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Regulation of the KATP-JNK gap junction signaling pathway by immunomodulator astragaloside IV attenuates neuropathic pain
  1. Wen-Ling Dai1,
  2. Li Zhang2,
  3. Liu Han3,
  4. Xing Yang4,
  5. Liang Hu4,
  6. Chen Miao5,
  7. Ling Song4,
  8. Hang Xiao6,
  9. Ji-Hua Liu1 and
  10. Wen-Tao Liu4,7
  1. 1Jiangsu Key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China
  2. 2Department of Anesthesiology, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
  3. 3Department of Anesthesiology, Nanjing Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu, China
  4. 4Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, China
  5. 5Department of pathology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
  6. 6Key Lab of Modern Toxicology (NJMU), Ministry of Education; Department of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
  7. 7Institute of Translational Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
  1. Correspondence to Dr Wen-Tao Liu, Pharmacology, Nanjing Medical University, Nanjing, China; painresearch{at}njmu.edu.cn; Dr Hang Xiao; hxiao{at}njmu.edu.cn; Professor Ji-Hua Liu; liujihua{at}cpu.edu.cn

Abstract

Background and objectives Gap junctions play a pivotal role in contributing to the formation of astroglial networks and in chronic pain. However, the mechanisms underlying the dysfunction of astroglial gap junctions in chronic pain have not been fully elucidated.

Methods Chronic constriction injury (CCI) of the sciatic nerve was used to establish rat neuropathic pain model. C6 cells were used to perform experiments in vitro. Von Frey hairs and Hargreave’s method were used to determine the withdrawal threshold of rats. Protein expression was detected by immunofluorescence and western blotting.

Results Astragaloside IV (AST IV) significantly attenuated neuropathic pain and suppressed the excitation of spinal astrocytes in rats with CCI. The antinociceptive effect of AST IV was reversed by the gap junction decoupler carbenoxolone (CBX). AST IV inhibited the high expression of phosphorylated connexin 43 (p-Cx43) and p-c-Jun N-terminal kinase (p-JNK) in spinal cord of rats with CCI. JNK inhibitor alleviated neuropathic pain, which was reversed by CBX. JNK inhibitor decreased the high expression of p-Cx43 in both rats with CCI and tumor necrosis factor-alpha (TNF-α)-treated C6 cells. Additionally, the analgesic effect of AST IV was reversed by the adenosine triphosphate-sensitive potassium (KATP) channel blocker, glibenclamide (Glib). Glib abolished the inhibitory effects of AST IV on p-JNK and p-Cx43 both in vivo and in vitro. KATP channel opener (KCO) mimicked the inhibitory effects of AST IV on p-JNK and p-Cx43 in TNF-α-treated C6 cells.

Conclusion Our results indicate that the sciatic nerve CCI induces the dysfunction of gap junctions in the spinal cord by activating KATP/JNK signaling to contribute to neuropathic pain. AST IV attenuates neuropathic pain via regulating the KATP-JNK gap junction axis.

  • Chronic pain: neuropathic pain
  • pain medicine
  • basic science of pain
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Footnotes

  • W-LD, LZ and LH contributed equally.

  • Contributors W-LD, LZ, LH and HX, J-HL, WL co-designed the overall study, W-LD, XY and LH performed the immunoassays and behavioral measures. CM, and LS carried out the cell cultures and performed related assays. W-LD and LH analyzed the results and wrote this manuscript. HX, J-HL and WL revised the manuscript. All authors read and approved the final manuscript.

  • Funding This work was supported by grants by the Major Project of 'Science and Technology Innovation Fund' of Nanjing Medical University (2017NJMUCX004) and the Natural Science Foundation of Jiangsu Province (Grants No BK20161033).

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval All experimental protocols were approved by the Animal Experimentation Ethics Committee of the China Pharmaceutical University.

  • Provenance and peer review Not commissioned; externally peer-reviewed.

  • Data availability statement Data are available upon reasonable request. Availability of data and materials: The data sets during and/or analysed during the current study are available from the corresponding author on reasonable request.

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