Abstract

Objectives

Neuropathic pain, with lots of clinical conditions in various diseases, whose physiopathology is implicated in inflammation. MicroRNAs (miRNAs) have largely been shown to exert anti-inflammatory effects against chronic diseases. We then evaluated the effects and regulatory mechanism of miR-140 on neuropathic pain.

Methods

Rats model with neuropathic pain were established via chronic constriction injury (CCI) and verified by determination of mechanical withdrawal threshold (MWT) and paw withdrawal latency (PWL). The expression level of miR-140 was determined via qRT-PCR (quantitative real-time polymerase chain reaction). Intrathecal injection of miR-140 agomiR was conducted to evaluate the influence of miR-140 on CCI rats via evaluation of MWT, PWL and inflammatory factors secretion. The binding target of miR-140 was predicted and characterized via dual luciferase activity assay.

Results

Decreased MWT and PWL, as well as increased inflammatory factor secretion, including IL (interleukin)-1β, IL-6 and interferon-γ (IFN-γ), were found in rats under CCI compared with sham rats. MiR-140 was decreased in rats under CCI. Intrathecal injection of miR-140 agomiR increased MWT and PWL, thus attenuating mechanical and thermal hyperalgesia in CCI rats. Moreover, decreased inflammatory factor secretion in rats under CCI injected with miR-140 agomiR, suggesting a negatively regulatory role of miR-140 on neuroinflammation. MiR-140 could bind with Sphingosine-1-phosphate receptor 1 (S1PR1). S1PR1 agonist, SEW2871, could reverse the suppression of miR-140 on neuropathic pain.

Conclusions

MiR-140 could mollify CCI-stimulated neuropathic pain via targeting S1PR1, suggesting a potential therapeutic target in the treatment of neuropathic pain.

中文翻译：

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miR-140 通过靶向 S1PR1 改善 CCI 大鼠的神经性疼痛

摘要

目标

神经病理性疼痛，在各种疾病中有很多临床症状，其病理生理学与炎症有关。MicroRNAs (miRNAs) 已在很大程度上被证明对慢性疾病发挥抗炎作用。然后我们评估了 miR-140 对神经性疼痛的影响和调节机制。

方法

通过慢性收缩损伤（CCI）建立神经性疼痛大鼠模型，并通过测定机械缩回阈值（MWT）和缩爪潜伏期（PWL）进行验证。miR-140 的表达水平通过qRT-PCR（定量实时聚合酶链反应）确定。鞘内注射miR-140 agomiR，通过评估MWT、PWL和炎症因子分泌，评估miR-140对CCI大鼠的影响。通过双荧光素酶活性测定预测和表征 miR-140 的结合靶标。

结果

与假大鼠相比，在 CCI 下的大鼠中发现 MWT 和 PWL 降低，以及炎症因子分泌增加，包括 IL（白细胞介素）-1β、IL-6 和干扰素-γ（IFN-γ）。在 CCI 下，大鼠的 MiR-140 降低。鞘内注射 miR-140 agomiR 增加 MWT 和 PWL，从而减轻 CCI 大鼠的机械和热痛觉过敏。此外，在 CCI 下注射 miR-140 agomiR 的大鼠炎症因子分泌减少，表明 miR-140 对神经炎症的负调节作用。MiR-140 可以与 1-磷酸鞘氨醇受体 1 (S1PR1) 结合。S1PR1 激动剂 SEW2871 可以逆转 miR-140 对神经性疼痛的抑制。

结论

MiR-140 可以通过靶向 S1PR1 来缓解 CCI 刺激的神经性疼痛，这表明它是治疗神经性疼痛的潜在治疗靶点。