Department of Biochemistry, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Department of Anesthesiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
FASEB J. 2022 Apr;36(4):e22236. doi: 10.1096/fj.202101678R.
Lysophosphatidic acid (LPA) exerts various biological activities through six characterized G protein-coupled receptors (LPA ). While LPA-LPA signaling contributes toward the demyelination and retraction of C-fiber and induces neuropathic pain, the effects of LPA-LPA signaling on acute nociceptive pain is uncertain. This study investigated the role of LPA-LPA signaling in acute nociceptive pain using the formalin test. The pharmacological inhibition of the LPA-LPA axis significantly attenuated formalin-induced nociceptive behavior. The LPA mRNA was expressed in satellite glial cells (SGCs) in dorsal root ganglion (DRG) and was particularly abundant in SGCs surrounding large DRG neurons, which express neurofilament 200. Treatment with LPA receptor (LPA ) antagonist inhibited the upregulation of glial markers and inflammatory cytokines in DRG following formalin injection. The LPA antagonist also attenuated phosphorylation of extracellular signal-regulated kinase, especially in SGCs and cyclic AMP response element-binding protein in the dorsal horn following formalin injection. LPA amounts after formalin injection to the footpad were quantified by liquid chromatography/tandem mass spectrometry, and LPA levels were found to be increased in the innervated DRGs. Our results indicate that LPA produced in the innervated DRGs promotes the activation of SGCs through LPA , increases the sensitivity of primary neurons, and modulates pain behavior. These results facilitate our understanding of the pathology of acute nociceptive pain and demonstrate the possibility of the LPA on SGCs as a novel target for acute pain control.
溶血磷脂酸（LPA）通过六种特征性 G 蛋白偶联受体（LPA）发挥各种生物学活性。虽然 LPA-LPA 信号传导有助于脱髓鞘和 C 纤维的回缩，并诱导神经性疼痛，但 LPA-LPA 信号传导对急性痛觉过敏的影响尚不确定。本研究使用福马林测试研究了 LPA-LPA 信号在急性痛觉过敏中的作用。LPA-LPA 轴的药理学抑制显著减弱了福马林诱导的痛觉行为。LPA 在背根神经节（DRG）中的卫星神经胶质细胞（SGC）中表达，在表达神经丝 200 的大 DRG 神经元周围的 SGC 中尤为丰富。用 LPA 受体（LPA）拮抗剂处理可抑制福马林注射后 DRG 中神经胶质标志物和炎性细胞因子的上调。LPA 拮抗剂还减弱了福马林注射后 SGC 和背角中环磷酸腺苷反应元件结合蛋白中细胞外信号调节激酶的磷酸化，特别是。通过液相色谱/串联质谱法定量足底注射福马林后 LPA 的含量，发现受神经支配的 DRG 中的 LPA 水平增加。我们的结果表明，受神经支配的 DRG 中产生的 LPA 通过 LPA 促进 SGC 的激活，增加初级神经元的敏感性，并调节疼痛行为。这些结果有助于我们理解急性痛觉过敏的病理学，并表明 SGC 上的 LPA 作为急性疼痛控制的新靶点的可能性。
