Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan.
Department of Anesthesiology and Pain Relief Center, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
Sci Rep. 2021 Feb 17;11(1):3984. doi: 10.1038/s41598-021-83569-3.
Lumbar spinal canal stenosis (LSS) or mechanical compression of dorsal root ganglion (DRG) is one of the causes of low back pain and neuropathic pain (NP). Lysophosphatidic acid (LPA) is a potent bioactive lipid mediator that is produced mainly from lysophosphatidylcholine (LPC) via autotaxin (ATX) and is known to induce NP via LPA receptor signaling in mice. Recently, we demonstrated that LPC and LPA were higher in cerebrospinal fluid (CSF) of patients with LSS. Based on the possible potential efficacy of the ATX inhibitor for NP treatment, we used an NP model with compression of DRG (CD model) and investigated LPA dynamics and whether ATX inhibition could ameliorate NP symptoms, using an orally available ATX inhibitor (ONO-8430506) at a dose of 30 mg/kg. In CD model, we observed increased LPC and LPA levels in CSF, and decreased threshold of the pain which were ameliorated by oral administration of the ATX inhibitor with decreased microglia and astrocyte populations at the site of the spinal dorsal horn projecting from injured DRG. These results suggested possible efficacy of ATX inhibitor for the treatment of NP caused by spinal nerve root compression and involvement of the ATX-LPA axis in the mechanism of NP induction.
腰椎管狭窄症（LSS）或背根神经节（DRG）的机械压迫是腰痛和神经性疼痛（NP）的原因之一。溶血磷脂酸（LPA）是一种有效的生物活性脂质介质，主要由自分泌酶（ATX）从溶血磷脂酰胆碱（LPC）产生，并通过在小鼠中的 LPA 受体信号诱导 NP。最近，我们证明了 LPC 和 LPA 在 LSS 患者的脑脊液（CSF）中含量更高。基于 ATX 抑制剂治疗 NP 的潜在疗效，我们使用 DRG 受压的 NP 模型（CD 模型），并使用一种口服可用的 ATX 抑制剂（ONO-8430506）在 30mg/kg 的剂量下，研究了 LPA 动力学以及 ATX 抑制是否可以改善 NP 症状。在 CD 模型中，我们观察到 CSF 中 LPC 和 LPA 水平升高，疼痛阈值降低，而口服 ATX 抑制剂可改善这些症状，同时损伤的 DRG 投射至脊髓背角的部位的小胶质细胞和星形胶质细胞数量减少。这些结果表明 ATX 抑制剂可能对由脊神经根压迫引起的 NP 治疗有效，并且 ATX-LPA 轴参与 NP 诱导的机制。
