Microglial activation mediates de novo lysophosphatidic acid production in a model of neuropathic pain
Microglial activation mediates de novo lysophosphatidic acid production in a model of neuropathic pain
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DOI：
10.1111/j.1471-4159.2010.06955.x
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发表时间：
2010-11-01
影响因子：
4.7
通讯作者：
Ueda, Hiroshi
中科院分区：
文献类型：
--
作者：
Ma, Lin;Nagai, Jun;Ueda, Hiroshi
我们最近证实，脊髓中溶血磷脂酸(LPA)的产生发生在神经损伤或LPA注射后的早期阶段，是神经病理性疼痛的外周机制的基础。在这项研究中，我们研究了脊髓小胶质细胞可能参与LPA介导的这种功能。鞘内注射LPA后，小胶质细胞CD11b基因表达和磷酸化p38蛋白表达迅速增加，小胶质细胞形态由分枝状变为阿米巴状。尽管早期使用米诺环素显著抑制了LPA诱导的神经病理性疼痛行为和小胶质细胞的激活，但晚期治疗并没有。早期用米诺环素治疗也阻止了LPA诱导的从头LPA的产生和胞浆磷脂酶A(2)的增加，这是一种与LPA合成相关的酶。在坐骨神经部分损伤时也观察到了类似的结果：早期(但不是晚期)米诺环素治疗显著抑制了损伤诱导的神经病理性疼痛、小胶质细胞的激活、LPA的从头产生以及胞浆磷脂酶A(2)和另一种LPA合成相关酶-钙非依赖性磷脂酶A(2)的活性增加。这些发现表明，小胶质细胞激活的早期阶段参与了LPA的产生，这是神经损伤诱导神经病理性疼痛的最初机制。
P>We recently demonstrated that de novo lysophosphatidic acid (LPA) production in the spinal cord occurs in the early phase after nerve injury or LPA injection, and underlies the peripheral mechanisms of neuropathic pain. In this study, we examined the possible involvement of spinal cord microglia in such LPA-mediated functions. Intrathecal LPA injection rapidly increased the gene expression of CD11b and protein expression of phosphor-p38, accompanied by a morphological change of microglia from a ramified to amoeboid shape. Although early treatment with minocycline significantly inhibited LPA-induced neuropathic pain-like behavior and microglial activation, late treatment did not. Early treatment with minocycline also blocked LPA-evoked de novo LPA production and the increased activation of cytosolic phospholipase A(2), an LPA synthesis-related enzyme. Similar results were observed when the sciatic nerve was partially injured: early, but not late, treatment with minocycline significantly inhibited the injury-induced neuropathic pain, microglial activation, de novo LPA production and the underlying increased activation of cytosolic phospholipase A(2) as well as calcium-independent phospholipase A(2), another LPA synthesis-related enzyme. These findings suggest that the early phase of microglial activation is involved in de novo LPA production, and that this underlies the initial mechanisms of nerve injury-induced neuropathic pain.