Uncovering the Mechanisms of Adenosine Receptor-Mediated Pain Control: Focus on the A 3 Receptor Subtype.

Agonists of the G _i protein-coupled A ₃ adenosine receptor (A ₃ AR) have shown important pain-relieving properties in preclinical settings of several pain models. Active as a monotherapy against chronic pain, A ₃ AR agonists can also be used in combination with classic opioid analgesics. Their safe pharmacological profile, as shown by clinical trials for other pathologies, i.e., rheumatoid arthritis, psoriasis and fatty liver diseases, confers a realistic translational potential, thus encouraging research studies on the molecular mechanisms underpinning their antinociceptive actions. A number of pathways, involving central and peripheral mechanisms, have been proposed. Recent evidence showed that the prototypical A ₃ AR agonist Cl-IB-MECA and the new, highly selective, A ₃ AR agonist MRS5980 inhibit neuronal (N-type) voltage-dependent Ca ²⁺ currents in dorsal root ganglia, a known pain-related mechanism. Other proposed pathways involve reduced cytokine production, immune cell-mediated responses, as well as reduced microglia and astrocyte activation in the spinal cord. The aim of this review is to summarize up-to-date information on A ₃ AR in the context of pain, including cellular and molecular mechanisms underlying this effect. Based on their safety profile shown in clinical trials for other pathologies, A ₃ AR agonists are proposed as novel, promising non-narcotic agents for pain control.