■SCN11A基因编码Nav1的α亚基。9通道,是初级感觉神经元兴奋性的调节因子.Nav1.9通道在躯体疼痛中起关键作用。SCN11A中具有功能获得突变R222S的人类表现出家族性阵发性疼痛。众所周知,携带与人R222S变体直系同源的突变的R222S敲入小鼠表现出体细胞痛觉过敏。这项研究调查了Scn11aR222S/R222S小鼠是否发生内脏痛觉过敏和肠动力障碍。
■我们使用CRISPR/Cas9系统产生了ScnllaR222S/R222S小鼠。ScnllaR222S/R222S小鼠的躯体疼痛阈值通过Hargreaves试验和福尔马林试验进行评估。通过全细胞膜片钳记录评估背根神经节(DRG)神经元的兴奋性。使用腹部戒断反射(AWR)测试内脏痛,乙酸引起的扭动,和福尔马林诱导的内脏伤害性试验。通过肠段的机械记录和碳粉推进试验来检测肠运动性。肠神经系统(ENS)的兴奋性可能会影响肠神经递质。肠神经递质参与调节肠道运动和分泌功能。因此,在肠组织中测量血管活性肠肽(VIP)和P物质(SP)。
■R222S突变诱导Scn11aR222S/R222S小鼠背根神经节神经元过度兴奋。Scn11aR222S/R222S小鼠表现出躯体痛觉过敏。此外,与野生型对照相比,Scn11aR222S/R222S小鼠的内脏痛阈值较低,肠运动减慢。此外,Scn11aR222S/R222S小鼠在肠组织中具有较低的SP和VIP浓度。
■这些结果表明Scn11aR222S/R222S小鼠表现出内脏痛觉过敏和肠动力障碍。
UNASSIGNED: The SCN11A gene encodes the α-subunit of the Nav1. 9 channel, which is a regulator of primary sensory neuron excitability. Nav1.9 channels play a key role in somatalgia. Humans with the gain-of-function mutation R222S in SCN11A exhibit familial episodic pain. As already known, R222S knock-in mice carrying a mutation orthologous to the human R222S variant demonstrate somatic hyperalgesia. This study investigated whether Scn11a R222S/R222S mice developed visceral hyperalgesia and intestinal dysmotility.
UNASSIGNED: We generated Scn11a R222S/R222S mice using the CRISPR/Cas9 system. The somatic pain threshold in Scn11a R222S/R222S mice was assessed by Hargreaves\' test and formalin test. The excitability of dorsal root ganglia (DRG) neurons was assessed by whole-cell patch-clamp recording. Visceralgia was tested using the abdominal withdrawal reflex (AWR), acetic acid-induced writhing, and formalin-induced visceral nociception tests. Intestinal motility was detected by a mechanical recording of the intestinal segment and a carbon powder propelling test. The excitability of the enteric nervous system (ENS) could influence gut neurotransmitters. Gut neurotransmitters participate in regulating intestinal motility and secretory function. Therefore, vasoactive intestinal peptide (VIP) and substance P (SP) were measured in intestinal tissues.
UNASSIGNED: The R222S mutation induced hyperexcitability of dorsal root ganglion neurons in Scn11a R222S/R222S mice. Scn11a R222S/R222S mice exhibited somatic hyperalgesia. In addition, Scn11a R222S/R222S mice showed lower visceralgia thresholds and slowed intestinal movements when compared with wild-type controls. Moreover, Scn11a R222S/R222S mice had lower SP and VIP concentrations in intestinal tissues.
UNASSIGNED: These results indicated that Scn11a R222S/R222S mice showed visceral hyperalgesia and intestinal dysmotility.