Papers of the Week

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, A adenosine receptor subtype (AAR), is expressed on the mitochondrial outer membrane. Ex vivo application of a highly selective AAR agonist, MRS5980, to saphenous nerve microfilaments harvested from male oxaliplatin-treated rats reversed the loss in ATP production underscoring mitoprotective effects resulting from AAR activation on mitochondria. Moreover, in vivo administration of AAR 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 AAR and indicate that activation of AAR protects mitochondrial function in primary afferent sensory axons against chemotherapy-induced neurotoxicity. Repurposing AAR 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. Alterations in mitochondrial function are central to the development of chemotherapy-induced neuropathy and ensuing pain syndromes. Here we show that the adenosine A receptor (AAR) is expressed on mitochondria and its activation can reverse deficits in mitochondrial ATP production in peripheral sensory nerves from animals with chemotherapy-induced neuropathic pain. Moreover, administration of AAR agonists during chemotherapy in animals prevented the development of pain and pathophysiological signs of neuropathy in sensory nerves such as the loss of intraepidermal nerve fibers and increased spontaneous firing. These findings identify for the first time mitochondrial AAR and show that activation of AAR protects mitochondrial function in primary afferent sensory axons against chemotherapy-induced neurotoxicity.