Neurochemical Research ( IF 3.7 ) Pub Date : 2023-08-10 , DOI: 10.1007/s11064-023-03998-6
Xiaoling Peng 1 , Jihong Wang 1 , Zheng Li 1 , Xiaoqian Jia 1 , Anqi Zhang 1 , Jie Ju 1 , Volker Eulenburg 2 , Feng Gao 1
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Background and Purpose: Morphine is amongst the most effective analgesics available for the management of severe pain. However, prolonged morphine treatment leads to analgesic tolerance which limits its clinical usage. Previous studies have demonstrated that melatonin ameliorates morphine tolerance by reducing neuroinflammation. However, little is known about the relationship between Toll like receptor 2 (TLR2) and neuroinflammation in morphine tolerance. The aim of this study was to explore the role of TLR2 in morphine tolerance and its connections with melatonin and Nod-like receptor protein 3 (NLRP3) inflammasome. Methods: Sprague-Dawley rats were treated with morphine for 7 days and tail-flick latency test was performed to identify the induction of analgesic tolerance. The roles of TLR2 in microglia activation and morphine tolerance were assessed pharmacologically, and the possible interactions between melatonin, TLR2 and NLRP3 inflammasome were investigated. Key Results: Morphine tolerance was accompanied by increased TLR2 expression and NLRP3 inflammasome activation in spinal cord. whereas melatonin level was down-regulated. Chronic melatonin administration resulted in a reduced TLR2 expression and NLRP3 inflammasome activation. Moreover, the analgesic effect of morphine was partially restored. Inhibition of TLR2 suppressed the microglia and NLRP3 inflammasome activation, as well as restored the spinal melatonin level while attenuated the development of morphine tolerance. Furthermore, the inhibition of microglia activation ameliorated morphine tolerance via inhibiting TLR2-NLRP3 inflammasome signaling in spinal cord. Conclusion: In this study, we directly demonstrate a TLR2-melatonin negative feedback loop regulating microglia and NLRP3 inflammasome activation during the development of morphine tolerance.
中文翻译:
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Toll 样受体 2-褪黑激素反馈环调节吗啡耐受大鼠脊髓 NLRP3 炎症小体的激活
背景和目的:吗啡是治疗剧烈疼痛最有效的镇痛药之一。然而,吗啡长期治疗会导致镇痛耐受,限制了其临床使用。先前的研究表明,褪黑激素通过减少神经炎症来改善吗啡耐受性。然而,人们对 Toll 样受体 2 (TLR2) 与吗啡耐受性神经炎症之间的关系知之甚少。本研究的目的是探讨 TLR2 在吗啡耐受中的作用及其与褪黑激素和 Nod 样受体蛋白 3 (NLRP3) 炎性体的联系。方法:用吗啡治疗Sprague-Dawley大鼠7天,并进行甩尾潜伏期试验来鉴定镇痛耐受的诱导情况。从药理学角度评估了 TLR2 在小胶质细胞激活和吗啡耐受中的作用,并研究了褪黑激素、TLR2 和 NLRP3 炎症小体之间可能的相互作用。主要结果:吗啡耐受伴随着脊髓中 TLR2 表达的增加和 NLRP3 炎性体的激活。而褪黑激素水平则下调。长期服用褪黑激素会导致 TLR2 表达减少和 NLRP3 炎性体激活。而且吗啡的镇痛作用也部分恢复。抑制 TLR2 可抑制小胶质细胞和 NLRP3 炎症小体的激活,并恢复脊髓褪黑激素水平,同时减弱吗啡耐受的发展。此外,抑制小胶质细胞活化可通过抑制脊髓中的 TLR2-NLRP3 炎性体信号传导改善吗啡耐受。结论:在本研究中,我们直接证明了吗啡耐受发展过程中 TLR2-褪黑激素负反馈环路调节小胶质细胞和 NLRP3 炎症小体激活。