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Dorsal root ganglia P2X4 and P2X7 receptors contribute to diabetes-induced hyperalgesia and the downregulation of electroacupuncture on P2X4 and P2X7

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Abstract

Diabetic neuropathic pain (DNP) is highly common in diabetes patients. P2X receptors play critical roles in pain sensitization. We previously showed that elevated P2X3 expression in dorsal root ganglion (DRG) contributes to DNP. However, the role of other P2X receptors in DNP is unclear. Here, we established the DNP model using a single high-dose streptozotocin (STZ) injection and investigated the expression of P2X genes in the DRG. Our data revealed elevated P2X2, P2X4, and P2X7 mRNA levels in DRG of DNP rats. The protein levels of P2X4 and P2X7 in DNP rats increased, but the P2X2 did not change significantly. To study the role of P2X4 and P2X7 in diabetes-induced hyperalgesia, we treated the DNP rats with TNP-ATP (2’,3’-O-(2,4,6-trinitrophenyl)-adenosine 5’-triphosphate), a nonspecific P2X1–7 antagonist, and found that TNP-ATP alleviated thermal hyperalgesia in DNP rats. 2 Hz electroacupuncture is analgesic against DNP and could downregulate P2X4 and P2X7 expression in DRG. Our findings indicate that P2X4 and P2X7 in L4–L6 DRGs contribute to diabetes-induced hyperalgesia, and that EA reduces thermal hyperalgesia and the expression of P2X4 and P2X7.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

ATP:

Adenosine 5′-triphosphate

AUC:

Area under the curve

BW:

Body weight

DNP:

Diabetic neuropathic pain

DRG:

Dorsal root ganglion

EA:

Electroacupuncture

FBG:

Fasting blood glucose

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

IF:

Immunofluorescence

i.p.:

Intraperitoneal

NS:

Normal saline

P2X:

Purinergic ligand-gated cationic channel

RT-qPCRs:

Real-time quantitative polymerase chain reactions

PWL:

Paw withdrawal latency

SD:

Standard deviation

STZ:

Streptozotocin

TNP-ATP:

2’,3’-O-(2,4,6-trinitrophenyl)-adenosine 5’-triphosphate

WB:

Western blotting

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Funding

This research was supported by the National Natural Science Foundation of China (81804181 to X.F.H. and 81774389 to Y.L.J.), the National Undergraduate Innovation and Entrepreneurship Training Program (202110344013), and the Key Laboratory of Acupuncture and Neurology of Zhejiang Province (2019E10011).

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  1. Qun-qi Hu, Xiao-fen He and Yi-qi Ma contributed equally.

Authors and Affiliations

  1. Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People’s Republic of China

    Qun-qi Hu, Xiao-fen He, Yi-qi Ma, Li-qian Ma, Si-ying Qu, Han-zhi Wang, Yu-rong Kang, Lu-hang Chen, Xiang Li, Bo-yu Liu, Xiao-mei Shao, Jun-fan Fang, Yi Liang, Jian-qiao Fang & Yong-liang Jiang

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Contributions

Xiao Fen He, Yongliang Jiang, and Jianqiao Fang conceived of and designed the experiments. Yurong Kang, Hanzhi Wang, and Siying Qu performed the animal experiments. Xiao Fen He, Hanzhi Wang, Siying Qu, and Xiang Li performed immunofluorescence. Luhang Chen, Liqian Ma, and Qunqi Hu performed WB and PCR. Boyu Liu, Yi Liang, Junfan Fang, and Xiaomei Shao analyzed the data. Qunqi Hu, Xiaofen He, and Yiqi Ma wrote the manuscripts. Qunqi Hu and Yiqi Ma participated in figures preparations. All authors read and approved the final manuscript.

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Correspondence to Jian-qiao Fang or Yong-liang Jiang.

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The study was approved by the ethics committee of Zhejiang Chinese Medical University, Hangzhou, China (Approval No. IACUC-20190805–04).

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Hu, Qq., He, Xf., Ma, Yq. et al. Dorsal root ganglia P2X4 and P2X7 receptors contribute to diabetes-induced hyperalgesia and the downregulation of electroacupuncture on P2X4 and P2X7. Purinergic Signalling 19, 29–41 (2023). https://doi.org/10.1007/s11302-022-09844-8

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