Department of Psychology & Neuroscience, University of Colorado at Boulder, Boulder, CO 80309-0345, USA.
Brain Behav Immun. 2013 May;30:24-32. doi: 10.1016/j.bbi.2013.01.005. Epub 2013 Jan 21.
We have previously observed that the non-opioid morphine metabolite, morphine-3-glucuronide, enhances pain via a toll-like receptor 4 (TLR4) dependent mechanism. The present studies were undertaken to determine whether TLR4-dependent pain enhancement generalizes to other classes of glucuronide metabolites. In silico modeling predicted that glucuronic acid alone and ethyl glucuronide, a minor but long-lasting ethanol metabolite, would dock to the same MD-2 portion of the TLR4 receptor complex previously characterized as the docking site for morphine-3-glucuronide. Glucuronic acid, ethyl glucuronide and ethanol all caused an increase in TLR4-dependent reporter protein expression in a cell line transfected with TLR4 and associated co-signaling molecules. Glucuronic acid-, ethyl glucuronide-, and ethanol-induced increases in TLR4 signaling were blocked by the TLR4 antagonists LPS-RS and (+)-naloxone. Glucuronic acid and ethyl glucuronide both caused allodynia following intrathecal injection in rats, which was blocked by intrathecal co-administration of the TLR4 antagonist LPS-RS. The finding that ethyl glucuronide can cause TLR4-dependent pain could have implications for human conditions such as hangover headache and alcohol withdrawal hyperalgesia, as well as suggesting that other classes of glucuronide metabolites could have similar effects.
我们之前已经观察到，非阿片类吗啡代谢物吗啡-3-葡糖苷酸通过 Toll 样受体 4（TLR4）依赖性机制增强疼痛。本研究旨在确定 TLR4 依赖性疼痛增强是否适用于其他类别的葡糖苷酸代谢物。计算机模拟预测，单独的葡萄糖醛酸和乙基葡糖苷酸（一种次要但持久的乙醇代谢物）将与先前表征为吗啡-3-葡糖苷酸结合位点的 TLR4 受体复合物的 MD-2 部分结合。葡萄糖醛酸、乙基葡糖苷酸和乙醇均在转染 TLR4 和相关共信号分子的细胞系中引起 TLR4 依赖性报告蛋白表达的增加。TLR4 拮抗剂 LPS-RS 和 (+)-纳洛酮阻断了葡萄糖醛酸、乙基葡糖苷酸和乙醇诱导的 TLR4 信号转导的增加。葡萄糖醛酸和乙基葡糖苷酸鞘内注射均可引起大鼠的痛觉过敏，TLR4 拮抗剂 LPS-RS 的鞘内共同给药可阻断其作用。乙基葡糖苷酸可引起 TLR4 依赖性疼痛的发现可能对人类疾病如宿醉头痛和酒精戒断性痛觉过敏有影响，并表明其他类别的葡糖苷酸代谢物可能有类似的作用。
