Department of Pain Management, The Affiliated Hospital of Qingdao University, Shandong Province 266003, China.
Qingdao Mental Health Center, Qingdao University, Shandong Province 266034, China.
Neuroscience. 2022 Jul 1;494:12-24. doi: 10.1016/j.neuroscience.2022.04.019. Epub 2022 Apr 27.
The current study aimed to investigate the role and underlying mechanism of Resolvin D1 (RvD1) alleviating spinal nerve ligation (SNL)-induced neuropathic pain (NP) and its interplay with regulatory cascades of Nod-like Receptor Protein 3 (NLRP3) inflammasome. Sprague-Dawley male rat models of SNL-stimulated NP were established, which were pre-treated with different doses of RvD1, WRW4 (ALX/FPR2 inhibitor) or U0126 (ERK inhibitor) for three successive days following the operation. Pain behavior was assessed by measuring changes in the mechanical sensitivity of the hind paws during an observation period of seven consecutive days. The spinal cord (SC) and dorsal root ganglions (DRGs) tissues were collected on postoperative day 7. Immunohistochemistry (IHC) and Western blot were performed to determine the expression levels of NLRP3 inflammasome complex, ALX/FPR2 receptor and extracellular signal-related kinase (ERK). The pro-inflammatory mediators (IL-1β and IL-18) were measured by enzyme-linked immunosorbent assay (ELISA). The results showed that RvD1 could alleviate mechanical allodynia significantly in the SNL-induced NP rat models. Also, RvD1 inhibited the expression of p-ERK, the NLRP3 inflammasomes complex and its corresponding downstream pro-inflammatory mediators which were significantly enhanced in the SC and DRGs of the rat SNL models. While these changes were partially reversed by pre-administration of WRW4 and further strengthened by co-treated with U0126. Our results suggest that RvD1 dependent on ALX/FPR2 may have an analgesic and anti-inflammatory influence on SNL-induced NP driven by inhibiting NLRP3 inflammasome via ERK signaling pathway. These data also provide strong support for the recent modulation of neuro-inflammatory priming and highlight the potential for specialized pro-resolving mediators (SPMs) as novel therapeutic avenues for NP.
本研究旨在探讨内源性消退素 D1（RvD1）缓解脊神经结扎（SNL）诱导的神经性疼痛（NP）的作用及其与 Nod 样受体蛋白 3（NLRP3）炎性小体调节级联反应的相互作用。建立了 SNL 刺激的 NP 雄性 Sprague-Dawley 大鼠模型，术后连续 3 天用不同剂量的 RvD1、WRW4（ALX/FPR2 抑制剂）或 U0126（ERK 抑制剂）预处理。通过在连续 7 天的观察期内测量后爪机械敏感性的变化来评估疼痛行为。术后第 7 天收集脊髓（SC）和背根神经节（DRG）组织。通过免疫组织化学（IHC）和 Western blot 测定 NLRP3 炎性小体复合物、ALX/FPR2 受体和细胞外信号调节激酶（ERK）的表达水平。通过酶联免疫吸附试验（ELISA）测定促炎介质（IL-1β 和 IL-18）。结果表明，RvD1 可显著缓解 SNL 诱导的 NP 大鼠模型中的机械性痛觉过敏。此外，RvD1 抑制了 NLRP3 炎性小体复合物及其在 SC 和 DRG 中相应下游促炎介质的表达，这些在大鼠 SNL 模型中明显增强。而这些变化部分被 WRW4 预处理逆转，并进一步被 U0126 共同处理增强。我们的结果表明，RvD1 依赖于 ALX/FPR2 可能通过 ERK 信号通路抑制 NLRP3 炎性小体对 SNL 诱导的 NP 具有镇痛和抗炎作用。这些数据还为神经炎症引发的最新调节提供了有力支持，并突出了专门的促解决介质（SPMs）作为 NP 新型治疗途径的潜力。
