Abstract
BackgroundMigraine 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.MethodsThis 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).ResultsRegarding 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.ConclusionsThese 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.
Highlights
Migraine is considered a neurovascular disorder, but its pathophysiological mechanisms are not yet fully understood
General considerations In order to facilitate the interpretation of the following results, the five JNJ antagonists (Table 1) were sub-divided, a priori, into 3 groups: (i) JNJ-39928122 and JNJ-40529749 have ~ 10 fold selectivity for A2A over A1 receptors; (ii) JNJ-41942914 and JNJ-40064440 are ~ 100 fold selective for A2A over A1 receptors; and (iii) JNJ-41501798 is ~ 700 fold selective for A2A over A1 receptors
The lower the selectivity (A2A over A1 receptors) the higher the potency of JNJ antagonists to block CGS21680-induced dural vasodilation To further uncover the nature of the adenosine receptors in the dural vasculature, we explored the effect of the JNJ antagonist with varying selectivity (A2A over A1 receptors)
Summary
Migraine is considered a neurovascular disorder, but its pathophysiological mechanisms are not yet fully understood. Migraine is a neurovascular disorder associated with activation of the trigeminovascular system and release of calcitonin gene-related peptide (CGRP) from trigeminal sensory perivascular nerves, which results in cranial vasodilation and stimulation of sensory nerve transmission [1]. In line with these neurovascular mechanisms: (i) plasma levels of CGRP, which increase during migraine, are normalized by triptans in parallel with amelioration of headache [2]; and (ii) CGRP receptor antagonists [1] and antibodies against CGRP or its receptor [3] are Haanes et al The Journal of Headache and Pain (2018) 19:41 effective in migraine treatment. Adenosine receptor antagonists may have potential therapeutic usefulness in the treatment of migraine; while caffeine, a non-selective adenosine receptor antagonist [5], is already present in several over-the-counter anti-headache/migraine medications [10]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
