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Analgesic effect of electroacupuncture on bone cancer pain in rat model: the role of peripheral P2X3 receptor

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Abstract

Upregulation of P2X3 receptor (P2X3R) has been strongly implicated in nociceptive signaling including bone cancer pain (BCP). The present study, using rat bone cancer model, aimed to explore the role of P2X3R in regulating rat pain behavior under the intervention of electroacupuncture (EA). The BCP model was successfully established by injection with MRMT-1 breast cancer cell into the medullary cavity of left tibia for 3 × 104 cells/3 μL PBS in rats as revealed by obvious bone destruction, decreased paw withdrawal thresholds (PWTs), and reduced paw withdrawal latencies (PWLs). Western blot analyses showed that P2X3R expression was significantly upregulated in ipsilateral lumbar 4–6 (L4-6) dorsal root ganglia (DRG), but the difference not seen in spinal cord dorsal horn (SCDH). With the in-depth study of P2X3R activation, we observed that intrathecal injection of P2X3R agonist α,β-meATP aggravated MRMT-1 induced BCP, while injection of P2X3R inhibitor A-317491 alleviated pain. Subsequently, we demonstrated that BCP induced mechanical allodynia and thermal hyperalgesia were attenuated after EA treatment. Under EA treatment, total P2X3R protein expression in ipsilateral DRGs was decreased, and it is worth mentioning that decreased expression of P2X3R membrane protein, which indicated that both the expression and membrane trafficking of P2X3R were inhibited by EA. The immunofluorescence assay showed that EA stimulation exerted functions by reducing the expression of P2X3R-positive cells in ipsilateral DRGs of BCP rats. Ca2+ imaging analysis revealed that the EA stimulation decreased the percentage of α,β-meATP responsive neurons in DRGs and inhibited calcium influx. Notably, the inhibitory effect of EA on mechanical allodynia and nociceptive flinches was abolished by intrathecal injection of α,β-meATP. These findings demonstrated EA stimulation ameliorated mechanical allodynia and thermal hyperalgesia in rat model of MRMT-1-induced BCP. EA exerts analgesic effect on BCP by reducing the overexpression and functional activity of P2X3R in ipsilateral DRGs of BCP rats. Our work first demonstrates the critical and overall role of P2X3R in EA’s analgesia against peripheral sensitization of MRMT-1-induced BCP and further supports EA as a potential therapeutic option for cancer pain in clinic.

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Data availability

All data included in this study are available upon request by contact with the corresponding author.

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Funding

This research was funded by National Natural Science Foundation of China (82174510 and 81674061), by Zhejiang Provincial Natural Science Funds (LGF21H270006), and by the Key Foundation of the Zhejiang Health Committee (2021ZZ017).

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  1. Shu-xin Tian, Ting Xu, and Ren-yi Shi contributed equally to this work.

Authors and Affiliations

  1. Department of Neurobiology and Acupuncture Research, The Third School of Clinical Medicine, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Zhejiang Chinese Medical University, 548 Binwen Road, Binjiang District, Hangzhou, 310053, Zhejiang Province, China

    Shu-xin Tian, Ting Xu, Yang-qian Cai, Ming-hui Wu, Si-jia Zhen, Wen Wang, You Zhou, Jun-ying Du, Jun-fan Fang, Xiao-mei Shao, Bo-yi Liu, Yong-liang Jiang, Xiao-fen He, Jian-qiao Fang & Yi Liang

  2. Department of Acupuncture and Moxibustion, Sanya Traditional Chinese Medicine Hospital, Sanya, 572000, China

    Ren-yi Shi

  3. Department of Acupuncture and Moxibustion, The Third Affiliated Hospital of Zhejiang, Chinese Medical University, Hangzhou, 310005, China

    Jian-qiao Fang & Yi Liang

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  1. Shu-xin Tian
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Contributions

Yi Liang designed the experiments. Yang-qian Cai performed the animal experiments. Ming-hui Wu, Si-jia Zeng, Wen Wang, and You Zhou analyzed the data. Shu-xin Tian and Ren-yi Shi wrote the initial manuscripts. Ting Xu participated in figure preparations. All authors contributed to revising the article and approved the final manuscript.

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Correspondence to Yi Liang.

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The study was approved by the ethics committee of Zhejiang Chinese Medical University, Hangzhou, China (Approval No. IACUC-20181022–01).

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Tian, Sx., Xu, T., Shi, Ry. et al. Analgesic effect of electroacupuncture on bone cancer pain in rat model: the role of peripheral P2X3 receptor. Purinergic Signalling 19, 13–27 (2023). https://doi.org/10.1007/s11302-022-09861-7

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