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A1 Adenosine Receptor Activation Inhibits P2X3 Receptor–Mediated ATP Currents in Rat Dorsal Root Ganglion Neurons

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Abstract

Purinergic signaling is involved in multiple pain processes. P2X3 receptor is a key target in pain therapeutics, while A1 adenosine receptor signaling plays a role in analgesia. However, it remains unclear whether there is a link between them in pain. The present results showed that the A1 adenosine receptor agonist N6-cyclopentyladenosine (CPA) concentration dependently suppressed P2X3 receptor–mediated and α,β-methylene-ATP (α,β-meATP)–evoked inward currents in rat dorsal root ganglion (DRG) neurons. CPA significantly decreased the maximal current response to α,β-meATP, as shown a downward shift of the concentration–response curve for α,β-meATP. CPA suppressed ATP currents in a voltage-independent manner. Inhibition of ATP currents by CPA was completely prevented by the A1 adenosine receptor antagonist KW-3902, and disappeared after the intracellular dialysis of either the Gi/o protein inhibitor pertussis toxin, the adenylate cyclase activator forskolin, or the cAMP analog 8-Br-cAMP. Moreover, CPA suppressed the membrane potential depolarization and action potential bursts, which were induced by α,β-meATP in DRG neurons. Finally, CPA relieved α,β-meATP-induced nociceptive behaviors in rats by activating peripheral A1 adenosine receptors. These results indicated that CPA inhibited the activity of P2X3 receptors in rat primary sensory neurons by activating A1 adenosine receptors and its downstream cAMP signaling pathway, revealing a novel peripheral mechanism underlying its analgesic effect.

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Acknowledgements

We are grateful to Miss. Ying Jin for providing the technical support to carry out this work.

Funding

This work was supported by the National Natural Science Foundation of China (No. 81671101).

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Authors and Affiliations

  1. School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, 88 Xianning Road, Xianning, 437100, Hubei, People’s Republic of China

    Jia-Wei Hao, Wen-Long Qiao, Qing Li, Shuang Wei, Xue-Mei Li, Ting-Ting Liu, Chun-Yu Qiu & Wang-Ping Hu

  2. School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, 88 Xianning Road, Xianning, 437100, Hubei, People’s Republic of China

    Jia-Wei Hao, Wen-Long Qiao, Qing Li & Shuang Wei

  3. Hubei College of Chinese Medicine, 87 Xueyuan Road, Jingzhou, 434020, Hubei, People’s Republic of China

    Wang-Ping Hu

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Contributions

WPH designed this research. JWH, WLQ, QL, SW, XML, TTL, and CYQ performed the experiments. JWH, WLQ, and QL participated in data analysis. JWH and WPH wrote the paper. All authors contributed substantially to this research and reviewed this manuscript.

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Correspondence to Wang-Ping Hu.

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Hao, JW., Qiao, WL., Li, Q. et al. A1 Adenosine Receptor Activation Inhibits P2X3 Receptor–Mediated ATP Currents in Rat Dorsal Root Ganglion Neurons. Mol Neurobiol 59, 7025–7035 (2022). https://doi.org/10.1007/s12035-022-03019-7

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