Exploration of purinergic receptors as potential anti-migraine targets using established pre-clinical migraine models
(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
- 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
- organization
- publishing date
- 2019-05-19
- 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
-
- scopus:85066833548
- pmid:31104506
- 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
- 2024-06-11 17:40:16
@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}},
keywords = {{CGRP release; middle meningeal artery; myograph; Novel drug candidates; P2X3 receptor; P2Y13 receptor}},
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}},
}