Background Inflammatory molecular signals are modulated by a variety of intracellular transduction pathways, the activation of which may induce and amplify the spread of inflammatory response. Suppresser of cytokine signaling 3 (SOCS3) is an established negative feedback regulation transcription factor associated with tumor, diabetes mellitus, inflammation and anaphylaxis. Herein, we investigated whether SOCS3 in the paraventricular nucleus (PVN) can attenuate pro-inflammatory responses, and thereby relieve the inflammatory pain. Methods Adeno-associated virus (AAV) overexpressing SOCS3 was pre-injected into the PVN. Three weeks later, rat model of chronic inflammatory pain was established via subcutaneous injection of complete Freund's adjuvant (CFA) into the plantar center of hind paws. The therapeutic effect of SOCS3 was tested by the measurement of thermal and mechanical allodynia. In mechanistic study, the protein level of SOCS3 was evaluated by Western blotting, and the expression of c-fos and Iba-1 were assessed by immunofluorescent staining. Results Inflammatory pain was associated with upregulated interleukin 6 (IL-6) and SOCS3 in PVN in the acute phase. Thermal hyperalgesia can be relieved by intra-PVN injection of IL-6 neutralizing antibody (NA). Meanwhile, the upregulated c-fos and microglial activation was reversed. Furthermore, SOCS3 expression in PVN was downregulated in the chronic phase. Intra-PVN injection of AAV overexpressing SOCS3 suppressed the activation of neurons and attenuated thermal hyperalgesia and mechanical allodynia. Conclusion Inhibition of IL-6 signaling attenuated inflammatory hyperalgesia in the acute phase. SOCS3 overexpression in the PVN attenuated inflammatory pain in the chronic phase via suppression of neuronal activation.

中文翻译：

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SOCS3在炎性疼痛大鼠模型下丘脑室旁核中的作用。

背景炎症分子信号受多种细胞内转导途径的调节，其激活可诱导和放大炎症反应的扩散。细胞因子信号抑制因子 3 (SOCS3) 是一种已建立的负反馈调节转录因子，与肿瘤、糖尿病、炎症和过敏反应相关。在此，我们研究了室旁核 (PVN) 中的 SOCS3 是否可以减弱促炎反应，从而缓解炎症性疼痛。方法 将过表达 SOCS3 的腺相关病毒 (AAV) 预注射到 PVN 中。三周后，通过将完全弗氏佐剂（CFA）皮下注射到后爪足底中心建立大鼠慢性炎性疼痛模型。通过测量热和机械异常性疼痛来测试 SOCS3 的治疗效果。在机理研究中，通过Western blotting评估SOCS3的蛋白水平，通过免疫荧光染色评估c-fos和Iba-1的表达。结果炎症性疼痛与PVN急性期白细胞介素6（IL-6）和SOCS3上调有关。PVN 内注射 IL-6 中和抗体 (NA) 可缓解热痛觉过敏。同时，上调的 c-fos 和小胶质细胞激活被逆转。此外，PVN 中 SOCS3 的表达在慢性期下调。PVN 内注射过表达 SOCS3 的 AAV 可抑制神经元的激活并减轻热痛觉过敏和机械异常性疼痛。结论抑制IL-6信号可减轻急性期炎症性痛觉过敏。PVN 中的 SOCS3 过表达通过抑制神经元激活减轻了慢性期的炎症性疼痛。