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Small-molecule natural product sophoricoside reduces peripheral neuropathic pain via directly blocking of NaV1.6 in dorsal root ganglion nociceptive neurons

Neuropsychopharmacology volume 50, pages 662–672 (2025)Cite this article

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Abstract

Peripheral neuropathic pain poses a significant global health challenge. Current drugs for peripheral neuropathic pain often fall short in efficacy or come with severe side effects, emphasizing the critical need for the development of highly effective and well-tolerated alternatives. Sophoricoside (SOP) is a nature product-derived isoflavone that possesses various pharmacological effects on inflammatory and neuropathy diseases. Here, in this study, analgesic effect was investigated by intrathecally administration of SOP/vehicle to spared nerve injury (SNI) or paclitaxel-induced peripheral neuropathic pain (PINP) rodent models, and mechanical allodynia was measured in Von Frey tests. Ipsilateral L4–L6 dorsal root ganglia (DRG) were used for protein expression. In silico molecular docking analysis was applied for assessing compound-target binding affinity. Primary cultured DRG neurons were utilized to investigate SOP’s effect on veratridine-triggered nociceptor activities and its selective inhibition of voltage-gated sodium channels subtype 1.6 (NaV1.6). The results showed SOP treatment alleviated mechanical allodynia in SNI and PINP rodent models (paw withdrawal threshold after 1 h of injection: SNI-vehicle: 1.385 ± 0.338 g; SNI-SOP: 9.963 ± 2.029 g, P < 0.001; PINP-vehicle: 5.040 ± 0.985 g; PINP-SOP: 8.287 ± 3.812 g, P = 0.004). SOP presented effects on both inhibiting veratridine-triggered nociceptor activities (oscillatory population: vehicle: 39.9 ± 7.3%; SOP: 30.7 ± 9.8%, P = 0.021) and selectively blocking NaV1.6 in DRG sensory neurons. Molecular docking analysis indicated direct binding between SOP and NaV1.6, leading to its endocytosis in DRG Sensory Neurons. In conclusion, SOP alleviated nociceptive allodynia induced by peripheral nerve injury via selectively blocking of NaV1.6 in DRG nociceptive neurons. we highlight its potential as an analgesic and elucidate its mechanism involving NaV1.6 endocytosis. This research opens avenues for exploring the analgesic effects of SOP and its potential impact on neuropathic pain therapy.

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Fig. 1: Effects of sophoricoside treatment on mechanical allodynia in rat models of peripheral neuropathic pain.
Fig. 2: Sophoricoside inhibited veratridine-triggered nociceptor activities of DRG neurons.
Fig. 3: Sophoricoside reduces the total NaV currents in DRG sensory neurons.
Fig. 4: Sophoricoside shows distinct effects on different subtypes of NaV channels.
Fig. 5: Sophoricoside directly binds to the active area of NaV1.6 channel and reduces NaV1.6 currents by promoting its endocytosis.

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Funding

This work was supported by the National Natural Science Foundation of China, Grant No. 82201376 and the Natural Science Foundation of Guangdong Province, Grant No. 2021A1515011129.

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  1. These authors contributed equally: Weijie Guo, Haoyi Yang.

Authors and Affiliations

  1. Health Science Center, Shenzhen University, Shenzhen, China

    Weijie Guo, Yuwei Wang, Tao Liu & Song Cai

  2. Department of Anesthesiology, Shenzhen People’s Hospital (The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China

    Haoyi Yang, Xiying Chen, Qiuyin Xu, Dizhou Zhao & Zhiming Shan

  3. Department of Periodontology & Oral Mucosa, Shenzhen Stomatology Hospital, Shenzhen, China

    Yunping Pan

  4. Laboratory and Clinical Research Institute for Pain, Department of Anaesthesiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China

    Zhiming Shan

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Contributions

Conceptualization, WG, ZS, and SC; data acquisition and analysis: animal model, XC and QX; behavior test, WG and TL; electrophysiological recording, WG, HY, and YW; molecular docking, DZ; manuscript drafting, YP, ZS, and SC. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Zhiming Shan or Song Cai.

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Guo, W., Yang, H., Wang, Y. et al. Small-molecule natural product sophoricoside reduces peripheral neuropathic pain via directly blocking of NaV1.6 in dorsal root ganglion nociceptive neurons. Neuropsychopharmacol. 50, 662–672 (2025). https://doi.org/10.1038/s41386-024-01998-w

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