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Cannabinoid receptor 2‑selective agonist JWH015 attenuates bone cancer pain through the amelioration of impaired autophagy flux induced by inflammatory mediators in the spinal cord

  • Authors:
    • Yanting Mao
    • Yulin Huang
    • Ying Zhang
    • Chenchen Wang
    • Hao Wu
    • Xinyu Tian
    • Yue Liu
    • Bailing Hou
    • Ying Liang
    • Hui Rong
    • Xiaoping Gu
    • Zhengliang Ma

  • View Affiliations

  • Published online on: October 25, 2019     https://doi.org/10.3892/mmr.2019.10772
  • Pages: 5100-5110

  • Copyright: © Mao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Bone cancer pain (BCP) is a severe complication of advanced bone cancer. Although cannabinoid receptor 2 (CB2) agonists may have an analgesic effect, the underlying mechanism remains unclear. CB2 serves a protective role in various pathological states through the activation of autophagy. Therefore, the present study aimed to determine whether the analgesic effects of the selective CB2 agonist JWH015 was mediated by the activation of autophagy in BCP. BCP was induced by the intra‑femur implantation of NCTC2472 fibrosarcoma cells in C3H/HeN mice. The pain behaviors were assessed on the following postoperative days. The selective CB2 agonist JWH015 (1 and 2 µg) was intrathecally administered on day 14 following implantation. AM630 (1 µg), a CB2 antagonist, was injected 30 min before JWH015 administration. Lipopolysaccharide (LPS; 100 nM)‑stimulated primary neurons were treated with JWH015 (1 µM) and AM630 (1 µM) to further verify the mechanism by which CB2 affects autophagy. The results demonstrated that autophagy flux was impaired in spinal neurons during BCP, as indicated by the increased ratio of microtubule‑associated protein 1 light chain 3β (LC3B)‑II/LC3B‑I and increased expression of p62. Intrathecal administration of JWH015 attenuated BCP, which was accompanied by the amelioration of impaired autophagy flux (decreased LC3B‑II/LC3B‑I ratio and decreased p62expression). In addition, the activation of glia cells and upregulation of the glia‑derived inflammatory mediators, interleukin (IL)‑1β and IL‑6 were suppressed by JWH015. In LPS‑stimulated primary neurons, IL‑1β and IL‑6 were increased, and autophagy flux was impaired; whereas treatment with JWH015 decreased the expression of IL‑1β and IL‑6, LC3B‑II/LC3B‑I ratio and expression of p62. These effects were by pretreatment with the CB2‑selective antagonist AM630. The results of the present study suggested that the impairment of autophagy flux was induced by glia‑derived inflammatory mediators in spinal neurons. Intrathecal administration of the selective CB2 agonist JWH015 ameliorated autophagy flux through the downregulation of IL‑1β and IL‑6 and attenuated BCP.
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December-2019
Volume 20 Issue 6

Print ISSN: 1791-2997
Online ISSN:1791-3004

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  • Impact Factor: 3.4
  • Ranked Medicine Research and Experimental
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  • CiteScore: 6.9
  • CiteScore Rank: Q2: #98/328 Biochemistry, Genetics and Molecular Biology
  • Source Normalized Impact per Paper (SNIP): 0.721
  • SCImago Journal Rank (SJR): 0.65
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Spandidos Publications style
Mao Y, Huang Y, Zhang Y, Wang C, Wu H, Tian X, Liu Y, Hou B, Liang Y, Rong H, Rong H, et al: Cannabinoid receptor 2‑selective agonist JWH015 attenuates bone cancer pain through the amelioration of impaired autophagy flux induced by inflammatory mediators in the spinal cord. Mol Med Rep 20: 5100-5110, 2019
APA
Mao, Y., Huang, Y., Zhang, Y., Wang, C., Wu, H., Tian, X. ... Ma, Z. (2019). Cannabinoid receptor 2‑selective agonist JWH015 attenuates bone cancer pain through the amelioration of impaired autophagy flux induced by inflammatory mediators in the spinal cord. Molecular Medicine Reports, 20, 5100-5110. https://doi.org/10.3892/mmr.2019.10772
MLA
Mao, Y., Huang, Y., Zhang, Y., Wang, C., Wu, H., Tian, X., Liu, Y., Hou, B., Liang, Y., Rong, H., Gu, X., Ma, Z."Cannabinoid receptor 2‑selective agonist JWH015 attenuates bone cancer pain through the amelioration of impaired autophagy flux induced by inflammatory mediators in the spinal cord". Molecular Medicine Reports 20.6 (2019): 5100-5110.
Chicago
Mao, Y., Huang, Y., Zhang, Y., Wang, C., Wu, H., Tian, X., Liu, Y., Hou, B., Liang, Y., Rong, H., Gu, X., Ma, Z."Cannabinoid receptor 2‑selective agonist JWH015 attenuates bone cancer pain through the amelioration of impaired autophagy flux induced by inflammatory mediators in the spinal cord". Molecular Medicine Reports 20, no. 6 (2019): 5100-5110. https://doi.org/10.3892/mmr.2019.10772