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CXCL12/CXCR4在携带Walker 256肿瘤的癌痛大鼠中参与CB2受体激动剂减轻吗啡耐受性的过程。

Involvement of CXCL12/CXCR4 in CB2 receptor agonist-attenuated morphine tolerance in Walker 256 tumor-bearing rats with cancer pain.

作者信息

Liu Dandan, Zhang Mingyue, Xu Xiaohai, Zhong Xuelai, Ma Chao, Zheng Xiaoyu, Wu Xiaohong, Wang Guonian

机构信息

Department of Anesthesiology, Harbin Medical University Cancer Hospital, Harbin, 150081, China.

Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.

出版信息

Eur J Med Res. 2024 Dec 18;29(1):580. doi: 10.1186/s40001-024-02207-6.

DOI:10.1186/s40001-024-02207-6
PMID:39696656
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11656961/
Abstract

While low-dose cannabinoid 2 (CB2) receptor agonists attenuate morphine tolerance in cancer pain models, chemokine ligand 12 (CXCL12)/chemokine receptor 4 (CXCR4) expression induces morphine tolerance. Whether CB2 receptor agonists attenuate morphine tolerance by modulating CXCL12/CXCR4 signaling or whether CXCL12/CXCR4 signaling affects the mu opioid receptor (MOR) in the development of morphine tolerance in cancer pain remains unclear. In this study, we investigated the attenuation of morphine tolerance by a non-analgesic dose of the CB2 receptor agonist AM1241, focusing specifically on the modulation of CXCL12/CXCR4 signaling and its effect on the MOR. Rats received intrathecal Walker 256 tumor cell implantations and were treated with morphine combined with the intrathecal injection of AM1241 or the CB2 receptor antagonists AM630 and AM1241, or a CXCL12-neutralizing antibody, exogenous CXCL12, or the CXCR4 antagonist AMD3100. Our results show that CXCL12 and CXCR4 levels increased significantly in morphine-tolerant rats and were reduced by AM1241 pretreatment, which was reversed by AM630. CXCL12/CXCR4 expression accelerated the development of morphine tolerance and downregulated MOR expression. CXCR4 colocalized with MOR and CB2. Therefore, a non-analgesic dose of AM1241 attenuated morphine tolerance via CXCL12/CXCR4 signaling, whereas CXCL12/CXCR4 signaling participated in the development of morphine tolerance, potentially by modulating MOR expression in Walker 256 tumor-bearing rats.

摘要

虽然低剂量大麻素2（CB2）受体激动剂可减轻癌症疼痛模型中的吗啡耐受性，但趋化因子配体12（CXCL12）/趋化因子受体4（CXCR4）的表达会诱导吗啡耐受性。CB2受体激动剂是否通过调节CXCL12/CXCR4信号来减轻吗啡耐受性，或者CXCL12/CXCR4信号在癌症疼痛吗啡耐受性发展过程中是否影响μ阿片受体（MOR）仍不清楚。在本研究中，我们研究了非镇痛剂量的CB2受体激动剂AM1241对吗啡耐受性的减轻作用，特别关注CXCL12/CXCR4信号的调节及其对MOR的影响。大鼠接受鞘内注射Walker 256肿瘤细胞，并接受吗啡联合鞘内注射AM1241或CB2受体拮抗剂AM630和AM1241，或CXCL12中和抗体、外源性CXCL12或CXCR4拮抗剂AMD3100治疗。我们的结果表明，吗啡耐受大鼠中CXCL12和CXCR4水平显著升高，AM1241预处理可使其降低，而AM630可逆转这种降低。CXCL12/CXCR4表达加速了吗啡耐受性的发展并下调了MOR表达。CXCR4与MOR和CB2共定位。因此，非镇痛剂量的AM1241通过CXCL12/CXCR4信号减轻吗啡耐受性，而CXCL12/CXCR4信号可能通过调节Walker 256荷瘤大鼠的MOR表达参与吗啡耐受性的发展。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0927/11656961/4bc944c59c7d/40001_2024_2207_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0927/11656961/2a53e25d3e13/40001_2024_2207_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0927/11656961/72a89418d970/40001_2024_2207_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0927/11656961/c65df7732ed4/40001_2024_2207_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0927/11656961/4bc944c59c7d/40001_2024_2207_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0927/11656961/2a53e25d3e13/40001_2024_2207_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0927/11656961/5c380854c75f/40001_2024_2207_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0927/11656961/03cdbdc0dc15/40001_2024_2207_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0927/11656961/72a89418d970/40001_2024_2207_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0927/11656961/c65df7732ed4/40001_2024_2207_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0927/11656961/4bc944c59c7d/40001_2024_2207_Fig6_HTML.jpg

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本文引用的文献

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