VPAC1 and VPAC2 receptors mediate tactile hindpaw hypersensitivity and carotid artery dilatation induced by PACAP38 in a migraine relevant mouse model.

Autor: Guo S; Department of Neurology, Danish Headache Center, Copenhagen University Hospital - Rigshospitalet Glostrup, Copenhagen, Denmark.; Translational Research Centre (TRACE), Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark.; Department of Odontology, Panum Institute, Faculty of Health, University of Copenhagen, Copenhagen, Denmark., Rasmussen RH; Department of Neurology, Danish Headache Center, Copenhagen University Hospital - Rigshospitalet Glostrup, Copenhagen, Denmark.; Translational Research Centre (TRACE), Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark., Hay-Schmidt A; Department of Odontology, Panum Institute, Faculty of Health, University of Copenhagen, Copenhagen, Denmark., Ashina M; Department of Neurology, Danish Headache Center, Copenhagen University Hospital - Rigshospitalet Glostrup, Copenhagen, Denmark.; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Asuni AA; Department of Preclinical Fluid Biomarkers and Occupancy, H. Lundbeck A/S, Copenhagen, Denmark., Jensen JM; Department of Neurology, Danish Headache Center, Copenhagen University Hospital - Rigshospitalet Glostrup, Copenhagen, Denmark.; Translational Research Centre (TRACE), Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark., Holm A; Center for RNA Medicine, Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark.; Department of Experimental Clinical Research, Translational Research Centre, Rigshospitalet Glostrup, Copenhagen, Denmark., Lauritzen SP; Department of Neurology, Danish Headache Center, Copenhagen University Hospital - Rigshospitalet Glostrup, Copenhagen, Denmark.; Translational Research Centre (TRACE), Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark., Dorsam G; Department of Microbiological Sciences, North Dakota State University, Fargo, USA., Hannibal J; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Department of Clinical Biochemistry, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark., Georg B; Department of Clinical Biochemistry, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark., Kristensen DM; Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.; Department of Science and Environment, Roskilde University, Roskilde, Denmark., Olesen J; Department of Neurology, Danish Headache Center, Copenhagen University Hospital - Rigshospitalet Glostrup, Copenhagen, Denmark.; Translational Research Centre (TRACE), Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark., Christensen SL; Department of Neurology, Danish Headache Center, Copenhagen University Hospital - Rigshospitalet Glostrup, Copenhagen, Denmark. sarah.louise.tangsgaard.christensen@regionh.dk.; Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. sarah.louise.tangsgaard.christensen@regionh.dk.
Jazyk: angličtina
Zdroj: The journal of headache and pain [J Headache Pain] 2024 Jul 31; Vol. 25 (1), pp. 126. Date of Electronic Publication: 2024 Jul 31.
DOI: 10.1186/s10194-024-01830-2
Abstrakt: Background: Pituitary adenylate cyclase-activating peptide (PACAP) is a neuropeptide pivotal in migraine pathophysiology and is considered a promising new migraine drug target. Although intravenous PACAP triggers migraine attacks and a recent phase II trial with a PACAP-inhibiting antibody showed efficacy in migraine prevention, targeting the PACAP receptor PAC1 alone has been unsuccessful. The present study investigated the role of three PACAP receptors (PAC1, VPAC1 and VPAC2) in inducing migraine-relevant hypersensitivity in mice.
Methods: Hindpaw hypersensitivity was induced by repeated PACAP38 injections. Tactile sensitivity responses were quantified using von Frey filaments in three knockout (KO) mouse strains, each lacking one of the PACAP-receptors (N total = 160). Additionally, ex vivo wire myography was used to assess vasoactivity of the carotid artery, and gene expression of PACAP receptors was examined by qPCR.
Results: PACAP38 induced hypersensitivity in WT controls (p < 0.01) that was diminished in VPAC1 and VPAC2 KO mice (p < 0.05). In contrast, PAC1 KO mice showed similar responses to WT controls (p > 0.05). Myograph experiments supported these findings showing diminished vasoactivity in VPAC1 and VPAC2 KO mice. We found no upregulation of the non-modified PACAP receptors in KO mice.
Conclusions: This study assessed all three PACAP receptors in a migraine mouse model and suggests a significant role of VPAC receptors in migraine pathophysiology. The lack of hypersensitivity reduction in PAC1 KO mice suggests the involvement of other PACAP receptors or compensatory mechanisms. The results indicate that targeting only individual PACAP receptors may not be an effective migraine treatment.
(© 2024. The Author(s).)
Databáze: MEDLINE
Externí odkaz: