The adenosine-receptor axis in chronic pain

Chronic pain is a widespread problem that plagues an estimated 10 to 30% of the world’s population. The current therapeutic repertoire is inadequate in managing patient pain with narcotic use resulting in a drug overdose epidemic, affirming the need for the development of new therapeutics. Adenosine and its four cognate receptors (A ₁ AR, A _2A AR, A _2B AR, and A ₃ AR) play essential roles in physiological and pathophysiological states, including chronic pain. For decades, preclinical and clinical studies have revealed that adenosine and A ₁ AR-and to a lesser extent A _2A AR-selective agonists have analgesic properties, yet their therapeutic utility has been limited by adverse cardiovascular side effects. There is no evidence that A _2B AR plays a role in pain. Recent preclinical studies have demonstrated that selective A ₃ AR agonists result in antinociception in models of acute and chronic pain while lacking unwanted side effects. These exciting preclinical observations of A ₃ AR agonists have been bolstered by clinical trials of A ₃ AR agonists in other disease states including rheumatoid arthritis and psoriasis that suggests a clinical benefit without cardiotoxicity. Our goal herein is to briefly discuss adenosine and its receptors in the context of pathological pain and examine what is known at present regarding A ₃ AR-mediated antinociception. We will highlight recent findings pertaining to A ₃ AR in pain and describe possible pathways by which A ₃ AR may mediate its effects and the current state of selective A ₃ AR agonists used in pain studies. The adenosine-to-A ₃ AR pathway represents an important endogenous system that can be targeted to provide safe, effective pain relief in patients suffering with chronic pain.