Characterization of the trigeminovascular actions of several adenosine A2A receptor antagonists in an in vivo rat model of migraine

Kristian A Haanes, Alejandro Labastida-Ramírez, Kayi Y Chan, René de Vries, Brian Shook, Paul Jackson, Jimmy Zhang, Christopher M Flores, Alexander H J Danser, Carlos M Villalón, Antoinette MaassenVanDenBrink

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Migraine is considered a neurovascular disorder, but its pathophysiological mechanisms are not yet fully understood. Adenosine has been shown to increase in plasma during migraine attacks and to induce vasodilation in several blood vessels; however, it remains unknown whether adenosine can interact with the trigeminovascular system. Moreover, caffeine, a non-selective adenosine receptor antagonist, is included in many over the counter anti-headache/migraine treatments.

Methods: This study used the rat closed cranial window method to investigate in vivo the effects of the adenosine A2A receptor antagonists with varying selectivity over A1 receptors; JNJ-39928122, JNJ-40529749, JNJ-41942914, JNJ-40064440 or JNJ-41501798 (0.3-10 mg/kg) on the vasodilation of the middle meningeal artery produced by either CGS21680 (an adenosine A2A receptor agonist) or endogenous CGRP (released by periarterial electrical stimulation).

Results: Regarding the dural meningeal vasodilation produced neurogenically or pharmacologically, all JNJ antagonists: (i) did not affect neurogenic vasodilation but (ii) blocked the vasodilation produced by CGS21680, with a blocking potency directly related to their additional affinity for the adenosine A1 receptor.

Conclusions: These results suggest that vascular adenosine A2A (and, to a certain extent, also A1) receptors mediate the CGS21680-induced meningeal vasodilation. These receptors do not appear to modulate prejunctionally the sensory release of CGRP. Prevention of meningeal arterial dilation might be predictive for anti-migraine drugs, and since none of these JNJ antagonists modified per se blood pressure, selective A2A receptor antagonism may offer a novel approach to antimigraine therapy which remains to be investigated in clinical trials.

Original languageEnglish
Article number41
Pages (from-to)1-10
Number of pages10
JournalThe journal of headache and pain
Volume19
Issue number1
DOIs
Publication statusPublished - 25 May 2018

Keywords

  • adenosine receptor
  • CGS21680
  • dural vasodilation
  • rat, vasodepressor response

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