Abstract
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.
Recommended Citation
T. M. Doyle and K. Janes and W. H. Xiao and G. R. Kolar and H. F. Luecke and M. A. Gratton and D. K. Tosh and K. A. Jacobson and G. J. Bennett and D. Salvemini, "Mitochondrial A3 Adenosine Receptor As A Mechanism For The Protective Effects Of A3AR Agonists On Chemotherapy-Induced Neuropathic Pain," Journal of Neuroscience, vol. 45, no. 3, article no. e1268242024, Society for Neuroscience, Jan 2025.
The definitive version is available at https://doi.org/10.1523/JNEUROSCI.1268-24.2024
Department(s)
Biological Sciences
Keywords and Phrases
A3AR agonist; CIPN; IENF; mitochondria
International Standard Serial Number (ISSN)
1529-2401; 0270-6474
Document Type
Article - Journal
Document Version
Final Version
File Type
text
Language(s)
English
Rights
© 2025 The Authors, All rights reserved.
Creative Commons Licensing
This work is licensed under a Creative Commons Attribution 4.0 License.
Publication Date
15 Jan 2025
PubMed ID
39653498
Comments
National Cancer Institute, Grant R01 CA169519