Article Text
PDF
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
This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.
Statistics from Altmetric.com
Footnotes
CW and KX are joint first authors.
Correction notice This article has been corrected since it published Online First. The funding statement has been updated and the joint author statatement added.
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 study was supported by the National Natural Science Foundation of China (Nos 81671087, 81971044, 81870871, 81701102, 81771142).
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.