Evidence that opioids may have toll-like receptor 4 and MD-2 effects.
Evidence that opioids may have toll-like receptor 4 and MD-2 effects.
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DOI：
10.1016/j.bbi.2009.08.004
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发表时间：
2010-01
影响因子：
15.1
通讯作者：
Watkins, Linda R.
中科院分区：
文献类型：
--
作者：
Hutchinson, Mark R.;Zhang, Yingning;Shridhar, Mitesh;Evans, John H.;Buchanan, Madison M.;Zhao, Tina X.;Slivka, Peter F.;Coats, Benjamen D.;Rezvani, Niloofar;Wieseler, Julie;Hughes, Travis S.;Landgraf, Kyle E.;Chan, Stefanie;Fong, Stephanie;Phipps, Simon;Falke, Joseph J.;Leinwand, Leslie A.;Maier, Steven F.;Yin, Hang;Rice, Kenner C.;Watkins, Linda R.
阿片样物质诱导的促炎性胶质细胞活化调节阿片样物质药理学的广泛方面，包括：急性和慢性阿片样物质镇痛的对抗、阿片样物质镇痛耐受、阿片样物质诱导的痛觉过敏、阿片样物质依赖的发展、阿片样物质奖赏和阿片样物质呼吸抑制。然而，导致阿片类药物诱导的促炎作用的机制仍未得到解决。Toll样受体4（TLR 4）的潜在参与进行了检查，在体外，在体内，和在电脑技术。吗啡在体外非立体选择性地诱导TLR 4信号传导，被经典的TLR 4拮抗剂阻断，并被纳洛酮非立体选择性地阻断。体内TLR 4信号传导的药理学阻断增强了急性鞘内吗啡镇痛，减弱了镇痛耐受、痛觉过敏和阿片类戒断行为的发展。TLR 4对阿片样物质作用的反对得到了TLR 4敲除小鼠的吗啡治疗的支持，其揭示了与野生型小鼠相比，镇痛剂量反应函数的显著三倍偏移。发现一系列结构不同的临床使用的阿片类镇痛药能够在体外激活TLR 4信号传导。由于吗啡-3-葡糖苷酸（一种无阿片受体活性的吗啡代谢物）显示出显著的TLR 4活性，而阿片受体活性代谢物吗啡-6-葡糖苷酸缺乏此类性质，因此确定了反应的选择性。在计算机对接模拟显示配体结合优先的LPS结合口袋的MD-2，而不是TLR 4。建立了计算机模拟到体外预测模型，并以相当高的准确度进行了测试。这些数据提供的证据表明，选择阿片类药物可能会非立体选择性地影响TLR 4信号传导，并具有部分通过TLR 4信号传导产生的行为后果。
Opioid-induced proinflammatory glial activation modulates wide-ranging aspects of opioid pharmacology including: opposition of acute and chronic opioid analgesia, opioid analgesic tolerance, opioid-induced hyperalgesia, development of opioid dependence, opioid reward, and opioid respiratory depression. However, the mechanism(s) contributing to opioid-induced proinflammatory actions remains unresolved. The potential involvement of toll like receptor 4 (TLR4) was examined using in vitro, in vivo, and in silico techniques. Morphine non-stereoselectively induced TLR4 signaling in vitro, blocked by a classical TLR4 antagonist and non-stereoselectively by naloxone. Pharmacological blockade of TLR4 signaling in vivo potentiated acute intrathecal morphine analgesia, attenuated development of analgesic tolerance, hyperalgesia, and opioid withdrawal behaviors. TLR4 opposition to opioid actions was supported by morphine treatment of TLR4 knockout mice, which revealed a significant threefold leftward shift in the analgesia dose response function, versus wildtype mice. A range of structurally diverse clinically employed opioid analgesics was found to be capable of activating TLR4 signaling in vitro. Selectivity in the response was identified since morphine-3-glucuronide, a morphine metabolite with no opioid receptor activity, displayed significant TLR4 activity, whilst the opioid receptor active metabolite, morphine-6-glucuronide, was devoid of such properties. In silico docking simulations revealed ligands bound preferentially to the LPS binding pocket of MD-2 rather than TLR4. An in silico to in vitro prediction model was built and tested with substantial accuracy. These data provide evidence that select opioids may non-stereoselectively influence TLR4 signaling and have behavioral consequences resulting, in part, via TLR4 signaling.
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影响因子：
2.9
作者：
Cui, Y;Chen, Y;Chen, PX
通讯作者：
Chen, PX
影响因子：
2
作者：
Cuschieri, Joseph;Bulger, Eileen;Maier, Ronald V
通讯作者：
Maier, Ronald V
影响因子：
15.1
作者：
Hutchinson, Mark R.;Northcutt, Alexis L.;Chao, Lindsey W.;Kearney, Jeffrey J.;Zhang, Yingning;Berkelhammer, Debra L.;Loram, Lisa C.;Rozeske, Robert R.;Bland, Sondra T.;Maier, Steven F.;Gleeson, Todd T.;Watkins, Linda R.
通讯作者：
Watkins, Linda R.
DOI：
10.1006/clin.1998.4518
发表时间：
1998-05-01
期刊：
CLINICAL IMMUNOLOGY AND IMMUNOPATHOLOGY
影响因子：
--
作者：
Lipovsky, MM;Gekker, G;Peterson, PK
通讯作者：
Peterson, PK
DOI：
10.1073/pnas.95.11.6326
发表时间：
1998-05-26
影响因子：
11.1
作者：
Gavériaux-Ruff, C;Matthes, HWD;Kieffer, BL
通讯作者：
Kieffer, BL