PACAP signaling is not involved in GTN- and levcromakalim-induced hypersensitivity in mouse models of migraine.

Abstract

BACKGROUND:

Calcitonin gene-related peptide (CGRP) antagonizing drugs represents the most important advance in migraine therapy for decades. However, these new drugs are only effective in 50-60% of patients. Recent studies have shown that the pituitary adenylate cyclase-activating peptide (PACAP38) pathway is independent from the CGRP signaling pathway. Here, we investigate PACAP38 signaling pathways in relation to glyceryl trinitrate (GTN), levcromakalim and sumatriptan.

METHODS:

In vivo mouse models of PACAP38-, GTN-, and levcromakalim-induced migraine were applied using tactile sensitivity to von Frey filaments as measuring readout. Signaling pathways involved in the three models were dissected using PACAP-inhibiting antibodies (mAbs) and sumatriptan.

RESULTS:

We showed that PACAP mAbs block PACAP38 induced hypersensitivity, but not via signaling pathways involved in GTN and levcromakalim. Also, sumatriptan has no effect on PACAP38-induced hypersensitivity relevant to migraine. This is the first study testing the effect of a PACAP-inhibiting drug on GTN- and levcromakalim-induced hypersensitivity.

CONCLUSIONS:

Based on the findings in our mouse model of migraine using migraine-inducing compounds and anti-migraine drugs, we suggest that PACAP acts via a distinct pathway. Using PACAP38 antagonism may be a novel therapeutic target of interest in a subgroup of migraine patients who do not respond to existing therapies.

• Authors: Song Guo, Charlotte Ernstsen, Anders Hay-Schmidt, David Møbjerg Kristensen, Messoud Ashina, Jes Olesen, Sarah Louise Christensen
• Journal: The journal of headache and pain (J Headache Pain) Vol. 23 Issue 1 Pg. 155 (Dec 05 2022) ISSN: 1129-2377 [Electronic] England
• PMID: 36471250 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s).

Chemical References

• Calcitonin Gene-Related Peptide
• Cromakalim
• Nitroglycerin
• Pituitary Adenylate Cyclase-Activating Polypeptide
• Sumatriptan

Topics

• Animals
• Mice
• Calcitonin Gene-Related Peptide (metabolism)
• Cromakalim (therapeutic use)
• Disease Models, Animal
• Migraine Disorders (chemically induced, drug therapy)
• Nitroglycerin (adverse effects)
• Pituitary Adenylate Cyclase-Activating Polypeptide (metabolism)
• Signal Transduction
• Sumatriptan (adverse effects)
• Drug Hypersensitivity (etiology)