糖皮质激素受体激动剂对神经病理性疼痛大鼠痛敏感反应的干预作用及其机制*

doi:10.12047/j.cjap.6270.2022.088

摘要/Abstract

摘要： 目的: 探讨糖皮质激素受体激动剂调控核苷酸结合寡聚化结构域样受体蛋白3(NLRP3)/白细胞介素1β(IL-1β)通路对神经病理性疼痛(NPP)大鼠痛敏反应的影响机制。方法: 40只SD大鼠分为对照组、模型组、NLRP3抑制剂组、治疗组,每组10只,应用坐骨神经慢性压迫性损伤法诱导NPP大鼠模型,模型组按照上述方法造模,NLRP3抑制剂组按照上述方法造模后给予NLRP3抑制剂(MCC950)干预,治疗组按照上述方法造模后给予糖皮质激素受体激动剂(地塞米松)干预,对照组给予等量生理盐水。干预28 d之后,比较各组机械痛阈、热痛阈、脊髓背角形态学变化、疼痛因子[前列腺素E2(PGE2)、P物质(SP)、5-羟色胺(5-HT)]、炎症因子[白细胞介素8(IL-8)、肿瘤坏死因子α(TNF-α)、白细胞介素6(IL-6)]、NLRP3/IL-1β通路蛋白表达量变化。结果: 六胺银染色结果显示,模型组神经原纤维变粗并缠结,可见颗粒空泡变性,内含嗜银颗粒,提示神经元坏死,与模型组比较,NLRP3抑制剂组和治疗组大鼠的神经原纤维缠结变少,颗粒空泡变性变少。TUNNEL染色结果提示,模型组大鼠神经元凋亡率较对照组显著增多(P＜0.05),NLRP3抑制剂组和治疗组神经元凋亡率较模型组显著减少(P＜0.05)。与对照组比较,模型组造模3、7、14、28 d的机械痛阈及热痛阈值显著降低(P＜0.05)。模型组SP、PGE2、5-HT、IL-6、IL-8、TNF-α及NLRP3、IL-1β蛋白表达量较对照组显著升高(P＜0.05)。与模型组比较,NLRP3抑制剂组和地塞米松治疗组3、7、14、28 d的机械痛阈及热痛阈值显著升高(P＜0.05)。NLRP3抑制剂组和地塞米松治疗组SP、PGE2、5-HT、IL-6、IL-8、TNF-α及NLRP3、IL-1β蛋白表达量较模型组显著降低(P＜0.05)。NLRP3抑制剂组和治疗组在上述指标之间的差异不具有统计学意义(P＞0.05)。结论: 糖皮质激素受体激动剂可能通过下调NLRP3/IL-1β通路减轻神经病理性疼痛大鼠痛敏反应,这可能是临床上糖皮质激素治疗NPP的分子学机制。

关键词: 糖皮质激素受体激动剂, NLRP3/IL-1β通路, 神经病理性疼痛, 大鼠, 痛敏反应

Abstract: Objective: To investigate the effects of glucocorticoid receptor agonists on hyperalgesia in rats with neuropathic pain (NPP) by regulating nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)/interleukin-1β (IL-1β) pathway and its mechanisms. Methods: Forty SD rats were divided into control group, NPP model group, NPP treated with NLRP3 inhibitor group and dexamethasone treatment group with 10 rats in each group. The NPP rat model was induced by vincristine. The model group was established according to the above method, the NLRP3 inhibitor group was treated with NLRP3 inhibitor (MCC950) after the NPP model was established, and the treatment group was treated with glucocorticoid receptor agonist (dexamethasone) after the model was established according to the design. The rats of the control group were given the same amount of normal saline. After 7 days of intervention, the mechanical pain threshold, thermal pain threshold, morphological changes of spinal dorsal horn, pain factors (prostaglandin E2 (PGE2), substance P (SP), 5-hydroxytryptamine (5-HT)), inflammatory factors (interleukin-8 (IL-8), tumor necrosis factor α (TNF-α), interleukin-6 (IL-6)), and NLRP3/IL-1β protein expressions were determined and compared among the four groups. Results: Compared with the model group, the pathological changes of spinal dorsal horn neurons in NLRP3 inhibitor group and treatment group were alleviated significantly, the arrangement of neurons was tended to be close, the number of neurons was gradually returned to normal, and the pyknosis of neurons was decreased. Compared with the control group, the mechanical pain threshold and thermal pain threshold of the model group were decreased significantly (P＜0.05), and the expressions of inflammatory factors, pain factors and NLRP3, IL-1β protein were increased significantly (P＜0.05); compared with the model group, the mechanical pain threshold and thermal pain threshold of the NLRP3 inhibitor group and the dexamethasone treatment group were increased significantly (P＜0.05), and the expressions of inflammatory factors, pain factors and NLRP3, IL-1β protein were decreased significantly (P＜ 0.05). The difference between NLRP3 inhibitor group and treatment group was not statistically significant (P＞0.05). Conclusion: Glucocorticoid receptor agonists may reduce the hyperalgesia of neuropathic pain rat model by down regulating NLRP3/IL-1β pathway, which may be the mechanism of dexamethasone on antiinflammatory of analgesia in early stage of NPP.

Key words: glucocorticoid receptor agonists, NLRP3/IL-1β pathway, neuropathic pain, mice, hyperalgesia

中图分类号:

R741

苟小红, 贺学农, 蒋世双, 陶武, 何朝辉. 糖皮质激素受体激动剂对神经病理性疼痛大鼠痛敏感反应的干预作用及其机制^*[J]. 中国应用生理学杂志, 2022, 38(5): 470-474.

GOU Xiao-hong, HE Xue-nong, JIANG Shi-shuang, TAO Wu, HE Chao-hui. Effects of glucocorticoid receptor agonists on hyperalgesia of rats with neuropathic pain and its mechanisms[J]. CJAP, 2022, 38(5): 470-474.

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糖皮质激素受体激动剂对神经病理性疼痛大鼠痛敏感反应的干预作用及其机制^*

Effects of glucocorticoid receptor agonists on hyperalgesia of rats with neuropathic pain and its mechanisms

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