TY - JOUR

T1 - The PACAP pathway is independent of CGRP in mouse models of migraine

T2 - Possible new drug target?

AU - Ernstsen, Charlotte

AU - Christensen, Sarah L.

AU - Rasmussen, Rikke H.

AU - Nielsen, Brian S.

AU - Jansen-Olesen, Inger

AU - Olesen, Jes

AU - Kristensen, David M.

N1 - Publisher Copyright: © 2022 The Author(s). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.

PY - 2022

Y1 - 2022

N2 - Calcitonin gene-related peptide (CGRP)-Antagonizing drugs represent a major advance in migraine treatment. However, up to 50% of patients do not benefit from monoclonal antibodies against CGRP or its receptor. Here, we test the hypothesis that a closely related peptide, pituitary adenylate cyclase-Activating peptide (PACAP-38), works independently of CGRP and thus might represent a new, alternative drug target. To understand differences in CGRP-and PACAP-mediated migraine pain, we used mouse models of provoked migraine-like pain based on multiple stimulations and subsequent measurement of tactile sensitivity response with von Frey filaments. Genetically modified mice lacking either functional CGRP receptors (Ramp1 knockout) or TRPA1 channels (Trpa1 knockout) were used together with CGRP-Targeting antibodies and chemical inhibitors in wild-Type mice (ntotal = 299). Ex vivo myograph studies were used to measure dilatory responses to CGRP and PACAP-38 in mouse carotid arteries. PACAP-38 provoked significant hypersensitivity and dilated the carotid arteries independently of CGRP. In contrast, glyceryl trinitrate-induced hypersensitivity is dependent on CGRP. Contrary to previous results with the migraine-inducing substances glyceryl trinitrate, cilostazol and levcromakalim, PACAP-38-induced hypersensitivity worked only partially through inhibition of ATP-sensitive potassium channels. Using multiple migraine-relevant models, these findings establish the PACAP-38 pathway as distinct from other migraine provoking pathways such as CGRP and glyceryl trinitrate. PACAP antagonism may therefore be a novel therapeutic target of particular interest in patients unresponsive to CGRP-Antagonizing drugs.

AB - Calcitonin gene-related peptide (CGRP)-Antagonizing drugs represent a major advance in migraine treatment. However, up to 50% of patients do not benefit from monoclonal antibodies against CGRP or its receptor. Here, we test the hypothesis that a closely related peptide, pituitary adenylate cyclase-Activating peptide (PACAP-38), works independently of CGRP and thus might represent a new, alternative drug target. To understand differences in CGRP-and PACAP-mediated migraine pain, we used mouse models of provoked migraine-like pain based on multiple stimulations and subsequent measurement of tactile sensitivity response with von Frey filaments. Genetically modified mice lacking either functional CGRP receptors (Ramp1 knockout) or TRPA1 channels (Trpa1 knockout) were used together with CGRP-Targeting antibodies and chemical inhibitors in wild-Type mice (ntotal = 299). Ex vivo myograph studies were used to measure dilatory responses to CGRP and PACAP-38 in mouse carotid arteries. PACAP-38 provoked significant hypersensitivity and dilated the carotid arteries independently of CGRP. In contrast, glyceryl trinitrate-induced hypersensitivity is dependent on CGRP. Contrary to previous results with the migraine-inducing substances glyceryl trinitrate, cilostazol and levcromakalim, PACAP-38-induced hypersensitivity worked only partially through inhibition of ATP-sensitive potassium channels. Using multiple migraine-relevant models, these findings establish the PACAP-38 pathway as distinct from other migraine provoking pathways such as CGRP and glyceryl trinitrate. PACAP antagonism may therefore be a novel therapeutic target of particular interest in patients unresponsive to CGRP-Antagonizing drugs.

KW - CGRP-independent

KW - migraine

KW - mouse model

KW - PACAP

KW - PACAP-38

U2 - 10.1093/brain/awac040

DO - 10.1093/brain/awac040

M3 - Journal article

C2 - 35136961

AN - SCOPUS:85125369769

VL - 145

SP - 2450

EP - 2460

JO - Brain

JF - Brain

SN - 0006-8950

IS - 7

ER -