Stroke is a leading cause of long-term disability worldwide with substantial economic costs. Hence, there is an urge for finding novel therapies to treat disability associated to stroke. This is the main reason research has focused on the discovery of key molecules involved in the functional prognosis of patients after stroke. Adenosine A2A and CB2 are receptors that have proven to be a new therapeutic target to consider in treatment of stroke. A common feature of these receptors in neurons is that their expression is upregulated in neuroinflammation process. On the one hand CB2R show a neuroprotective role, delaying neurodegenerative processes after an infart, while A2AR is associated with neuroinflammation, since, blockade of A2AR show neuroprotection in different neurodegenerative processes. One possible mechanism underlying this neuroprotection could be the control of neuroinflammation, that is associated with brain damage. Another possibility could be associated to cannabinoid system regulation. We here show a close interrelationship between those receptors in transfected cells and neuronal primary cultures where they are able to physically interact and affect the signaling of each other due to allosteric interaction within an A2A-CB2 receptor heteromer (A2A-CB2Het). Particularly relevant is the A2A-CB2Het expression increase in samples from an ischemic with hypoglycemia mice model. The most relevant finding was that blockade to A2A receptors resulted in increased CB2R-mediated signaling. This heteromer-specific feature suggests that A2AR antagonists would potentiate, via microglia, the neuroprotective action of endocannabinoids with important implications for an AD therapy.