Ferroptosis Inhibitor Ferrostatin-1 Attenuates Morphine Tolerance Development in Rats by Inhibiting Dorsal Root Ganglion Neuronal Ferroptosis

Abstract OBJECTIVES: This investigation aimed to assess the impact of ferrostatin-1 on the progression of morphine tolerance and elucidate the underlying mechanisms involved. METHODS: The rats in this experiment were categorized into six groups: Control, pantoprazole, morphine, pantoprazole + morphine, morphine tolerance, and pantoprazole + morphine tolerance. The antinociceptive action was evaluated using both the hot plate and tail-flick tests. Subsequent to the completion of the analgesic tests, tissue samples were gathered from the dorsal root ganglia (DRG) for subsequent analysis. The levels of glutathione, glutathione peroxidase 4 (GPX4), and nuclear factor erythroid 2-related factor 2 (Nrf2), along with the measurements of total oxidant status (TOS) and total antioxidant status (TAS), were assessed in the tissues of the dorsal root ganglion (DRG). RESULTS: Following tolerance development, the administration of ferrostatin resulted in a notable decrease in morphine tolerance. Additionally, ferrostatin treatment resulted in elevated levels of glutathione, GPX4, Nrf2, and TOS, while concurrently causing a decrease in TAS levels. CONCLUSION: The outcomes of our study establish that ferrostatin-1 has the capability to mitigate the progression of morphine tolerance by suppressing ferroptosis and decreasing oxidative stress in neurons of the dorsal root ganglia (DRG). These results suggest that Ferrostatin-1 holds promise as a potential therapeutic intervention to prevent or attenuate the formation of morphine tolerance.