Inhibition of spinal 15-LOX-1 attenuates TLR4-dependent, nonsteroidal anti-inflammatory drug-unresponsive hyperalgesia in male rats.
Inhibition of spinal 15-LOX-1 attenuates TLR4-dependent, nonsteroidal anti-inflammatory drug-unresponsive hyperalgesia in male rats.
复制标题
DOI：
10.1097/j.pain.0000000000001373
复制
发表时间：
2018-12
期刊：
影响因子：
7.4
通讯作者：
Yaksh TL
中科院分区：
文献类型：
--
作者：
Gregus AM;Buczynski MW;Dumlao DS;Norris PC;Rai G;Simeonov A;Maloney DJ;Jadhav A;Xu Q;Wei SC;Fitzsimmons BL;Dennis EA;Yaksh TL
虽然非甾体抗炎药 (NSAID) 是治疗轻度至中度躯体疼痛的一线疗法，但通常认为它们对神经性疼痛无效。在目前的研究中，通过鞘内（IT）注射脂多糖（LPS）的活性成分KDO2脂质A（KLA）直接激活脊髓Toll样4受体（TLR4），引起强烈的触觉异常性疼痛，尽管脊髓中COX代谢物的表达升高，但对环氧合酶（COX）抑制无反应。 IT KLA 增加腰脊髓中 12-脂氧合酶介导的 hepoxilin 的产生，同时出现触觉异常性疼痛。在原代脊髓小胶质细胞中也观察到了 TLR4 诱导的 hepoxilin 产生，但在星形胶质细胞中没有观察到，并且伴随着小胶质细胞 12/15-脂氧合酶 15-LOX-1 表达的增加。用 12/15-脂氧合酶抑制剂 CDC 或针对大鼠 15-LOX-1 的选择性抗体进行脊柱预处理，可以完全预防 IT KLA 引起的触觉异常性疼痛。类似地，用选择性抑制剂 ML127 或 ML351 预处理既降低了 HEK-293T 细胞中异源表达的 15-LOX-1 大鼠同源物的活性，又完全消除了 IT KLA 后体内 NSAID 无反应性异常性疼痛。最后，NDGA 对脊髓 12/15-脂氧合酶的抑制既可以防止 II 期福尔马林退缩，又可以逆转福尔马林引起的持续性触觉异常性疼痛。总而言之，这些发现表明脊髓 TLR4 介导的过度病理状态至少部分是通过小胶质细胞 15-LOX-1 的激活介导的。
While nonsteroidal inflammatory drugs (NSAIDs) are the first line of therapeutics for the treatment of mild to moderate somatic pain, they are not generally considered to be effective for neuropathic pain. In the current study, direct activation of spinal Toll-like 4 receptors (TLR4) by the intrathecal (IT) administration of KDO2 lipid A (KLA), the active component of lipopolysaccharide (LPS), elicits a robust tactile allodynia that is unresponsive to cyclooxygenase (COX) inhibition, despite elevated expression of COX metabolites in the spinal cord. IT KLA increases 12-Lipoxygenase-mediated hepoxilin production in the lumbar spinal cord, concurrent with expression of the tactile allodynia. The TLR4-induced hepoxilin production also was observed in primary spinal microglia, but not in astrocytes, and was accompanied by increased microglial expression of the 12/15-lipoxygenase enzyme 15-LOX-1. IT KLA-induced tactile allodynia was completely prevented by spinal pretreatment with the 12/15-Lipoxygenase inhibitor CDC or a selective antibody targeting rat 15-LOX-1. Similarly, pretreatment with the selective inhibitors ML127 or ML351 both reduced activity of the rat homolog of 15-LOX-1 heterologously expressed in HEK-293T cells and completely abrogated NSAID-unresponsive allodynia in vivo following IT KLA. Finally, spinal 12/15-Lipoxygenase inhibition by NDGA both prevents Phase II Formalin flinching and reverses Formalin-induced persistent tactile allodynia. Taken together, these findings suggest that spinal TLR4-mediated hyperpathic states are mediated at least in part through activation of microglial 15-LOX-1.
登录
查看更多内容
DOI：
10.1523/jneurosci.3295-09.2010
发表时间：
2010-01-13
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Clark AK;Staniland AA;Marchand F;Kaan TK;McMahon SB;Malcangio M
通讯作者：
Malcangio M
影响因子：
3.5
作者：
Ivanov I;Kuhn H;Heydeck D
通讯作者：
Heydeck D
影响因子：
7.6
作者：
Diogenes, A.;Ferraz, C. C. R.;Hargreaves, K. M.
通讯作者：
Hargreaves, K. M.
影响因子：
7.4
作者：
Christianson CA;Dumlao DS;Stokes JA;Dennis EA;Svensson CI;Corr M;Yaksh TL
通讯作者：
Yaksh TL
影响因子：
7.4
作者：
Christianson CA;Corr M;Firestein GS;Mobargha A;Yaksh TL;Svensson CI
通讯作者：
Svensson CI