The adenosine-receptor axis in chronic pain

Daniela Salvemini, Timothy M. Doyle, Tally M. Largent-Milnes, Todd W Vanderah

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)413-437
Number of pages25
StatePublished - 2018


  • A AR
  • A AR agonists
  • A AR-mediated antinociception
  • Acute pain
  • Adenosine receptors
  • Chronic pain

ASJC Scopus subject areas

  • General Medicine


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