Shanzhiside methylester, the principle effective iridoid glycoside from the analgesic herb Lamiophlomis rotata, reduces neuropathic pain by stimulating spinal microglial β-endorphin expression
Shanzhiside methylester, the principle effective iridoid glycoside from the analgesic herb Lamiophlomis rotata, reduces neuropathic pain by stimulating spinal microglial β-endorphin expression
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山栀苷甲酯是来自镇痛草药 Lamiophlomis rotata 的主要有效环烯醚萜苷，通过刺激脊髓小胶质细胞 β-内啡肽表达来减轻神经性疼痛
DOI：
10.1016/j.neuropharm.2015.09.010
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发表时间：
2016-02-01
影响因子：
4.7
通讯作者：
Wang, Yong-Xiang
中科院分区：
文献类型：
--
作者：
Fan, Hui;Li, Teng-Fei;Wang, Yong-Xiang
独一味（Lamiophlomis rotata，Lrotata，Duyiwei）是一种常用的藏药镇痛药。山栀苷甲酯（SM）是旋花中主要有效的环烯醚萜苷，是一种小分子胰高血糖素样肽-1（GLP-1）受体激动剂。本研究旨在探讨SM抗异常性疼痛的信号机制，确定SM诱导抗异常性疼痛耐受的能力，并阐明SM与吗啡或SM与β-内啡肽在抗异常性疼痛和抗异常性疼痛耐受中的相互作用。鞘内注射SM对脊神经损伤诱导的神经病大鼠产生剂量依赖性和持久（>4小时）的抗异常性疼痛作用，最大抑制率为49%，预计ED 50为40.4 μ g。SM和肽类GLP-1受体激动剂艾塞那肽治疗7天未诱导对抗异常性疼痛的自身耐受或对吗啡或β-内啡肽的交叉耐受。相反，吗啡和β-内啡肽诱导的自身耐受和交叉耐受SM和exenadine。在脊髓背角和初级小胶质细胞，SM显着诱发β-内啡肽的表达，这是完全阻止小胶质细胞抑制剂米诺环素和p38丝裂原活化蛋白激酶（MAPK）抑制剂SB 203580。SM抗异常性疼痛被GLP-1受体拮抗剂exendin（9-39）、米诺环素、β-内啡肽抗血清、μ-阿片受体拮抗剂CTAP和SB 203580完全抑制。SM和exenglycine特异性激活脊髓p38 MAPK磷酸化。这些结果表明SM通过激活脊髓GLP-1受体并随后通过p38 MAPK信号传导刺激小胶质细胞β-内啡肽表达来减轻神经性疼痛。刺激内源性β-内啡肽的表达可能是发现和开发长期治疗慢性疼痛的镇痛药的一种新的有效策略。(C)2015爱思唯尔有限公司版权所有。
Lamiophlomis rotata (L rotata, Duyiwei) is an orally available Tibetan analgesic herb widely prescribed in China. Shanzhiside methylester (SM) is a principle effective iridoid glycoside of L rotata and serves as a small molecule glucagon-like peptide-1 (GLP-1) receptor agonist. This study aims to evaluate the signal mechanisms underlying SM anti-allodynia, determine the ability of SM to induce anti-allodynic tolerance, and illustrate the interactions between SM and morphine, or SM and beta-endorphin, in anti-allodynia and anti-allodynic tolerance. Intrathecal SM exerted dose-dependent and long-lasting (>4 h) anti-allodynic effects in spinal nerve injury-induced neuropathic rats, with a maximal inhibition of 49% and a projected ED50 of 40.4 mu g. SM and the peptidic GLP-1 receptor agonist exenatide treatments over 7 days did not induce self-tolerance to anti-allodynia or cross-tolerance to morphine or beta-endorphin. In contrast, morphine and beta-endorphin induced self-tolerance and cross-tolerance to SM and exenatide. In the spinal dorsal horn and primary microglia, SM significantly evoked beta-endorphin expression, which was completely prevented by the microglial inhibitor minocycline and p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580. SM anti-allodynia was totally inhibited by the GLP-1 receptor antagonist exendin(9-39), minocycline, beta-endorphin antiserum, mu-opioid receptor antagonist CTAP, and SB203580. SM and exenatide specifically activated spinal p38 MAPK phosphorylation. These results indicate that SM reduces neuropathic pain by activating spinal GLP-1 receptors and subsequently stimulating microglial beta-endorphin expression via the p38 MAPK signaling. Stimulation of the endogenous beta-endorphin expression may be a novel and effective strategy for the discovery and development of analgesics for the long-term treatment of chronic pain. (C) 2015 Elsevier Ltd. All rights reserved.