Kristian A Haanes1,2, Alejandro Labastida-Ramírez1, Frank W Blixt3, Eloisa Rubio-Beltrán1, Clemens M Dirven4, Alexander Hj Danser1, Lars Edvinsson2,3, Antoinette MaassenVanDenBrink1. 1. Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. 2. Clinical Experimental Research Department, Copenhagen University Hospital, Rigshospitalet-Glostrup, Glostrup, Denmark. 3. Department of Clinical Sciences, Division of Experimental Vascular Research, Lund University, Lund, Sweden. 4. Department of Neurosurgery, Erasmus Medical Center, Rotterdam, The Netherlands.
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 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.
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 humanmiddle 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.
Authors: Karin Warfvinge; Diana N Krause; Aida Maddahi; Jacob C A Edvinsson; Lars Edvinsson; Kristian A Haanes Journal: J Headache Pain Date: 2020-11-10 Impact factor: 7.277
Authors: Isabella Mai Christiansen; Jacob C A Edvinsson; Philip V Reducha; Lars Edvinsson; Kristian Agmund Haanes Journal: J Headache Pain Date: 2022-02-21 Impact factor: 7.277
Authors: Jacob C A Edvinsson; Aida Maddahi; Isabella M Christiansen; Philip V Reducha; Karin Warfvinge; Majid Sheykhzade; Lars Edvinsson; Kristian A Haanes Journal: J Headache Pain Date: 2022-02-17 Impact factor: 7.277
Authors: J C A Edvinsson; A Viganò; A Alekseeva; E Alieva; R Arruda; C De Luca; N D'Ettore; I Frattale; M Kurnukhina; N Macerola; E Malenkova; M Maiorova; A Novikova; P Řehulka; V Rapaccini; O Roshchina; G Vanderschueren; L Zvaune; A P Andreou; K A Haanes Journal: J Headache Pain Date: 2020-06-05 Impact factor: 8.588
Authors: Jacob C A Edvinsson; Karin Warfvinge; Diana N Krause; Frank W Blixt; Majid Sheykhzade; Lars Edvinsson; Kristian A Haanes Journal: J Headache Pain Date: 2019-11-12 Impact factor: 7.277