Adenosine receptors in the nervous system: pathophysiological implications

Adenosine is a ubiquitous homeostatic substance released from most cells, including neurones and glia. Once in the extracellular space, adenosine modifies cell functioning by operating G-protein-coupled receptors (GPCR; A(1), A(2A), A(2B), A(3)) that can inhibit (A(1)) or enhance (A(2)) neuronal communication. Interactions between adenosine receptors and other G-protein-coupled receptors, ionotropic receptors and receptors for neurotrophins also occur, and this might contribute to a fine-tuning of neuronal function. Manipulations of adenosine receptors influence sleep and arousal, cognition and memory, neuronal damage and degeneration, as well as neuronal maturation. These actions might have therapeutic implications for neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, as well as for other neurological situations such as epilepsy, idiopathic pain or even drug addition. Peripheral side effects associated with adenosine receptor agonists limit their usefulness in therapeutics; in contrast, adenosine receptor antagonists appear to have less side effects as it is the case of the well-known non-selective antagonists theophylline (present in tea) or caffeine (abundant in coffee and tea), and their emerging beneficial actions in Parkinson's disease and Alzheimer's disease are encouraging. A(1) receptor antagonism may also be useful to enhance cognition and facilitate arousal, as well as in the periphery when deficits of neurotransmitter release occur (e.g. myasthenic syndromes). Enhancement of extracellular adenosine levels through drugs that influence its metabolism might prove useful approaches in situations such as neuropathic pain, where enhanced activation of inhibitory adenosine A(1) receptors is beneficial. One might then consider adenosine as a fine-tuning modulator of neuronal activity, which via subtle effects causes harmonic actions on neuronal activity. Whenever this homeostasis is disrupted, pathology may be installed and selective receptor antagonism or agonism required.