Evidence for De Novo Synthesis of Lysophosphatidic Acid in the Spinal Cord through Phospholipase A2 and Autotaxin in Nerve Injury-Induced Neuropathic Pain
Evidence for De Novo Synthesis of Lysophosphatidic Acid in the Spinal Cord through Phospholipase A2 and Autotaxin in Nerve Injury-Induced Neuropathic Pain
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DOI：
10.1124/jpet.109.164830
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发表时间：
2010-05-01
影响因子：
3.5
通讯作者：
Ueda, Hiroshi
中科院分区：
文献类型：
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作者：
Ma, Lin;Uchida, Hitoshi;Ueda, Hiroshi
我们之前报道过，溶血磷脂酸（LPA）可引发神经损伤诱导的神经性疼痛及其潜在机制。此外，我们最近证实，鞘内注射LPA可通过自分泌运动因子（ATX）的作用诱导LPA的从头合成，ATX可将溶血磷脂酰胆碱转化为LPA。在此，我们通过使用对表达LPA(1)受体的B103细胞进行高灵敏度生物滴定测定法，研究了神经损伤诱导的LPA从头合成情况。神经损伤导致脊髓背角和背根同侧产生高水平的LPA，但在背根神经节、脊神经或坐骨神经中未出现这种情况。神经损伤诱导的LPA产生在损伤后3小时达到最大值，随后在6小时内迅速下降。在ATX杂合突变小鼠中，LPA的产生显著减弱，而脑脊液中ATX的浓度和活性不受神经损伤的影响。另一方面，胞质型磷脂酶A(2)（cPLA(2)）和钙离子非依赖性磷脂酶A(2)（iPLA(2)）的活性增强，在损伤后1小时达到峰值。在损伤后1小时鞘内注射cPLA(2)和iPLA(2)的混合抑制剂花生四烯酸三氟甲基酮或iPLA(2)抑制剂溴代烯醇内酯，可基本消除LPA的从头合成和类似神经性疼痛的行为。然而，在损伤后6小时给予这些抑制剂对神经性疼痛没有显著影响。这些研究结果表明，早期由磷脂酶A(2)（PLA(2)）和ATX介导的LPA从头合成与神经损伤诱导的神经性疼痛有关。
We previously reported that lysophosphatidic acid (LPA) initiates nerve injury-induced neuropathic pain and its underlying mechanisms. In addition, we recently demonstrated that intrathecal injection of LPA induces de novo LPA production through the action of autotaxin (ATX), which converts lysophosphatidylcholine to LPA. Here, we examined nerve injury-induced de novo LPA production by using a highly sensitive biological titration assay with B103 cells expressing LPA(1) receptors. Nerve injury caused high levels of LPA production in the ipsilateral sides of the spinal dorsal horn and dorsal roots, but not in the dorsal root ganglion, spinal nerve, or sciatic nerve. Nerve injury-induced LPA production reached its maximum at 3 h after injury, followed by a rapid decline by 6 h. The LPA production was significantly attenuated in ATX heterozygous mutant mice, whereas the concentration and activity of ATX in cerebrospinal fluid were not affected by nerve injury. On the other hand, the activities of cytosolic phospholipase A(2) (cPLA(2)) and calcium-independent phospholipase A(2) (iPLA(2)) were enhanced, with peaks at 1 h after injury. Both de novo LPA production and neuropathic pain-like behaviors were substantially abolished by intrathecal injection of arachidonyl trifluoromethyl ketone, a mixed inhibitor of cPLA(2) and iPLA(2), or bromoenol lactone, an iPLA(2) inhibitor, at 1 h after injury. However, administration of these inhibitors at 6 h after injury had no significant effect on neuropathic pain. These findings provide evidence that PLA(2)- and ATX-mediated de novo LPA production in the early phase is involved in nerve injury-induced neuropathic pain.