米诺环素通过抑制脊髓星形胶质细胞中的核因子κB减轻大鼠骨癌疼痛。

Minocycline attenuates bone cancer pain in rats by inhibiting NF-κB in spinal astrocytes.

作者信息

Song Zhen-Peng, Xiong Bing-Rui, Guan Xue-Hai, Cao Fei, Manyande Anne, Zhou Ya-Qun, Zheng Hua, Tian Yu-Ke

机构信息

Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.

School of Psychology, Social Work and Human Sciences, University of West London, Brentford, Middlesex, TW8 9GA, UK.

出版信息

Acta Pharmacol Sin. 2016 Jun;37(6):753-62. doi: 10.1038/aps.2016.1. Epub 2016 May 9.

DOI:10.1038/aps.2016.1

PMID:27157092

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4954763/

Abstract

AIM

To investigate the mechanisms underlying the anti-nociceptive effect of minocycline on bone cancer pain (BCP) in rats.

METHODS

A rat model of BCP was established by inoculating Walker 256 mammary carcinoma cells into tibial medullary canal. Two weeks later, the rats were injected with minocycline (50, 100 μg, intrathecally; or 40, 80 mg/kg, ip) twice daily for 3 consecutive days. Mechanical paw withdrawal threshold (PWT) was used to assess pain behavior. After the rats were euthanized, spinal cords were harvested for immunoblotting analyses. The effects of minocycline on NF-κB activation were also examined in primary rat astrocytes stimulated with IL-1β in vitro.

RESULTS

BCP rats had marked bone destruction, and showed mechanical tactile allodynia on d 7 and d 14 after the operation. Intrathecal injection of minocycline (100 μg) or intraperitoneal injection of minocycline (80 mg/kg) reversed BCP-induced mechanical tactile allodynia. Furthermore, intraperitoneal injection of minocycline (80 mg/kg) reversed BCP-induced upregulation of GFAP (astrocyte marker) and PSD95 in spinal cord. Moreover, intraperitoneal injection of minocycline (80 mg/kg) reversed BCP-induced upregulation of NF-κB, p-IKKα and IκBα in spinal cord. In IL-1β-stimulated primary rat astrocytes, pretreatment with minocycline (75, 100 μmol/L) significantly inhibited the translocation of NF-κB to nucleus.

CONCLUSION

Minocycline effectively alleviates BCP by inhibiting the NF-κB signaling pathway in spinal astrocytes.

摘要

目的

研究米诺环素对大鼠骨癌痛（BCP）抗伤害感受作用的潜在机制。

方法

通过将Walker 256乳腺癌细胞接种到胫骨骨髓腔建立大鼠BCP模型。两周后，大鼠每天两次注射米诺环素（鞘内注射50、100μg；或腹腔注射40、80mg/kg），连续3天。采用机械性缩爪阈值（PWT）评估疼痛行为。大鼠安乐死后，取脊髓进行免疫印迹分析。还在体外IL-1β刺激的原代大鼠星形胶质细胞中检测米诺环素对NF-κB激活的影响。

结果

BCP大鼠有明显的骨质破坏，术后第7天和第14天出现机械性触诱发痛。鞘内注射米诺环素（100μg）或腹腔注射米诺环素（80mg/kg）可逆转BCP诱导的机械性触诱发痛。此外，腹腔注射米诺环素（80mg/kg）可逆转BCP诱导的脊髓中胶质纤维酸性蛋白（星形胶质细胞标志物）和突触后致密蛋白95的上调。而且，腹腔注射米诺环素（80mg/kg）可逆转BCP诱导的脊髓中NF-κB、磷酸化IκB激酶α和IκBα的上调。在IL-1β刺激的原代大鼠星形胶质细胞中，用米诺环素（75、100μmol/L）预处理可显著抑制NF-κB向细胞核的转位。