Past studies have shown that a drug called adenosine may be effective for pain relief in humans, but the medication activates an array of circuits, or “pathways,” causing a number of side effects. It has been unclear as to which specific pathway mediates the pain-relieving effects of adenosine
They found that activating a receptor in the brain called A3 halted or reversed chronic pain in the rodents, and that this receptor could be activated by a small adenosine molecule and other small-molecule medication created by the National Institutes of Health.
What is more, activating the A3 receptor with a small adenosine molecule did not alter the normal pain threshold in rodents or trigger the reward center of the brain – a process that can lead to addiction with opioid use.
The team notes that A3AR agonists are already undergoing clinical trials for treatment of inflammation and cancer, and – as demonstrated in this study – the drugs have caused no serious side effects so far.
“These studies suggest that A3AR activation by highly selective small molecular weight A3AR agonists – such as MRS5698 – activates a pain-reducing pathway supporting the idea that we could develop A3AR agonists as possible new therapeutics to treat chronic pain,” adds Prof. Salvemini.
Here’s the PubMed article:
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.