Involvement of lysophosphatidic acid–induced astrocyte activation underlying the maintenance of partial sciatic nerve injury–induced neuropathic pain
Involvement of lysophosphatidic acid–induced astrocyte activation underlying the maintenance of partial sciatic nerve injury–induced neuropathic pain
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DOI：
10.1097/j.pain.0000000000001316
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发表时间：
2018-06
期刊：
影响因子：
7.4
通讯作者：
H. Ueda;Hiroyuki Neyama;J. Nagai;Y. Matsushita;T. Tsukahara;R. Tsukahara
中科院分区：
文献类型：
--
作者：
H. Ueda;Hiroyuki Neyama;J. Nagai;Y. Matsushita;T. Tsukahara;R. Tsukahara
摘要我们以前已经证明，溶血磷脂酸（LPA）在神经性疼痛（NeuP）发展的初始机制中起着关键作用。在这里，我们研究了LPA受体机制和LPA的生产是否与部分坐骨神经结扎（pSNL）后的晚期阶段的胶质细胞活化有关，通过使用小胶质细胞抑制剂，Mac 1-皂草素或星形胶质细胞抑制剂，和L--氨基己二酸（L-AA）。虽然单次鞘内注射LPA 1/3拮抗剂Ki-16425在脊髓损伤后第7天不影响痛阈，但重复各化合物的治疗逐渐将基础痛阈逆转至对照水平。鞘内注射小胶质细胞抑制剂Mac-1-saporin可在pSNL后14天逆转迟发性痛觉过敏和LPA的产生，而L-AA可抑制痛觉过敏，但对LPA的产生无影响。Ki-16425处理在pSNL后第14天消除了小鼠脊髓背角中活化星形胶质细胞中CXCL 1的上调，并且Ki-16425逆转了LPA诱导的原代培养星形胶质细胞中几种趋化因子基因表达的上调，这一发现证明了LPA受体参与体内星形胶质细胞活化。最后，我们发现，观察到显着的痛觉过敏与鞘内给药的原代培养的星形胶质细胞，这已被刺激的LPA在Ki-16425可逆的方式。所有这些结果表明，LPA的生产和LPA 1/3受体的激活，通过不同的胶质细胞机制中发挥关键作用的维持，以及在NeuP的启动机制。
Abstract We have previously demonstrated that lysophosphatidic acid (LPA) plays key roles in the initial mechanisms for neuropathic pain (NeuP) development. Here, we examined whether LPA receptor mechanisms and LPA production are related to the glial activation at a late stage after partial sciatic nerve ligation (pSNL) by use of microglial inhibitor, Mac1-saporin or astrocyte inhibitor, and L--aminoadipate (L-AA). Although single intrathecal injection of LPA1/3 antagonist, Ki-16425 did not affect the pain threshold at day 7 after the spinal cord injury, repeated treatments of each compound gradually reversed the basal pain threshold to the control level. The intrathecal administration of a microglia inhibitor, Mac-1-saporin reversed the late hyperalgesia and LPA production at day 14 after the pSNL, whereas L-AA inhibited the hyperalgesia, but had no effect on LPA production. The involvement of LPA receptors in astrocyte activation in vivo was evidenced by the findings that Ki-16425 treatments abolished the upregulation of CXCL1 in activated astrocytes in the spinal dorsal horn of mice at day 14 after the pSNL, and that Ki-16425 reversed the LPA-induced upregulation of several chemokine gene expressions in primary cultured astrocytes. Finally, we found that significant hyperalgesia was observed with intrathecal administration of primary cultured astrocytes, which had been stimulated by LPA in a Ki-16425–reversible manner. All these findings suggest that LPA production and LPA1/3 receptor activation through differential glial mechanisms play key roles in the maintenance as well as initiation mechanisms in NeuP.