Department of Psychology and The Center for Neuroscience, University of Colorado at Boulder, Boulder, CO 80309-0345, USA
Brain Behav Immun. 2010 Jan;24(1):83-95. doi: 10.1016/j.bbi.2009.08.004. Epub 2009 Aug 11.
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.
阿片类药物诱导的促炎性神经胶质激活调节阿片类药物药理学的广泛方面，包括：对抗急性和慢性阿片类药物镇痛、阿片类药物镇痛耐受、阿片类药物引起的痛觉过敏、阿片类药物依赖的发展、阿片类药物奖赏和阿片类药物呼吸抑制。然而，导致阿片类药物引起的炎症反应的机制仍未解决。使用体外、体内和计算技术研究了 Toll 样受体 4 (TLR4) 的潜在参与。吗啡在体外非对映选择性地诱导 TLR4 信号，被经典 TLR4 拮抗剂和非对映选择性地被纳洛酮阻断。体内 TLR4 信号的药理学阻断增强了鞘内吗啡的急性镇痛作用，减弱了镇痛耐受、痛觉过敏和阿片类药物戒断行为的发展。TLR4 对阿片类药物作用的拮抗作用得到了 TLR4 敲除小鼠的吗啡治疗的支持，与野生型小鼠相比，这种作用导致镇痛剂量反应函数向左移动了三倍。发现一系列结构多样的临床应用的阿片类药物镇痛剂能够在体外激活 TLR4 信号。由于吗啡-3-葡糖苷酸，一种没有阿片受体活性的吗啡代谢物，显示出显著的 TLR4 活性，而具有阿片受体活性的代谢物吗啡-6-葡糖苷酸则没有这种特性，因此在反应中确定了选择性。计算对接模拟表明配体优先结合到 MD-2 而不是 TLR4 的 LPS 结合口袋。建立并测试了一个从计算到体外的预测模型，具有相当高的准确性。这些数据提供了证据表明，一些阿片类药物可能非对映选择性地影响 TLR4 信号，并导致行为后果，部分原因是通过 TLR4 信号。
