Liproxstatin-1 Attenuates Morphine Tolerance through Inhibiting Spinal Ferroptosis-like Cell Death.

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.