酸敏离子通道 3 在神经生长因子调控的切口过度表达参与大鼠术后痛觉。

Acid-sensing Ion Channel 3 Overexpression in Incisions Regulated by Nerve Growth Factor Participates in Postoperative Nociception in Rats.

出版信息

Anesthesiology. 2020 Dec 1;133(6):1244-1259. doi: 10.1097/ALN.0000000000003576.

Abstract

BACKGROUND

Acid-sensing ion channel 3 (ASIC3) upregulation has been reported in dorsal root ganglion neurons after incision and contributes to postoperative nociception. This study hypothesized that upregulation of ASIC3 in incised tissues is induced by nerve growth factor through the phosphoinositide 3-kinase/protein kinase B signaling pathway.

METHODS

A plantar incision model was established in adult male and female Sprague-Dawley rats. ASIC3 was inhibited by APETx2 treatment, small interfering RNA treatment, or ASIC3 knockout. Sciatic nerve ligation was performed to analyze ASIC3 transport. A nerve growth factor antibody and a phosphoinositide 3-kinase inhibitor were used to investigate the mechanism by which nerve growth factor regulates ASIC3 expression.

RESULTS

Acid-sensing ion channel 3 inhibition decreased incisional guarding and mechanical nociception. ASIC3 protein levels were increased in skin and muscle 4 h after incision (mean ± SD: 5.4 ± 3.2-fold in skin, n = 6, P = 0.001; 4.3 ± 2.2-fold in muscle, n = 6, P = 0.001). Sciatic nerve ligation revealed bidirectional ASIC3 transport. Nerve growth factor antibody treatment inhibited the expression of ASIC3 (mean ± SD: antibody 2.3 ± 0.8-fold vs. vehicle 4.9 ± 2.4-fold, n = 6, P = 0.036) and phosphorylated protein kinase B (mean ± SD: antibody 0.8 ± 0.3-fold vs. vehicle 1.8 ± 0.8-fold, n = 6, P = 0.010) in incised tissues. Intraplantar injection of nerve growth factor increased the expression of ASIC3 and phosphorylated protein kinase B. ASIC3 expression and incisional pain-related behaviors were inhibited by pretreatment with the phosphoinositide 3-kinase inhibitor LY294002.

CONCLUSIONS

Acid-sensing ion channel 3 overexpression in incisions contributes to postoperative guarding and mechanical nociception. Bidirectional transport of ASIC3 between incised tissues and dorsal root ganglion neurons occurs through the sciatic nerve. Nerve growth factor regulates ASIC3 expression after plantar incision through the phosphoinositide 3-kinase/protein kinase B signaling pathway.

摘要

背景

酸感应离子通道 3（ASIC3）在切口后背根神经节神经元中的上调已被报道，并有助于术后疼痛。本研究假设切口组织中 ASIC3 的上调是由神经生长因子通过磷脂酰肌醇 3-激酶/蛋白激酶 B 信号通路诱导的。

方法

在成年雄性和雌性 Sprague-Dawley 大鼠中建立足底切口模型。通过 APETx2 处理、小干扰 RNA 处理或 ASIC3 敲除抑制 ASIC3。进行坐骨神经结扎以分析 ASIC3 转运。使用神经生长因子抗体和磷脂酰肌醇 3-激酶抑制剂来研究神经生长因子调节 ASIC3 表达的机制。

结果

酸感应离子通道 3 抑制可减少切口防御和机械性痛觉过敏。ASIC3 蛋白水平在切口后 4 小时在皮肤和肌肉中增加（皮肤平均 ± SD：5.4 ± 3.2 倍，n = 6，P = 0.001；肌肉平均 ± SD：4.3 ± 2.2 倍，n = 6，P = 0.001）。坐骨神经结扎显示 ASIC3 的双向转运。神经生长因子抗体处理抑制 ASIC3 的表达（平均 ± SD：抗体 2.3 ± 0.8 倍与载体 4.9 ± 2.4 倍，n = 6，P = 0.036）和磷酸化蛋白激酶 B（平均 ± SD：抗体 0.8 ± 0.3 倍与载体 1.8 ± 0.8 倍，n = 6，P = 0.010）在切口组织中。足底注射神经生长因子增加 ASIC3 和磷酸化蛋白激酶 B 的表达。预先使用磷脂酰肌醇 3-激酶抑制剂 LY294002 可抑制 ASIC3 表达和切口相关的疼痛行为。