Department of Anaesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College , Huazhong University of Science and Technology , Wuhan , 430030 Hubei Province , China.
Department of Ophthalmology, Tongji Hospital, Tongji Medical College , Huazhong University of Science and Technology , Wuhan , 430030 Hubei Province , China.
ACS Chem Neurosci. 2019 Dec 18;10(12):4824-4833. doi: 10.1021/acschemneuro.9b00539. Epub 2019 Nov 14.
Morphine tolerance is a classic, challenging clinical issue. However, the mechanism underlying this phenomenon remains poorly understood. Recently, studies have shown that ferroptosis correlates with drug resistance. Therefore, this study investigated whether spinal cord ferroptosis contributes to morphine tolerance. C57BL/6 mice were continuously subcutaneously injected with morphine, with or without the ferroptosis inhibitor liproxstatin-1. We found that chronic morphine exposure led to morphine antinociception tolerance, accompanied by loss of spinal cord neurons, increase in the levels of iron, malondialdehyde, and reactive oxygen species, and decreases in the levels of superoxide dismutase. Additionally, inflammatory response and mitochondrial shrinkage, processes that are involved in ferroptosis, were observed. Simultaneously, we found that 10 mg/kg of liproxstatin-1 could alleviate iron overload by balancing transferrin receptor protein 1/ferroportin expression and attenuate morphine tolerance by increasing glutathione peroxidase 4 levels, while reducing the levels of malondialdehyde and reactive oxygen species. It also downregulated the expression of extracellularly regulated protein kinases that had been induced by chronic morphine exposure. Our results indicate that spinal cord ferroptosis contributes to morphine tolerance, while liproxstatin-1 attenuates the development of morphine tolerance. These findings suggest that ferroptosis may be a potential therapeutic target for morphine tolerance.
吗啡耐受是一个经典的、具有挑战性的临床问题。然而，这种现象的机制仍知之甚少。最近的研究表明，铁死亡与耐药性相关。因此，本研究探讨了脊髓铁死亡是否导致吗啡耐受。C57BL/6 小鼠连续皮下注射吗啡，或同时给予铁死亡抑制剂 liproxstatin-1。我们发现，慢性吗啡暴露导致吗啡镇痛耐受，同时伴有脊髓神经元丢失、铁、丙二醛和活性氧水平升高，以及超氧化物歧化酶水平降低。此外，还观察到炎症反应和线粒体收缩，这些过程与铁死亡有关。同时，我们发现 10mg/kg 的 liproxstatin-1 可以通过平衡转铁蛋白受体蛋白 1/铁蛋白表达来缓解铁过载，并通过增加谷胱甘肽过氧化物酶 4 水平来减轻吗啡耐受，同时降低丙二醛和活性氧水平。它还下调了慢性吗啡暴露诱导的细胞外调节蛋白激酶的表达。我们的结果表明，脊髓铁死亡导致吗啡耐受，而 liproxstatin-1 减轻了吗啡耐受的发展。这些发现表明，铁死亡可能是治疗吗啡耐受的潜在靶点。
