeptides that mediate the attack, PACAP-38 among them. doi 10.1093/brain/awn307 · PMC10994530
Pain neuropeptide increases it.
PACAP-38 is co-released with other neuropeptides from activated trigeminal afferents during neurogenic inflammation. doi 10.1093/brain/awn307 · PMC10994530
What it drives
It increases Neurovascular calm.
Intravenous infusion of PACAP-38 elicits migraine attacks in people with migraine, while healthy individuals experience mild or no headache; phase II results demonstrated the effectiveness of a monoclonal antibody against PACAP signaling for migraine prevention. doi 10.1093/brain/awn307 · PMC10994530
It increases Calms histamine response.
PACAP-38 is a potent degranulator of dura mast cells, a step shared with the nitric oxide pathway. doi 10.1093/brain/awn307 · PMC10994530
It increases Headache peptide.
PACAP and CGRP signaling converge on trigeminovascular activation; both provoke migraine on infusion and both are validated antibody targets. doi 10.1093/brain/awn307 · PMC10994530
It increases Potassium channel gating.
The neuropeptides PACAP and CGRP activate KATP channels via the adenylyl cyclase pathway. doi 10.3390/cells11152406 · PMC10418850
See it on the map
Open the causal map to follow this pathway upstream and downstream, arrow by arrow, each with its study.