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

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.

Caffeine and Primary (Migraine) Headaches—Friend or Foe?

“…Like other analgesics (55), caffeine increases dopamine release (18), probably via inhibition of A 2A R (56). Notably, A 2A receptor antagonists did not affect dural meningeal vasodilatation caused by CGRP in a rat model (57). The recent marketing of CGRP receptor antibodies and the development of CGRP antagonists has been considered a major breakthrough in the migraine field (58).…”

Sudden Caffeine Withdrawal Triggers Migraine—A Randomized Controlled Trial

“…Fried et al ( 32 ) suggested that it is the adenosine receptor A2A signaling that contribute to headache via modulation of intracellular cyclic adenosine monophosphate (cAMP) in neurons and glia to subsequently affect glutaminergic synaptic signaling. Based on an in vivo rat model of migraine, ( 39 ) suggested that A2A receptor antagonism may offer a novel approach to antimigraine therapy. Imaging studies using positron emission tomography (PET) A1AR- ( 31 ) and A2AR-ligands are suitable for studying the cerebral effects of caffeine ( 40 ), and may perhaps also be suitable for studying the effects of caffeine withdrawal as a trigger for migraine in vivo .…”

The role of adenosine and P2Y receptors expressed by multiple cell types in pain transmission

“…In fact, adenosine application to the rodent isolated middle meningeal artery exerts vasodilation, which is considered one of the triggering events for a migraine attack (Haanes & Edvinsson, 2014). This effect is observed also in living animals thanks to in vivo videomicroscopy and is blocked by selective A2A receptor antagonists and by caffeine, a non-selective adenosine receptor antagonist, which is often included in over-the-counter drugs for acute migraine attacks (Haanes et al 2018). Thus, the modulation of cerebral vessel diameter through A2A receptors can be one of the mechanisms through which caffeine contribute to reduce migraine and headache attacks.…”

“…In the field of adenosine-mediated signaling, some of the above-mentioned problems have now started to be solved, thanks to the invaluable efforts of medicinal chemists. New selective and potent A3 adenosine receptor agonists are now available , new A1 receptor agonists devoid of any cardiac actions have been designed and tested as analgesic agents (Petrelli et al, 2017;2018), and new selective A2A receptor antagonists acting as vasodilators in migraine are currently under development (Haanes et al, 2018). When dealing with adenosine agonists, an important issue to be considered is represented by the massive (ab)use of the methylxanthine caffeine, which acts as antagonist at various adenosine receptor subtype and could therefore alter the results of clinical trials and, prospectively, the beneficial effects of any agonist which will reach the market (Chen et al, 2013).…”