The Role of Adenosine Signaling in Headache: A Review

Abstract

Migraine is the third most prevalent disease on the planet, yet our understanding of its mechanisms and pathophysiology is surprisingly incomplete. Recent studies have built upon decades of evidence that adenosine, a purine nucleoside that can act as a neuromodulator, is involved in pain transmission and sensitization. Clinical evidence and rodent studies have suggested that adenosine signaling also plays a critical role in migraine headache. This is further supported by the widespread use of caffeine, an adenosine receptor antagonist, in several headache treatments. In this review, we highlight evidence that supports the involvement of adenosine signaling in different forms of headache, headache triggers, and basic headache physiology. This evidence supports adenosine A2A receptors as a critical adenosine receptor subtype involved in headache pain. Adenosine A2A receptor signaling may contribute to headache via the modulation of intracellular Cyclic adenosine monophosphate (cAMP) production or 5' AMP-activated protein kinase (AMPK) activity in neurons and glia to affect glutamatergic synaptic transmission within the brainstem. This evidence supports the further study of adenosine signaling in headache and potentially illuminates it as a novel therapeutic target for migraine.

The Role of Dietary Antioxidants in the Pathogenesis of Neurodegenerative Diseases and Their Impact on Cerebral Oxidoreductive Balance

“…Studies have confirmed the protective properties of alkaloids relative to oxidative damage induced by free radicals [156,157]. Caffeine present in coffee blocks the receptors of adenosine A1 and A2 and contributes to increased activity of the central nervous system [158]. The blocking of adenosine A1 receptors causes an increase in the release of neurotransmitters such as acetylcholine, noradrenaline, and dopamine.…”

“…The blocking of adenosine A1 receptors causes an increase in the release of neurotransmitters such as acetylcholine, noradrenaline, and dopamine. The inactivation of adenosine A2 receptors leads to increased dopamine activity and its stronger bonding to the D2 receptor, it also protects dopaminergic receptors against toxic factors [158,159]. The influence of caffeine on dopamine activity may be significant in AD and PD [19,160].…”

The research progress on the mechanism of adenosine A1 receptor-mediated calcitonin gene-related peptide to relieve migraine

“…Their combination plays an important role in the transmission and regulation of nociceptive information and inflammatory response. 11 A1Rs are widely distributed in various systems of the body. However, it is most widespread in the nervous system.…”

“…Adenosine, a purine nucleoside, can act as a nerve regulator that participates in the transmission and sensitization of pain. 11 Studies have shown that adenosine has analgesic effect when administered via veins, reticular structure of brain stem and lateral ventricle. 14 Due to the high affinity between adenosine and A1R, adenosine's analgesic effect may be mainly mediated by A1R.…”

“…However, activated A1R can alleviate migraine by inhibiting the activation of glial cells. 11 Postsynaptic analgesia:…”