Anales RANF

S1-04 TARGETING ADENOSINE RECEPTORS TO TREAT NEUROPATHIC PAIN L. Luongo 1 , D. Salvemini 2 1 Department of Experimental Medicine, Division of Pharmacology, University of Campania “L. Vanvitelli”, 80138, Naples; 2 Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO 63104 Chronic pain is a global burden that promotes disability and unnecessary suffering. The mechanisms underlying neuropathic pain are still poorly understood and efficacious treatment of has not been achieved. Thus, new therapeutic targets are needed. 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. Preliminary data showed that both adenosine kinase and A3 receptors are overexpressed in astrocytes in peripheral neuropathic pain model as compared to the sham mice. 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.