Inflammation is present in neurological and peripheral disorders. Thus, targeting inflammation has emerged as a viable option for treating these disorders. Previous work indicated pretreatment with beta-funaltrexamine (β-FNA), a selective mu-opioid receptor (MOR) antagonist, inhibited inflammatory signaling in vitro in human astroglial cells, as well as lipopolysaccharide (LPS)-induced neuroinflammation and sickness-like-behavior in mice. This study explores the protective effects of β-FNA when treatment occurs 10 h after LPS administration and is the first-ever investigation of the sex-dependent effects of β-FNA on LPS-induced inflammation in the brain and peripheral tissues, including the intestines. Male and female C57BL/6J mice were administered LPS followed by treatment with β-FNA-immediately or 10 h post-LPS. Sickness- and anxiety-like behavior were assessed using an open-field test and an elevated-plus-maze test, followed by the collection of whole brain, hippocampus, prefrontal cortex, cerebellum/brain stem, plasma, spleen, liver, large intestine (colon), proximal small intestine, and distal small intestine. Levels of inflammatory chemokines/cytokines (interferon γ-induced-protein, IP-10 (CXCL10); monocyte-chemotactic-protein 1, MCP-1 (CCL2); interleukin-6, IL-6; interleukin-1β, IL-1β; and tumor necrosis factor-alpha, TNF-α) in tissues were measured using an enzyme-linked immunosorbent assay. Western blot analysis was used to assess nuclear factor-kappa B (NF-κB) expression. There were sex-dependent differences in LPS-induced inflammation across brain regions and peripheral tissues. Overall, LPS-induced CXCL10, CCL2, TNF-α, and NF-κB were most effectively downregulated by β-FNA; and β-FNA effects differed across brain regions, peripheral tissues, timing of the dose, and in some instances, in a sex-dependent manner. β-FNA reduced LPS-induced anxiety-like behavior most effectively in female mice. These findings provide novel insights into the sex-dependent anti-inflammatory effects of β-FNA and advance this agent as a potential therapeutic option for reducing both neuroinflammation an intestinal inflammation.

中文翻译：

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β-FNA 的抗炎作用在 LPS 诱导的炎症的临床前模型中具有性别依赖性

炎症存在于神经和外周疾病中。因此，靶向炎症已成为治疗这些疾病的可行选择。先前的研究表明，用一种选择性 mu-阿片受体 (MOR) 拮抗剂 β-呋纳曲胺 (β-FNA) 进行预处理可抑制体外人星形胶质细胞的炎症信号传导，以及脂多糖 (LPS) 诱导的神经炎症和疾病样-老鼠的行为。本研究探讨了 LPS 给药后 10 小时治疗时 β-FNA 的保护作用，并且是有史以来首次研究 β-FNA 对 LPS 诱导的大脑和周围组织炎症的性别依赖性影响，包括肠道. 对雄性和雌性 C57BL/6J 小鼠施用 LPS，然后立即或在 LPS 后 10 小时用 β-FNA 处理。使用开放场测试和高架加迷宫测试评估疾病和焦虑样行为，然后收集全脑、海马、前额叶皮层、小脑/脑干、血浆、脾脏、肝脏、大肠（结肠）、近端小肠和远端小肠。炎症趋化因子/细胞因子（干扰素 γ 诱导蛋白，IP-10 (CXCL10)；单核细胞趋化蛋白 1，MCP-1 (CCL2)；白细胞介素 6，IL-6；白细胞介素 1β，IL-1β ; 和肿瘤坏死因子-α，TNF-α）在组织中使用酶联免疫吸附测定法进行测量。Western blot 分析用于评估核因子-kappa B (NF-κB) 的表达。LPS 诱导的大脑区域和外周组织炎症存在性别依赖性差异。总体而言，LPS 诱导的 CXCL10、CCL2、TNF-α、和 NF-κB 最有效地被 β-FNA 下调；和 β-FNA 的影响在大脑区域、外周组织、剂量时间上存在差异，并且在某些情况下，以性别依赖的方式存在差异。β-FNA 在雌性小鼠中最有效地减少 LPS 诱导的焦虑样行为。这些发现为 β-FNA 的性别依赖性抗炎作用提供了新的见解，并推动该药物作为减少神经炎症和肠道炎症的潜在治疗选择。