Morphine, a typical opiate, is widely used for controlling pain but can lead to various side effects with long-term use, including addiction, analgesic tolerance, and hyperalgesia. At present, however, the mechanisms underlying the development of morphine analgesic tolerance are not fully understood. This tolerance is influenced by various opioid receptor and kinase protein modifications, such as phosphorylation and ubiquitination. Here, we established a murine morphine tolerance model to investigate whether and how -nitrosoglutathione reductase (GSNOR) is involved in morphine tolerance. Repeated administration of morphine resulted in the down-regulation of GSNOR, which increased excessive total protein -nitrosation in the prefrontal cortex. Knockout or chemical inhibition of GSNOR promoted the development of morphine analgesic tolerance and neuron-specific overexpression of GSNOR alleviated morphine analgesic tolerance. Mechanistically, GSNOR deficiency enhanced -nitrosation of cellular protein kinase alpha (PKCα) at the Cys78 and Cys132 sites, leading to inhibition of PKCα kinase activity, which ultimately promoted the development of morphine analgesic tolerance. Our study highlighted the significant role of GSNOR as a key regulator of PKCα -nitrosation and its involvement in morphine analgesic tolerance, thus providing a potential therapeutic target for morphine tolerance.

中文翻译：

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S-亚硝基谷胱甘肽还原酶通过限制 PKCα S-亚硝化减轻吗啡镇痛耐受


吗啡是一种典型的阿片类药物，广泛用于控制疼痛，但长期使用会导致各种副作用，包括成瘾、镇痛耐受和痛觉过敏。然而，目前吗啡镇痛耐受发生的机制尚不完全清楚。这种耐受性受到各种阿片受体和激酶蛋白修饰的影响，例如磷酸化和泛素化。在这里，我们建立了小鼠吗啡耐受模型来研究β-亚硝基谷胱甘肽还原酶（GSNOR）是否以及如何参与吗啡耐受。重复给予吗啡会导致 GSNOR 下调，从而增加前额皮质中过度的总蛋白亚硝化。 GSNOR 的敲除或化学抑制促进吗啡镇痛耐受的发展，GSNOR 的神经元特异性过度表达减轻吗啡镇痛耐受。从机制上讲，GSNOR缺陷增强了细胞蛋白激酶α（PKCα）在Cys78和Cys132位点的亚硝化，导致PKCα激酶活性受到抑制，最终促进吗啡镇痛耐受的发展。我们的研究强调了 GSNOR 作为 PKCα 亚硝化关键调节因子的重要作用及其参与吗啡镇痛耐受，从​​而为吗啡耐受提供了潜在的治疗靶点。