Department of Anesthesiology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
Department of Pain management, First affiliated Hospital, Zhengzhou University, Zhengzhou, Henan 450052, China.
Neuropeptides. 2022 Jun;93:102243. doi: 10.1016/j.npep.2022.102243. Epub 2022 Mar 18.
The analgesic efficacy of morphine can be affected by a variety of factors. Our previous studies demonstrated that chemokine (CXC motif) ligand 10 (CXCL10) could induce algesia directly and attenuate the analgesic effect produced by a single dose of morphine. However, the underlying mechanism remains unclear. In the present study, we aimed to further investigate the mechanism of CXCL10-mediated inhibition on morphine analgesic effect. According to our findings, recombinant CXCL10 protein (rmCXCL10) could increase the phosphorylation of serine-threonine kinase AKT reduced by morphine in spinal cord. Blocking AKT activation by phosphoinositide 3-kinase (PI3K) inhibitor could effectively attenuate CXCL10-induced algesia, and reverse the decrease of paw withdrawal thresholds caused by the co-administration of morphine and rmCXCL10. Furthermore, rmCXCL10 could enhance the spinal expression of pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β, which could be blocked by PI3K inhibitor. In summary, these findings suggest that PI3K-AKT signaling pathway mediates the effect of CXCL10 on the regulation of morphine analgesia and the release of cytokines in spinal cord. Our study provides a new insight into the mechanism of chemokine-relative pain regulation.
吗啡的镇痛效果会受到多种因素的影响。我们之前的研究表明，趋化因子（CXC 基序）配体 10（CXCL10）可直接引起痛觉过敏，并减弱单次吗啡剂量产生的镇痛作用。然而，其潜在机制尚不清楚。在本研究中，我们旨在进一步探讨 CXCL10 介导的吗啡镇痛效应抑制的机制。根据我们的发现，重组 CXCL10 蛋白（rmCXCL10）可增加脊髓中吗啡降低的丝氨酸-苏氨酸激酶 AKT 的磷酸化。通过磷酸肌醇 3-激酶（PI3K）抑制剂阻断 AKT 激活可有效减弱 CXCL10 诱导的痛觉过敏，并逆转吗啡和 rmCXCL10 共同给药引起的足撤回阈值降低。此外，rmCXCL10 可增强脊髓中促炎细胞因子（包括 TNF-α、IL-6 和 IL-1β）的表达，PI3K 抑制剂可阻断其表达。总之，这些发现表明，PI3K-AKT 信号通路介导了 CXCL10 对吗啡镇痛调节和脊髓细胞因子释放的影响。我们的研究为趋化因子相关疼痛调节的机制提供了新的见解。
