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

摘要:

目的：评估钠通道Nav1.7及Nav1.8选择性抑制剂对急性炎性疼痛和术后疼痛的影响。方法：实验一：将健康雄性小鼠（C57BL/6J）随机分为溶媒组（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，将造模小鼠随机分为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L3-L5背根神经节（Dorsal root ganglion, DRG）组织，通过RNA-Seq、qPCR、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、GDC-0276和Nav1.8选择性抑制剂VX-548对基础痛阈、福尔马林诱导的炎性痛以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表达水平不变，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。

Abstract:

Objective: To assess the analgesic effects of sodium channel Nav1.7 and Nav1.8 selective inhibitors on acute inflammatory pain and post-operative pain. Methods: Experiment 1: Healthy male 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 and 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, and GDC-0276) and Nav1.8 inhibitor groups (VX-150 and VX-548), and the effects on mechanical and thermal allodynia were assessed. The ipsilateral L3-L5 dorsal root ganglions (DRGs) 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 inhibitors PF-05089771, GDC-0276 and Nav1.8 selective inhibitor VX-548 alleviated basal pain threshold, formalin-induced inflammatory pain and plantar incision-induced hyperalgesia. The Nav1.7 expression in ipsilateral DRGs 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.