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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
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
organization
publishing date
type
Contribution to journal
publication status
epub
subject
keywords
CGRP release, middle meningeal artery, myograph, Novel drug candidates, P2X3 receptor, P2Y13 receptor
in
Cephalalgia
publisher
Wiley-Blackwell
external identifiers
  • 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
2019-07-09 04:49:28
@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},
  keyword      = {CGRP release,middle meningeal artery,myograph,Novel drug candidates,P2X3 receptor,P2Y13 receptor},
  language     = {eng},
  month        = {05},
  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},
  year         = {2019},
}