吗啡,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,包括上瘾,镇痛耐受性,和痛觉过敏。目前,然而,吗啡镇痛耐受发展的潜在机制尚不完全清楚.这种耐受性受各种阿片受体和激酶蛋白修饰的影响,如磷酸化和泛素化。这里,我们建立了小鼠吗啡耐受模型,以研究S-亚硝基谷胱甘肽还原酶(GSNOR)是否以及如何参与吗啡耐受.反复服用吗啡导致GSNOR下调,这增加了前额叶皮质中过多的总蛋白S-亚硝化。GSNOR的敲除或化学抑制促进了吗啡镇痛耐受的发展,GSNOR的神经元特异性过表达减轻了吗啡镇痛耐受。机械上,GSNOR缺陷增强了细胞蛋白激酶α(PKCα)在Cys78和Cys132位点的S-亚硝化,导致PKCα激酶活性的抑制,最终促进了吗啡镇痛耐受性的发展。我们的研究强调了GSNOR作为PKCαS-亚硝化的关键调节因子的重要作用及其在吗啡镇痛耐受中的参与,从而为吗啡耐受提供了一个潜在的治疗靶点.
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 S-nitrosoglutathione reductase (GSNOR) is involved in morphine tolerance. Repeated administration of morphine resulted in the down-regulation of
GSNOR, which increased excessive total protein S-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 S-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 S-nitrosation and its involvement in morphine analgesic tolerance, thus providing a potential therapeutic target for morphine tolerance.