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

Haanes, Kristian A. ; Labastida-Ramírez, Alejandro ; Blixt, Frank W. LU ; Rubio-Beltrán, Eloisa ; Dirven, Clemens M. ; Danser, Alexander H.J. ; Edvinsson, Lars LU and MaassenVanDenBrink, Antoinette (2019) In Cephalalgia 39(11). p.1421-1434
Abstract

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... (More)

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.

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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
CGRP release, middle meningeal artery, myograph, Novel drug candidates, P2X3 receptor, P2Y13 receptor
in
Cephalalgia
volume
39
issue
11
pages
1421 - 1434
publisher
Wiley-Blackwell
external identifiers
  • pmid:31104506
  • scopus:85066833548
ISSN
0333-1024
DOI
10.1177/0333102419851810
language
English
LU publication?
yes
id
bb914e35-f52d-4c4d-9446-ae66cefe3a8e
date added to LUP
2019-06-25 13:04:52
date last changed
2020-10-27 04:14:50
@article{bb914e35-f52d-4c4d-9446-ae66cefe3a8e,
  abstract     = {<p>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.</p>},
  author       = {Haanes, Kristian A. and Labastida-Ramírez, Alejandro and Blixt, Frank W. and Rubio-Beltrán, Eloisa and Dirven, Clemens M. and Danser, Alexander H.J. and Edvinsson, Lars and MaassenVanDenBrink, Antoinette},
  issn         = {0333-1024},
  language     = {eng},
  month        = {05},
  number       = {11},
  pages        = {1421--1434},
  publisher    = {Wiley-Blackwell},
  series       = {Cephalalgia},
  title        = {Exploration of purinergic receptors as potential anti-migraine targets using established pre-clinical migraine models},
  url          = {http://dx.doi.org/10.1177/0333102419851810},
  doi          = {10.1177/0333102419851810},
  volume       = {39},
  year         = {2019},
}