Duloxetine (DLX) is a selective serotonin and noradrenaline reuptake inhibitor (SNRI) used for the treatment of pain, but it has been reported to show side effects in 10–20% of patients. Its analgesic efficacy in central pain is putatively related to its influence on descending inhibitory neuronal pathways. However, DLX can also affect the activation of microglia. This study was performed to investigate whether PLGA nanoparticles (NPs), which are expected to enhance targeting to microglia, can improve the analgesic efficacy and limit the side effects of DLX. PLGA NPs encapsulating a low dose of DLX (DLX NPs) were synthesized and characterized and their localization was determined. The analgesic and anti-inflammatory effects of DLX NPs were evaluated in a spinal nerve ligation (SNL)-induced neuropathic pain model. The analgesic effect of DLX lasted for only a few hours and disappeared within 1 day. However, DLX NPs alleviated mechanical allodynia, and the effect was maintained for 1 week. DLX NPs were localized to the spinal microglia and suppressed microglial activation, phosphorylation of p38/NF-κB-mediated pathways and the production of inflammatory cytokines in the spinal dorsal horn of SNL rats. We demonstrated that DLX NPs can provide a prolonged analgesic effect by enhanced targeting of microglia. Our observations imply that DLX delivery through nanoparticle encapsulation allows drug repositioning with a prolonged analgesic effect, and reduces the potential side effects of abuse and overdose.

中文翻译：

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PLGA纳米粒增强度洛西汀对神经病理性疼痛小胶质细胞作用的应用

度洛西汀 (DLX) 是一种选择性 5-羟色胺和去甲肾上腺素再摄取抑制剂 (SNRI)，用于治疗疼痛，但据报道它在 10-20% 的患者中出现副作用。其在中枢性疼痛中的镇痛功效可能与其对下行抑制性神经元通路的影响有关。然而，DLX 也会影响小胶质细胞的激活。进行这项研究是为了研究 PLGA 纳米粒子 (NPs) 是否可以提高对小胶质细胞的靶向性，是否可以提高镇痛效果并限制 DLX 的副作用。合成并表征了封装低剂量 DLX (DLX NPs) 的 PLGA NPs，并确定了它们的定位。在脊神经结扎 (SNL) 诱导的神经性疼痛模型中评估了 DLX NPs 的镇痛和抗炎作用。DLX的镇痛作用仅持续数小时，并在1天内消失。然而，DLX NPs 减轻了机械性异常性疼痛，并维持了 1 周。DLX NPs 定位于脊髓小胶质细胞并抑制 SNL 大鼠脊髓背角的小胶质细胞活化、p38/NF-κB 介导通路的磷酸化和炎性细胞因子的产生。我们证明了 DLX NPs 可以通过增强对小胶质细胞的靶向作用来提供延长的镇痛作用。我们的观察表明，通过纳米颗粒封装的 DLX 递送允许具有长期镇痛作用的药物重新定位，并减少滥用和过量用药的潜在副作用。DLX NPs 定位于脊髓小胶质细胞并抑制 SNL 大鼠脊髓背角的小胶质细胞活化、p38/NF-κB 介导通路的磷酸化和炎性细胞因子的产生。我们证明了 DLX NPs 可以通过增强对小胶质细胞的靶向作用来提供延长的镇痛作用。我们的观察表明，通过纳米颗粒封装的 DLX 递送允许具有长期镇痛作用的药物重新定位，并减少滥用和过量用药的潜在副作用。DLX NPs 定位于脊髓小胶质细胞并抑制 SNL 大鼠脊髓背角的小胶质细胞活化、p38/NF-κB 介导通路的磷酸化和炎性细胞因子的产生。我们证明了 DLX NPs 可以通过增强对小胶质细胞的靶向作用来提供延长的镇痛作用。我们的观察表明，通过纳米颗粒封装的 DLX 递送允许具有长期镇痛作用的药物重新定位，并减少滥用和过量用药的潜在副作用。