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

Abstract

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.

RETRACTED: Resibufogenin inhibited colorectal cancer cell growth and tumorigenesis through triggering ferroptosis and ROS production mediated by GPX4 inactivation

“…Ferroptosis is an iron‐dependent oxidative cell death (Tang et al, 2019), and is characterized by iron‐dependent reactive oxygen species (ROS) accumulation and inactivation of cellular antioxidant glutathione (GSH) (Sui et al, 2018). This type of cell death (ferroptosis) is genetically, biochemically and morphologically distinct from apoptosis (Chen et al, 2019; Tang et al, 2019). Recent studies have investigated the involvement of pyroptotic cell death in cancer development (Belavgeni et al, 2019; Carbone & Melino, 2019), and found that RSL3‐induced cell ferroptosis was relevant to CRC progression (Sui et al, 2018).…”

Selenium: Tracing Another Essential Element of Ferroptotic Cell Death

“…The bona fide ferroptosis inhibitors ferrostatin-1 (Dixon et al, 2012) and liproxstatin-1 (Friedmann Angeli et al, 2014) exert their function as efficient radical trapping antioxidants (RTA), thereby preventing cellular autoxidation (Zilka et al, 2017). The protective effects of these compounds in mouse disease models include ischemia/reperfusion injuries of the kidney, liver, brain, heart, and intestine (Fang et al, 2019;Friedmann Angeli et al, 2014;Li et al, 2019aLi et al, , 2019bLinkermann et al, 2014;Tuo et al, 2017), acute renal failure (Friedmann Angeli et al, 2014), intracerebral hemorrhage (Li et al, 2017), neurodegeneration (Hambright et al, 2017), hemochromatosis (Wang et al, 2017), non-alcoholic steatohepatitis (Qi et al, 2020), and morphine tolerance (Chen et al, 2019), underlining the pathological role of lipid peroxidation and associated ferroptosis in numerous disease contexts. Vitamin E is perhaps the most efficient natural RTA found in organisms (Zilka et al, 2017).…”

Inhibition of ferroptosis‐like cell death attenuates neuropathic pain reactions induced by peripheral nerve injury in rats

“…More importantly, iron levels are regulated by several elements, such as by TFR and FPN1 (Qiu et al., 2020). TFR can recognize iron binding with transferrin and import iron from transferrin into the cells by endocytosis, while FPN1 is the only known iron exporter that can transport iron from the inside to the outside of a cell (Chen et al., 2019; Xu et al., 2019). It was proposed that the imbalance in the levels of TFR and FPN1 may lead to iron accumulation (Qiu et al., 2020).…”

“…Emerging evidence has highlighted the contribution of iron accumulation‐induced ferroptosis in mechanisms underlying diseases of the nervous system (Lewerenz et al., 2018). For example, in the spinal cord, iron accumulation may be correlated with remifentanil‐induced postoperative hyperalgesia and morphine tolerance, and therapies based on the inhibition of iron accumulation and ferroptosis have been demonstrated to be clinically useful in intervening with these neurological symptoms (Chen et al., 2019; Shu et al., 2015).…”