TY - JOUR

T1 - PACAP signaling is not involved in GTN- and levcromakalim-induced hypersensitivity in mouse models of migraine

AU - Guo, Song

AU - Ernstsen, Charlotte

AU - Hay-Schmidt, Anders

AU - Ashina, Messoud

AU - Olesen, Jes

AU - Christensen, Sarah Louise

N1 - Correction: https://thejournalofheadacheandpain.biomedcentral.com/articles/10.1186/s10194-023-01606-0

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

KW - PACAP

KW - Levcromakalim

KW - GTN

KW - Migraine

KW - Von Frey

KW - Monoclonal antibodies

KW - CYCLASE-ACTIVATING POLYPEPTIDE

KW - GENE-RELATED PEPTIDE

KW - ADENYLATE-CYCLASE

KW - DOUBLE-BLIND

KW - MESSENGER-RNA

KW - EPISODIC MIGRAINE

KW - EFFICACY

KW - SAFETY

KW - VIP

KW - SUMATRIPTAN

U2 - 10.1186/s10194-022-01523-8

DO - 10.1186/s10194-022-01523-8

M3 - Journal article

C2 - 36471250

VL - 23

JO - Journal of Headache and Pain

JF - Journal of Headache and Pain

SN - 1129-2369

M1 - 155

ER -