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Exploration of purinergic receptors as potential anti-migraine targets using established pre-clinical migraine models

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  • Kristian A Haanes
  • Alejandro Labastida-Ramírez
  • Frank W Blixt
  • Eloisa Rubio-Beltrán
  • Clemens M Dirven
  • Alexander Hj Danser
  • Lars Edvinsson
  • Antoinette MaassenVanDenBrink
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BACKGROUND: The current understanding of mechanisms behind migraine pain has been greatly enhanced with the recent therapies targeting calcitonin gene-related peptide and its receptor. The clinical efficacy of calcitonin gene-related peptide-blocking drugs indicates that, at least in a considerable proportion of patients, calcitonin gene-related peptide is a key molecule in migraine pain. There are several receptors and molecular pathways that can affect the release of and response to calcitonin gene-related peptide. One of these could be purinergic receptors that are involved in nociception, but these are greatly understudied with respect to migraine.

OBJECTIVE: We aimed to explore purinergic receptors as potential anti-migraine targets.

METHODS: We used the human middle meningeal artery as a proxy for the trigeminal system to screen for possible anti-migraine candidates. The human findings were followed by intravital microscopy and calcitonin gene-related peptide release measurements in rodents.

RESULTS: We show that the purinergic P2Y13 receptor fulfills all the features of a potential anti-migraine target. The P2Y13 receptor is expressed in both the human trigeminal ganglion and middle meningeal artery and activation of this receptor causes: a) middle meningeal artery contraction in vitro; b) reduced dural artery dilation following periarterial electrical stimulation in vivo and c) a reduction of CGRP release from both the dura and the trigeminal ganglion in situ. Furthermore, we show that P2X3 receptor activation of the trigeminal ganglion causes calcitonin gene-related peptide release and middle meningeal artery dilation.

CONCLUSION: Both an agonist directed at the P2Y13 receptor and an antagonist of the P2X3 receptor seem to be viable potential anti-migraine therapies.

Original languageEnglish
JournalCephalalgia : an international journal of headache
Volume39
Issue number11
Pages (from-to)1421-1434
Number of pages14
ISSN0333-1024
DOIs
Publication statusPublished - Oct 2019

ID: 57526504