Endogenous adenosine A3 receptor activation selectively alleviates persistent pain states

Joshua W. Little, Amanda Ford, Ashley M. Symons-Liguori, Zhoumou Chen, Kali Janes, Timothy Doyle, Jennifer Xie, Livio Luongo, Dillip K. Tosh, Sabatino Maione, Kirsty Bannister, Anthony H. Dickenson, Todd W. Vanderah, Frank Porreca, Kenneth A. Jacobson, Daniela Salvemini

Research output: Contribution to journalArticlepeer-review

115 Scopus citations


Chronic pain is a global burden that promotes disability and unnecessary suffering. To date, efficacious treatment of chronic pain has not been achieved. Thus, new therapeutic targets are needed. Here, we demonstrate that increasing endogenous adenosine levels through selective adenosine kinase inhibition produces powerful analgesic effects in rodent models of experimental neuropathic pain through the A3 adenosine receptor (A3AR, now known as ADORA3) signalling pathway. Similar results were obtained by the administration of a novel and highly selective A3AR agonist. These effects were prevented by blockade of spinal and supraspinal A3AR, lost in A3AR knock-out mice, and independent of opioid and endocannabinoid mechanisms. A3AR activation also relieved non-evoked spontaneous pain behaviours without promoting analgesic tolerance or inherent reward. Further examination revealed that A3AR activation reduced spinal cord pain processing by decreasing the excitability of spinal wide dynamic range neurons and producing supraspinal inhibition of spinal nociception through activation of serotonergic and noradrenergic bulbospinal circuits. Critically, engaging the A3AR mechanism did not alter nociceptive thresholds in non-neuropathy animals and therefore produced selective alleviation of persistent neuropathic pain states. These studies reveal A3AR activation by adenosine as an endogenous anti-nociceptive pathway and support the development of A3AR agonists as novel therapeutics to treat chronic pain.

Original languageEnglish (US)
Pages (from-to)28-35
Number of pages8
Issue number1
StatePublished - Dec 11 2015


  • AAR
  • Adenosine
  • Chronic pain
  • Rostral ventromedial medulla
  • Spontaneous pain

ASJC Scopus subject areas

  • Clinical Neurology


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