Identification of A3 adenosine receptor agonists as novel non-narcotic analgesics

Chronic pain negatively impacts the quality of life in a variety of patient populations. The current therapeutic repertoire is inadequate in managing patient pain and warrants the development of new therapeutics. Adenosine and its four cognate receptors (A(1), A(2A), A(2B) and A(3)) have important roles in physiological and pathophysiological states, including chronic pain. Preclinical and clinical studies have revealed that while adenosine and agonists of the A(1) and A(2A) receptors have antinociceptive properties, their therapeutic utility is limited by adverse cardiovascular side effects. In contrast, our understanding of the A(3) receptor is only in its infancy, but exciting preclinical observations of A(3) receptor antinociception, which have been bolstered by clinical trials of A(3) receptor agonists in other disease states, suggest pain relief without cardiovascular side effects and with sufficient tolerability. Our goal herein is to briefly discuss adenosine and its receptors in the context of pathological pain and to consider the current data regarding A(3) receptor-mediated antinociception. We will highlight recent findings regarding the impact of the A(3) receptor on pain pathways and examine the current state of selective A(3) receptor agonists used for these studies. The adenosine-to-A(3) receptor pathway represents an important endogenous system that can be targeted to provide safe, effective pain relief from chronic pain.