Schematic illustration of proposed PN-DMT1(-)IRE-iron accumulation signaling in remifentanil-induced postoperative hyperalgesia. Activated glutamate-NMDA receptor (trafficking from the intracellular pool to surface pool) causes cellular calcium influx, via promoting the interaction between superoxide and nitric oxide, leading to PN formation. PN results in MnSOD nitration, forming excessive superoxide and triggering a feedforward mechanism to maintain elevated PN. PN activates DMT1(-)IRE and induces abnormal iron accumulation, leading to the development of hyperalgesia. Thus, PN decomposition with hydrogen-rich saline and iron chelation inhibit hyperalgesia. Possible mechanisms by which PN facilitates DMT1(-)IRE include NF-κB activation and elevated levels of proinflammatory cytokines IL-1β, IL-6, and TNF-α. Ca²⁺ = calcium ion; DMT1(+)IRE = divalent metal transporter 1 with iron-responsive element; DMT1(-)IRE = divalent metal transporter 1 without iron-responsive element; Fe²⁺ = ferrous ion; IL-1β = interleukin-1 beta; IL-6 = interleukin-6; MnSOD = manganese superoxide dismutase; NF-κB = nuclear factor kappa B; NMDA = N-methyl-d-aspartate; nNOS = neuronal nitric oxide synthase; NO = nitric oxide; O₂⁻ = superoxide; PN = peroxynitrite; SIH = salicylaldehyde isonicotinoyl hydrazone; TNF-α = tumor necrosis factor-alpha.