Qiao Wen-Long, Li Qing, Hao Jia-Wei, Wei Shuang, Li Xue-Mei, Liu Ting-Ting, Qiu Chun-Yu, Hu Wang-Ping
School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, Xianning, China.
School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, China.
Front Pharmacol. 2022 Jun 20;13:928647. doi: 10.3389/fphar.2022.928647. eCollection 2022.
Lysophosphatidic acid (LPA), a lipid metabolite, plays a role in both neuropathic and inflammatory pain through LPA receptors. P2X3 receptor has also been shown to participate in these pathological processes. However, it is still unclear whether there is a link between LPA signaling and P2X3 receptors in pain. Herein, we show that a functional interaction between them in rat dorsal root ganglia (DRG) neurons. Pretreatment of LPA concentration-dependently enhanced α,β-methylene-ATP (α,β-meATP)-induced inward currents mediated by P2X3 receptors. LPA significantly increased the maximal current response of α,β-meATP, showing an upward shift of the concentration-response curve for α,β-meATP. The LPA enhancement was independent on the clamping-voltage. Enhancement of P2X3 receptor-mediated currents by LPA was prevented by the LPA receptor antagonist Ki16198, but not by the LPA receptor antagonist H2L5185303. The LPA-induced potentiation was also attenuated by intracellular dialysis of either G-protein inhibitor or protein kinase C (PKC) inhibitor, but not by Rho inhibitor. Moreover, LPA significantly changed the membrane potential depolarization and action potential burst induced by α,β-meATP in DRG neurons. Finally, LPA exacerbated α,β-meATP- induced nociceptive behaviors in rats. These results suggested that LPA potentiated the functional activity of P2X3 receptors in rat primary sensory neurons through activation of the LPA receptor and its downstream PKC rather than Rho signaling pathway, indicating a novel peripheral mechanism underlying the sensitization of pain.
溶血磷脂酸（LPA）是一种脂质代谢产物，通过LPA受体在神经性疼痛和炎性疼痛中均发挥作用。P2X3受体也已被证明参与这些病理过程。然而，LPA信号传导与疼痛中的P2X3受体之间是否存在联系仍不清楚。在此，我们表明它们在大鼠背根神经节（DRG）神经元中存在功能相互作用。LPA预处理以浓度依赖的方式增强了由P2X3受体介导的α,β-亚甲基ATP（α,β-meATP）诱导的内向电流。LPA显著增加了α,β-meATP的最大电流反应，显示α,β-meATP浓度-反应曲线向上移位。LPA增强作用与钳制电压无关。LPA受体拮抗剂Ki16198可阻止LPA对P2X3受体介导电流的增强作用，但LPA受体拮抗剂H2L5185303则不能。LPA诱导的增强作用也因细胞内透析G蛋白抑制剂或蛋白激酶C（PKC）抑制剂而减弱，但不受Rho抑制剂影响。此外，LPA显著改变了DRG神经元中由α,β-meATP诱导的膜电位去极化和动作电位爆发。最后，LPA加剧了大鼠中α,β-meATP诱导的伤害性反应行为。这些结果表明，LPA通过激活LPA受体及其下游的PKC而非Rho信号通路增强了大鼠初级感觉神经元中P2X3受体的功能活性，表明疼痛敏化存在一种新的外周机制。
