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BmK DKK13, A Scorpion Toxin, Alleviates Pain Behavior in a Rat Model of Trigeminal Neuralgia by Modulating Voltage-Gated Sodium Channels and MAPKs/CREB Pathway

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Abstract

BmK DKK13 (DKK13) is a mutated recombinant peptide, which has a significant antinociception in a rat model of the inflammatory pain. The purpose of this study was to evaluate the antinociceptive effect of DKK13 on trigeminal neuralgia (TN) in rats. Male Sprague–Dawley (SD) rats were treated with the chronic constriction injury of the infraorbital nerve (IoN-CCI) model to induce stable symptoms of TN. DKK13 (1.0 mg/kg, 2.0 mg/kg and 4.0 mg/kg, i.v.) or morphine (4.0 mg/kg, i.v.) was administered by tail vein once on day 14 after IoN-CCI injury. Behavioral tests, electrophysiology and western blotting were performed to investigate the role and underlying mechanisms of DKK13 on IoN-CCI model. Behavioral test results showed that DKK13 could significantly increase the mechanical pain and thermal radiation pain thresholds of IoN-CCI rats and inhibit the asymmetric spontaneous pain scratching behavior. Electrophysiological results showed that DKK13 could significantly reduce the current density of Nav1.8 in the ipsilateral side of trigeminal ganglion (TG) neurons in IoN-CCI rats, and the steady-state activation and inactivation curves of Nav1.8 shifted, respectively, to the direction of hyperpolarization and depolarization. Western blotting results showed that DKK13 significantly reduced the expression of Nav1.8 and the phosphorylation levels of key proteins of MAPKs/CREB pathway in TG tissues of IoN-CCI rats. In brief, DKK13 has a significant antinociceptive effect on IoN-CCI rats, which may be achieved by changing the dynamic characteristics of Nav1.8 channel and regulating the protein phosphorylation in MAPKs/CREB pathway.

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All data generated or analyzed during this study are included in this published article and its supplementary information files.

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Acknowledgments

This study was supported by the National Natural Science Foundation of China (grant number: 81073081, 81973227), Scientific Research Foundation of the Education Department of Liaoning Province (2021), Scientific Research Staring Foundation for the Returned Overseas Scholars, Shenyang Pharmaceutical University (grant number: GGJJ2021101), and National Science and Technology Major Project of the Ministry of Science and Technology of China (grant number: 2018ZX09735005).

Funding

This research was funded by the National Natural Science Foundation of China (grant number: 81073081, 81973227), Scientific Research Foundation of the Education Department of Liaoning Province (2021), Scientific Research Staring Foundation for the Returned Overseas Scholars, Shenyang Pharmaceutical University (grant number: GGJJ2021101), and National Science and Technology Major Project of the Ministry of Science and Technology of China (grant number: 2018ZX09735005).

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  1. Ran Yang and Yongbo Song contributed equally to this work.

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  1. Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, 110016, China

    Ran Yang, Haipeng Wang, Chunyun Chen, Fei Bai & Chunli Li

  2. School of Life Sciences and Biopharmaceutical Science, Shenyang Pharmaceutical University, Shenyang, 110016, China

    Yongbo Song

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Chun-li Li did conceptualization, supervision and funding acquisition; Hai-peng Wang, Chun-yun Chen and Bai Fei performed methodology; Ran Yang and Hai-peng Wang done formal analysis, visualization and data curation; Yong-bo Song did resources; Ran Yang contributed to writing—original draft preparation; Chun-li Li and Ran Yang performed writing—review and editing. All authors have read and agreed to the published version of the manuscript.

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Supplementary file1 Supplementary Materials Fig. S1 (a1-f1) Homology modeling structure of BmK ANGP and its mutants. (a2-f2) Interaction model of BmK ANGP and its mutants with Nav1.8. Tab. S1. Results of acetic acid writhing test of BmK ANGP and its mutants. (DOCX 1417 kb)

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Yang, R., Song, Y., Wang, H. et al. BmK DKK13, A Scorpion Toxin, Alleviates Pain Behavior in a Rat Model of Trigeminal Neuralgia by Modulating Voltage-Gated Sodium Channels and MAPKs/CREB Pathway. Mol Neurobiol 59, 4535–4549 (2022). https://doi.org/10.1007/s12035-022-02855-x

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