Evidence for a role of heat shock protein-90 in toll like receptor 4 mediated pain enhancement in rats.
Evidence for a role of heat shock protein-90 in toll like receptor 4 mediated pain enhancement in rats.
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DOI：
10.1016/j.neuroscience.2009.09.046
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发表时间：
2009-12-29
期刊：
影响因子：
3.3
通讯作者：
Watkins, L. R.
中科院分区：
文献类型：
--
作者：
Hutchinson, M. R.;Ramos, K. M.;Loram, L. C.;Wieseler, J.;Sholar, P. W.;Kearney, J. J.;Lewis, M. T.;Crysdale, N. Y.;Zhang, Y.;Harrison, J. A.;Maier, S. F.;Rice, K. C.;Watkins, L. R.
脊髓小胶质细胞Toll样受体-4（TLR 4）参与增强神经病理性疼痛和对抗吗啡镇痛。本研究旨在探讨鞘内注射脂多糖（一种经典的TLR 4激动剂）对TLR 4介导的疼痛调节作用。然而，我们的初步研究表明，鞘内脂多糖未能诱导低阈值的机械异常性疼痛在幼稚大鼠，提示TLR 4激动可能不足以增强疼痛。这些研究探索了需要第二个信号的可能性;即热休克蛋白90（HSP 90）。鉴于其作为TLR 4信号传导调节剂的已知重要性，选择该候选物进行研究。体外TLR 4细胞信号传导和疼痛调节的体内行为研究的组合表明，神经性疼痛的TLR 4增强和吗啡镇痛的TLR 4抑制各自可能需要HSP 90作为观察到的作用的辅因子。体外研究表明，DMSO增强HSP 90的释放，提示这可能是DMSO增强TLR 4信号传导的一种方式。虽然2 μg和100 μg脂多糖鞘内注射在测试的时间过程中没有诱导机械性异常性疼痛，但1 μg脂多糖与增强HSP 90介导的TLR 4信号传导的药物共同给药现在诱导了强烈的异常性疼痛。为了支持这种异常性疼痛是通过TLR 4/HSP 90途径介导的，通过鞘内共同施用HSP 90抑制剂、TLR 4抑制剂、小胶质细胞/单核细胞活化抑制剂（因为单核细胞衍生的细胞是表达TLR 4的主要细胞类型）和白介素-1受体拮抗剂（因为这种促炎细胞因子是TLR 4活化的下游结果）来预防或逆转。总之，这些结果首次表明，TLR 4激活是必要的，但不足以诱导脊髓介导的疼痛增强。相反，数据表明，TLR 4依赖性疼痛现象可能需要TLR 4受体复合物的多个组分的贡献。
Spinal cord microglial toll-like receptor-4 (TLR4) has been implicated in enhancing neuropathic pain and opposing morphine analgesia. The present study was initiated to explore TLR4-mediated pain modulation by intrathecal lipopolysaccharide, a classic TLR4 agonist. However, our initial study revealed that intrathecal lipopolysaccharide failed to induce low-threshold mechanical allodynia in naive rats, suggestive that TLR4 agonism may be insufficient to enhance pain. These studies explore the possibility that a second signal is required; namely, heat shock protein-90 (HSP90). This candidate was chosen for study given its known importance as a regulator of TLR4 signaling. A combination of in vitro TLR4 cell signaling and in vivo behavioral studies of pain modulation suggest that TLR4-enhancement of neuropathic pain and TLR4-suppression of morphine analgesia each likely require HSP90 as a cofactor for the effects observed. In vitro studies revealed that DMSO enhances HSP90 release, suggestive that this may be a means by which DMSO enhances TLR4 signaling. While 2 µg and 100 µg lipopolysaccharide intrathecally did not induce mechanical allodynia across the time course tested, co-administration of 1 µg lipopolysaccharide with a drug that enhances HSP90-mediated TLR4 signaling now induced robust allodynia. In support of this allodynia being mediated via a TLR4/HSP90 pathway, it was prevented or reversed by intrathecal co-administration of a HSP90 inhibitor, a TLR4 inhibitor, a microglia/monocyte activation inhibitor (as monocytes-derived cells are the predominant cell type expressing TLR4), and interleukin-1 receptor antagonist (as this proinflammatory cytokine is a downstream consequence of TLR4 activation). Together, these results suggest for the first time that TLR4 activation is necessary but not sufficient to induce spinally mediated pain enhancement. Rather, the data suggest that TLR4-dependent pain phenomena may require contributions by multiple components of the TLR4 receptor complex.
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