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Inhibition of ASIC-Mediated Currents by Activation of Somatostatin 2 Receptors in Rat Dorsal Root Ganglion Neurons

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Abstract

Somatostatin (SST) and its analogues like octreotide (OCT) have analgesic effect on a variety of pain through peripheral SST receptors (SSTRs). However, the precise molecular mechanisms have not yet been fully elucidated. This research aimed to identify possible antinociceptive mechanisms, showing functional links of the SSTR2 and acid-sensing ion channels (ASICs). Herein, we reported that OCT inhibited the electrophysiological activity of ASICs in rat dorsal root ganglia (DRG) neurons. OCT concentration-dependently decreased the peak amplitude of acid-evoked inward currents, which were mediated by ASICs. OCT shifted concentration-response curve to protons downwards, with a decrease of 36.53 ± 5.28% in the maximal current response to pH 4.5 in the presence of OCT. OCT inhibited ASIC-mediated currents through SSTR2, since the inhibition was blocked by Cyn 154806, a specific SSTR2 antagonist. The OCT inhibition of ASIC-mediated currents was mimicked by H-89, a membrane-permeable inhibitor of PKA, and reversed by internal treatment of an adenylyl cyclase activator forskolin or 8-Br-cAMP. OCT also decreased the number of action potentials induced by acid stimuli through SSTR2. Finally, peripheral administration of 20 μM OCT, but not 2 μM OCT, significantly relieved nociceptive responses to intraplantar injection of acetic acid in rats. This occurred through local activation of SSTR2 in the injected hindpaw and was reversed following co-application of Cyn 154806. Our results indicate that activation SSTR2 by OCT can inhibit the activity of ASICs via an intracellular cAMP and PKA signaling pathway in rat DRG neurons. These observations demonstrate a cross-talk between ASICs and SSTR2 in peripheral sensory neurons, which was a novel peripheral analgesic mechanism of SST and its analogues.

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Data Availability

The data used and/or analyzed in this study are available from the corresponding author on reasonable request.

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Funding

This work was supported by the National Natural Science Foundation of China (No. 81671101) and the Campus Scientific Research Programs of Hubei University of Science and Technology (No. 2021-22X09).

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  1. Ting-Ting Liu and Shuang Wei contributed equally to this work.

Authors and Affiliations

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

    Ting-Ting Liu, Shuang Wei, Ying Jin, Chun-Yu Qiu & Wang-Ping Hu

  2. Department of Pharmacology, Hubei University of Science and Technology, 88 Xianning Road, Xianning, 437100, Hubei, People’s Republic of China

    Shuang Wei

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Contributions

WPH designed this research. TTL, SW, YJ, and CYQ performed the experiments. TTL and SW participated in data analysis. TTL, SW, 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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All experimental protocols were approved by the animal research ethics committee of Hubei University of Science and Technology in full accordance with the ethical guidelines of the National Institutes of Health for the care and use of laboratory animals.

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Liu, TT., Wei, S., Jin, Y. et al. Inhibition of ASIC-Mediated Currents by Activation of Somatostatin 2 Receptors in Rat Dorsal Root Ganglion Neurons. Mol Neurobiol 58, 2107–2117 (2021). https://doi.org/10.1007/s12035-020-02257-x

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