Department of Physiology, Shihezi University Medical College, Shihezi, Xinjiang 832002, P.R. China.
Department of Pharmacology, Shihezi University Pharmaceutical College, Shihezi, Xinjiang 832002, P.R. China.
Int J Mol Med. 2020 Aug;46(2):782-794. doi: 10.3892/ijmm.2020.4611. Epub 2020 May 20.
Nav1.7 is closely associated with neuropathic pain. Hydrogen sulfide (H2S) has recently been reported to be involved in numerous biological functions, and it has been shown that H2S can enhance the sodium current density, and inhibiting the endogenous production of H2S mediated by cystathionine β‑synthetase (CBS) using O‑(carboxymethyl)hydroxylamine hemihydrochloride (AOAA) can significantly reduce the expression of Nav1.7 and thus the sodium current density in rat dorsal root ganglion (DRG) neurons. In the present study, it was shown that the fluorescence intensity of H2S was increased in a spared nerve injury (SNI) model and AOAA inhibited this increase. Nav1.7 is expressed in DRG neurons, and the expression of CBS and Nav1.7 were increased in DRG neurons 7, 14 and 21 days post‑operation. AOAA inhibited the increase in the expression of CBS, phosphorylated (p)‑MEK1/2, p‑ERK1/2 and Nav1.7 induced by SNI, and U0126 (a MEK blocker) was able to inhibit the increase in p‑MEK1/2, p‑ERK1/2 and Nav1.7 expression. However, PF‑04856264 did not inhibit the increase in CBS, p‑MEK1/2, p‑ERK1/2 or Nav1.7 expression induced by SNI surgery. The current density of Nav1.7 was significantly increased in the SNI model and administration of AOAA and U0126 both significantly decreased the density. In addition, AOAA, U0126 and PF‑04856264 inhibited the decrease in rheobase, and the increase in action potential induced by SNI in DRG neurons. There was no significant difference in thermal withdrawal latency among each group. However, the time the animals spent with their paw lifted increased significantly following SNI, and the time the animals spent with their paw lifted decreased significantly following the administration of AOAA, U0126 and PF‑04856264. In conclusion, these data show that Nav1.7 expression in DRG neurons is upregulated by CBS‑derived endogenous H2S in an SNI model, contributing to the maintenance of neuropathic pain.
Nav1.7 与神经性疼痛密切相关。硫化氢（H2S）最近被报道参与了许多生物学功能，并且已经表明 H2S 可以增强钠电流密度，而使用 O-（羧甲基）羟胺半盐酸盐（AOAA）抑制胱硫醚 β-合成酶（CBS）介导的内源性 H2S 的产生可以显著降低大鼠背根神经节（DRG）神经元中 Nav1.7 的表达和钠电流密度。在本研究中，研究表明在 spared nerve injury（SNI）模型中 H2S 的荧光强度增加，而 AOAA 抑制了这种增加。Nav1.7 表达于 DRG 神经元中，并且 CBS 和 Nav1.7 的表达在术后 7、14 和 21 天增加。AOAA 抑制了 SNI 诱导的 CBS、磷酸化（p）-MEK1/2、p-ERK1/2 和 Nav1.7 表达的增加，而 U0126（MEK 阻断剂）能够抑制 p-MEK1/2、p-ERK1/2 和 Nav1.7 表达的增加。然而，PF-04856264 不能抑制 SNI 手术后 CBS、p-MEK1/2、p-ERK1/2 或 Nav1.7 表达的增加。Nav1.7 电流密度在 SNI 模型中显著增加，而 AOAA 和 U0126 的给药均显著降低了密度。此外，AOAA、U0126 和 PF-04856264 抑制了 SNI 诱导的 DRG 神经元中基强度和动作电位的增加。各组之间的热退缩潜伏期没有显著差异。然而，动物的爪子抬起时间在 SNI 后显著增加，而 AOAA、U0126 和 PF-04856264 的给药后爪子抬起时间显著减少。总之，这些数据表明，CBS 衍生的内源性 H2S 上调了 DRG 神经元中 Nav1.7 的表达，有助于维持神经性疼痛。
