The efficacy of µ-opioid receptors (MOR) in neuropathic pain is low and with numerous side effects that limited their use. Chronic neuropathic pain is also linked with emotional disorders that aggravate the sensation of pain and which treatment has not been resolved. This study investigates whether the administration of an oxindole, 5-fluoro-2-oxindole, could inhibit the nociceptive and emotional behaviors and increase the effectiveness of morphine via modulating the microglia and activating the nuclear factor erythroid-2 related factor 2 (Nrf2) signaling pathway and MOR expression. In C57BL/6 mice with neuropathic pain provoked by the total constriction of sciatic nerve we studied the effects of 10 mg/kg 5-fluoro-2-oxindole in: (i) the allodynia and hyperalgesia caused by the injury; (ii) the anxiety- and depressive-like behaviors; (iii) the local antinociceptive actions of morphine; (iv) the expression of CD11b/c (a microglial marker), the antioxidant and detoxificant enzymes Nrf2, heme oxygenase 1 (HO-1) and NAD(P)H:quinone oxidoreductase-1 (NQO1), and of MOR in the spinal cord and hippocampus. Results showed that the inhibition of the main nociceptive symptoms and the anxiety- and depressive-like behaviors induced by 5-fluoro-2-oxindole were accompanied with the suppression of microglial activation and the activation of Nrf2/HO-1/NQO1 signaling pathway in the spinal cord and/or hippocampus. This treatment also potentiated the pain-relieving activities of morphine by normalizing the reduced MOR expression. This work demonstrates the antinociceptive, anxiolytic and antidepressant effects of 5-fluoro-2-oxindole, suggests a new strategy to enhance the antinociceptive actions of morphine and proposes a new mechanism of action of oxindoles during chronic neuropathic pain.

μ-阿片受体（MOR）在神经性疼痛中的疗效较低，并且有许多副作用限制了其使用。慢性神经性疼痛还与情绪障碍有关，情绪障碍会加剧疼痛感，而治疗方法尚未得到解决。本研究探讨使用羟吲哚（5-氟-2-羟吲哚）是否可以通过调节小胶质细胞和激活核因子红细胞 2 相关因子 2 (Nrf2) 信号来抑制伤害性和情绪行为并提高吗啡的有效性途径和 MOR 表达。在坐骨神经完全收缩引起神经性疼痛的 C57BL/6 小鼠中，我们研究了 10 mg/kg 5-氟-2-羟吲哚对以下方面的影响： (i) 损伤引起的异常性疼痛和痛觉过敏； (ii) 类似焦虑和抑郁的行为； (iii) 吗啡的局部镇痛作用； (iv) CD11b/c（小胶质细胞标志物）、抗氧化剂和解毒酶 Nrf2、血红素加氧酶 1 (HO-1) 和 NAD(P)H:醌氧化还原酶-1 (NQO1) 以及 MOR 的表达脊髓和海马体。结果显示，5-氟-2-羟吲哚对主要伤害性症状和焦虑、抑郁样行为的抑制伴随着小胶质细胞活化的抑制和Nrf2/HO-1/NQO1信号通路的激活。脊髓和/或海马体。这种治疗还通过使减少的 MOR 表达正常化来增强吗啡的镇痛活性。这项工作证明了 5-氟-2-oxindole 的抗伤害、抗焦虑和抗抑郁作用，提出了增强吗啡抗伤害作用的新策略，并提出了 oxindole 在慢性神经性疼痛期间的新作用机制。