The Role of Adenosine Signaling in Headache: A Review

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 adenosinesignaling also plays a critical role in migraine headache. This is further supported by the widespread use of caffeine, an adenosine receptor antagonist, in several headachetreatments. In this review, we highlight evidence that supports the involvement of adenosinesignaling in different forms of headache, headachetriggers, and basic headachephysiology. This evidence supports adenosine A2A receptorsas a critical adenosine receptorsubtype involved in headachepain. Adenosine A2A receptorsignaling may contribute to headachevia the modulation of intracellular Cyclic adenosine monophosphate(cAMP) production or 5' AMP-activated protein kinase(AMPK) activity in neurons and glia to affect glutamatergicsynaptic transmission within the brainstem. This evidence supports the further study of adenosinesignaling in headacheand potentially illuminates it as a novel therapeutic target for migraine.