Endogenous adenosine A(3) receptor activation selectively alleviates persistent pain states

Adenosine's analgesic effects have previously been attributed to A(1) and A(2A) adenosine receptors. However, Little et al. now show that A(3) adenosine receptor activation by endogenous adenosine and potent agonists selectively suppresses persistent pain states by activating brain-to-spinal cord circuits that inhibit pain processing. Targeting A(3) receptors could help relieve chronic pain.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 A(3) adenosine receptor (A(3)AR, now known as ADORA3) signalling pathway. Similar results were obtained by the administration of a novel and highly selective A(3)AR agonist. These effects were prevented by blockade of spinal and supraspinal A(3)AR, lost in A(3)AR knock-out mice, and independent of opioid and endocannabinoid mechanisms. A(3)AR activation also relieved non-evoked spontaneous pain behaviours without promoting analgesic tolerance or inherent reward. Further examination revealed that A(3)AR 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 A(3)AR mechanism did not alter nociceptive thresholds in non-neuropathy animals and therefore produced selective alleviation of persistent neuropathic pain states. These studies reveal A(3)AR activation by adenosine as an endogenous anti-nociceptive pathway and support the development of A(3)AR agonists as novel therapeutics to treat chronic pain.