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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 …