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

The role of extracellular nucleotides and nucleosides as signaling molecules in cell-to-cell communication has now been clearly established. This is particularly true in the central and peripheral nervous system, where purines and pyrimidines are involved in both physiological and pathological interactions between neurons and surrounding glial cells. It can be thus foreseen that the purinergic system could represent a new potential target for the development of effective analgesics, also through the normalization of neuronal functions and the inhibition of glial cell activation. Research in the last 15 years has progressively confirmed this hypothesis, but no purinergic-based analgesics have reach the market so far; in the present review we have collected the more recent discoveries on the role of G protein-coupled P2Y nucleotide and of adenosine receptors expressed by both neurons and glial cells under painful conditions, and we have highlighted some of the challenges that must be faced to translate basic and preclinical studies to clinics.