Sigma-1受体/ p38 MAPK在完全弗氏佐剂诱发的炎症疼痛模型中通过穴位埋线调节疼痛中的作用
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Role of Sigma-1 Receptor/p38 MAPK Inhibition in Acupoint Catgut Embedding–Mediated Analgesic Effects in Complete Freund’s Adjuvant-Induced Inflammatory Pain
背景与目的
内质网伴侣蛋白Sigma-1受体（Sig-1R）和丝裂原活化蛋白激酶（MAPKs）参与疼痛的致病机制。穴位刺激在炎性疼痛中发挥抗痛觉过敏作用。然而，Sig-1 R和MAPKs是否与穴位刺激诱发的镇痛作用相关联尚不清楚。本研究探讨了穴位埋线（ACE）的镇痛作用以及抑制Sig-1 R和MAPKs在穴位埋线镇痛中的作用。
方 法
大鼠鞘内植入导管，穴位埋线应用于大鼠炎性疼痛模型（完全弗氏佐剂[CFA]椎间盘内注射）。双侧“昆仑”（BL60），“足三里”（ST36）和“三阴交”（SP6）穴位，鞘内每天给予Sig-1R激动剂PRE084或盐水。在完全弗氏佐剂注射前和完全弗氏佐剂注射后1,3和5天测量爪退缩阈值和爪水肿。并在完全弗氏佐剂注射后1,3和5天，采用Western bolt检测脊髓Sig-1R，p38MAPK和细胞外信号调节激酶（ERK）的蛋白表达水平以及采用免疫组织化学检测Sig-1。
结 果
穴位埋线表现出特异性的止痛作用。穴位埋线增加爪退缩阈值，并在1,3和5天显著降低完全弗氏佐剂诱发的爪水肿。穴位埋线降低Sig-1R的蛋白表达，其在注射完全弗氏佐剂后1,3和5天显著增加。穴位埋线在第1天和3天降低p38 MAPK和ERK的表达，第5天并不降低p38 MAPK和ERK的表达。然而，注射Sig-1R激动剂PRE084显著逆转了这些改变，除了不改变ERK表达。
结 论
本研究表明在完全弗氏佐剂诱发的炎性疼痛模型中，穴位埋线表现出抗痛觉过敏作用，其通过抑制Sig-1R降低p38 MAPK的表达，但不改变ERK的表达，发挥抗痛觉过敏的作用。
原始文献摘要
Du K,Wang X，Chi L,et al.Role of Sigma-1 Receptor/p38 MAPK Inhibition in Acupoint Catgut Embedding–Mediated Analgesic Effects in Complete Freund’s Adjuvant-Induced Inflammatory Pain.Anesth Analg.2017 Aug;125(2):662-669. doi: 10.1213/ANE.0000000000001857.
Abstract
BACKGROUND: The endoplasmic reticulum chaperone protein Sigma-1 receptor (Sig-1 R) and mitogen-activated protein kinases (MAPKs) are involved in the mechanism of pain.Acupoint stimulation exerts an exact antihyperalgesic effect in inflammatory pain.However,whether Sig-1R and MAPKs are associated with the acupoint stimulation-induced analgesic effects is not clear.This study investigated the analgesic effect of acupoint catgut embedding (ACE) and the inhibition of Sig-1 R and MAPKs in ACE analgesia.
METHODS: Rats were prepared with intrathecal catheter implantation.ACE was applied to bilateral“Kunlun”(BL60),“Zusanli”(ST36),and “Sanyinjiao”(SP6) acupoints in the rat model of inflammatory pain (complete Freund’s adjuvant [CFA] intraplantar injection).Then,Sig-1R
agonist PRE084 or saline was intrathecally given daily.The paw withdrawal thresholds and paw edema were measured before CFA injection and at 1,3, and 5 day after CFA injection.Western bolt was used to evaluate the protein expression of spinal Sig-1R,p38MAPK,and extracellular Signal-regulated kinase (ERK),and immunohistochemistry of Sig-1R was detected at 1, 3, and 5 days after CFA injection.
RESULTS: ACE exhibited specific analgesic effects.ACE increased paw withdrawal thresholds and markedly decreased CFA-induced paw edema at 1, 3,and 5 days.ACE downregulated the protein expression of Sig-1R,which was increased significantly at 1,3,and 5 days after CFA injection.ACE decreased the expression of p38 MAPK and ERK at 1 and 3 days but not at 5 days.However,an injection of Sig-1R agonist PRE084 markedly reversed these alterations,except ERK expression.
CONCLUSIONS: The present study demonstrated that ACE exhibited antihyperalgesic effects via the inhibition of the Sig-1R that modulated p38 MAPK,but not ERK, expression in the CFAinduced inflammatory pain model in rats.
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