Mitochondrial A₃ Adenosine Receptor as a Mechanism for the Protective Effects of A₃AR Agonists on Chemotherapy-Induced Neuropathic Pain

Alterations in mitochondrial function are the linchpin in numerous disease states including in the development of chemotherapy-induced neuropathic pain (CIPN), a major dose-limiting toxicity of widely used chemotherapeutic cytotoxins. In CIPN, mitochondrial dysfunction is characterized by deficits in mitochondrial bioenergetics (e.g., decreased ATP production) that are thought to drive the degeneration of the peripheral nerve sensory axon terminal sensory arbors in the skin (the intraepidermal nerve fibers; IENFs) and induce abnormal spontaneous discharge in peripheral nerve sensory axons. Preserving mitochondrial function is anticipated to prevent CIPN. We have now discovered that the G-protein-coupled receptor, A₃ adenosine receptor subtype (A₃AR), is expressed on the mitochondrial outer membrane. Ex vivo application of a highly selective A₃AR agonist, MRS5980, to saphenous nerve microfilaments harvested from male oxaliplatin-treated rats reversed the loss in ATP production underscoring mitoprotective effects resulting from A₃AR activation on mitochondria. Moreover, in vivo administration of A₃AR agonists to rats during oxaliplatin treatment was associated with reduced IENF loss and a lower incidence of spontaneous discharge in peripheral afferent axons. These effects are accompanied by improved mitochondrial ATP production in primary afferent sensory axons and overall inhibition of the development of neuropathic pain. These data identify for the first time mitochondrial A₃AR and indicate that activation of A₃AR protects mitochondrial function in primary afferent sensory axons against chemotherapy-induced neurotoxicity. Repurposing A₃AR agonists that are already in clinical trials as anticancer agents as adjunct to chemotherapeutics will address a major unmet medical need for which there are no FDA-approved drugs.