Nav1.7和Nav1.8选择性抑制剂对急性术后疼痛的镇痛效力

Analgesic effects of Nav1.7 and Nav1.8 selective inhibitors in acute post-operative pain

目的:评估钠通道Nav1.7及Nav1.8选择性抑制剂对急性炎性痛和术后疼痛的影响。方法:实验一:将健康小鼠(C57BL/6J)采用随机数字表法分为溶媒组(Vehicle)、Nav1.7抑制剂给药组(PF-05089771、GDC-0276、GX-201、Ds-1971a)和Nav1.8抑制剂给药组(VX-150、VX-548),行为学检测机械和热痛基础阈值以及福尔马林诱导的疼痛反应。实验二:构建足底切口损伤术后疼痛模型,将造模小鼠采用随机数字表法分为Vehicle组、Nav1.7抑制剂给药组(PF-05089771、GDC-0276)和Nav1.8抑制剂给药组(VX-150和VX-548),行为学检测切口损伤引起的机械和热痛过敏。另取造模小鼠的同侧L_3~L_5背根神经节(dorsal root ganglion,DRG)组织,通过RNA-Seq、q PCR、WB、IF等方法检测Nav1.7和Nav1.8在术后疼痛模型中的表达变化。结果:Nav1.7选择性抑制剂PF-05089771和Nav1.8选择性抑制剂VX-548对基础痛阈、福尔马林所致炎性痛及足底切口损伤所致的痛觉过敏有缓解作用;造模同侧DRG组织Nav1.7和Nav1.8表达水平不变,但Nav1.8阳性大直径DRG神经元比例增加。结论:Nav1.7和Nav1.8选择性抑制剂对急性术后疼痛具有显著镇痛效力,Nav1.8在NF200阳性中大神经元的分布增加可能参与切口损伤所致痛觉敏化的发生。

Objective:To assess the analgesic effects of sodium channel Nav1.7 and Nav1.8 selective inhibi-tors on acute inflammatory pain and post-operative pain.Methods:Experiment 1:Healthy mice(C57BL/6J)were randomly divided into vehicle group,Nav1.7 inhibitor groups(PF-05089771,GDC-0276,GX-201 and Ds-1971a),and Nav1.8 inhibitor groups(VX-150,VX-548).The effects of above selective inhibitors on basal mechanical and thermal thresholds,as well as formalin-induced inflammatory pain,were examined.Experiment 2:A plantar incision injury-induced post-operative pain model was established,and the modeled mice were randomly divided into vehicle group,Nav1.7 inhibitor groups(PF-05089771,GDC-0276)and Nav1.8 inhibitor groups(VX-150,VX-548),and the effects on mechanical and thermal allodynia were assessed.The ipsilateral L3-L5 dorsal root ganglion(DRG)were collected after plantar incision injury and changes in the expression of sodium channel isoforms(especially Nav1.7 and Nav1.8)were measured using RNA-Seq,qPCR,WB and IF.Results:Nav1.7 selective inhibitor PF-05089771 and Nav1.8 selective inhibitor VX-548 alleviated basal pain threshold,formalin-induced inflammatory pain and plantar incision-induced hyperalgesia.The Nav1.7 and Nav1.8 expression in ipsilateral DRG remained unchanged,but there was an increase in the proportion of Nav1.8-positive large-diameter DRG neurons.Conclusion:Selective inhibitors of Nav1.7 and Nav1.8 exhibit analgesic effects in acute post-operative pain and the increased distribution of Nav1.8 in NF200+neurons may contribute to incision-induced hyperalgesia.