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Spinal cannabinoid receptor 2 activation reduces hypersensitivity associated with bone cancer pain and improves the integrity of the blood–spinal cord barrier
  1. Chenchen Wang,
  2. Ke Xu,
  3. Yu Wang,
  4. Yanting Mao,
  5. Yulin Huang,
  6. Ying Liang,
  7. Yue Liu,
  8. Jing Hao,
  9. Xiaoping Gu,
  10. Zhengliang Ma and
  11. Yu'e Sun
  1. Department of Anesthesiology, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, Nanjing, Jiangsu, China
  1. Correspondence to Dr Zhengliang Ma, Department of Anesthesiology, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, Nanjing 210008, China; mazhengliang1964{at}nju.edu.cn

Abstract

Background Disruption of the blood–spinal cord barrier (BSCB) can facilitate inflammation that results in pain hypersensitivity. Proinflammatory cytokines produced by activated microglia and astrocytes damage the BSCB. This study aims to explore whether the BSCB is damaged in the bone cancer pain (BCP) model and to investigate a potential role and mechanism of JWH015 ((2-methyl-1-propyl-1H-indol-3-yl)−1-naphthalenylmethanone), a selective cannabinoid receptor 2 (CB2R) agonist, in preserving the BSCB integrity in the BCP model.

Methods We used a male mouse model of BCP. Pain hypersensitivity was measured over time. Evans blue dye extravasation, transmission electron microscopy and Western blotting were performed to investigate the permeability and structural integrity of the BSCB. Immunofluorescence staining and western blotting were used to investigate the effect of JWH015 on the activation of glial cells and the levels of proinflammatory cytokines.

Results A single intrathecal injection of JWH015 ameliorated pain hypersensitivity, the BSCB disruption and microglia and astrocyte activation. Decreases in the expression of ZO-1 and claudin-5 were partially restored by JWH015. The levels of the proinflammatory cytokines interleukin-1β and tumor necrosis factor-α and the enzyme MMP9 were reduced by JWH015. However, all effects were prevented by pretreatment with a CB2R-selective antagonist, AM630 ((6-iodo-2-methyl-1-(2-morpholinoethyl)−1H-indol-3-yl)(4-methoxyphenyl)methanone).

Conclusions JWH015 alleviates neuroinflammation and maintains the BSCB integrity and permeability in a mouse model of BCP, which is probably mediated by inhibiting glial cells activation. This study reveals the new analgesic mechanism of JWH015 on BCP and provides a perspective to explore novel drugs that target the BSCB to control BCP.

  • animal studies
  • basic science of pain
  • pharmacology: other
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Footnotes

  • Contributors CW, ZM and YS conceived and designed the experiments. CW conducted the study and wrote the manuscript. KX helped conduct the study and collect the data. YW and YM helped conduct the study. YL helped collect the data. YH helped to analyze the data. JH helped conduct the supplementary experiment. YL helped revise the manuscript. XG helped revise the manuscript. ZM and YS are the authors responsible for archiving the study files. All authors read and approved the final manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval All experimental procedures were in strict accordance with the applicable ARRIVE guidelines and approved by the Animal Care and Use Committee of the Medical School of Nanjing University.

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

  • Data availability statement All data relevant to the study are included in the article or uploaded as online supplementary information. No additional information.

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