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 increases 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 peroxida...