• Ruichen Shu, Linlin Zhang, Hao Zhang, Yuan Li, Chunyan Wang, Lin Su, Hongwei Zhao, and Guolin Wang.
• Department of Anesthesiology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
• J Pain. 2021 Jan 1; 22 (1): 32-47.

AbstractN-methyl-D-aspartate (NMDA) receptor activation is known to be critical in remifentanil-induced hyperalgesia. Evidence indicates that iron accumulation participates in NMDA neurotoxicity. This study aims to investigate the role of iron accumulation in remifentanil-induced hyperalgesia. Remifentanil was delivered intravenously in rats to induce hyperalgesia. The NMDA receptor antagonist MK-801 was intrathecally administrated. The levels of divalent metal transporter 1 without iron-responsive element [DMT1(-)IRE] and iron were detected. Behavior testing was performed in DMT1(-)IRE knockdown rats and rats treated with iron chelator DFO. Meanwhile, the spinal dorsal horn neurons were cultured and transfected with DMT1(-)IRE siRNA, and then respectively incubated with remifentanil and MK-801. The levels of intracellular Ca2+ and iron were assessed by fluorescence imaging. Our data revealed that spinal DMT1(-)IRE and iron content significantly increased in remifentanil-treated rats, and MK-801 inhibited the enhancements. DMT1(-)IRE knockdown and DFO prevented against remifentanil-induced hyperalgesia. Notably, the levels of Ca2+ and iron increased in remifentanil-incubated neurons, and these growths can be blocked by MK-801. DMT1(-)IRE knockdown attenuated iron accumulation but did not influence Ca2+ influx. This study suggests that DMT1(-)IRE-mediated iron accumulation is likely to be the downstream event following NMDA receptor activation and Ca2+ influx, contributing to remifentanil-induced hyperalgesia. PERSPECTIVE: Remifentanil-induced hyperalgesia is common even when used within clinical accepted doses. This study presents that aberrant iron accumulation is involved in the development of remifentanil-induced hyperalgesia in vivo and in vitro. Iron chelation may be a potential therapeutic strategy for the prevention of hyperalgesia in populations at high risk.Copyright © 2020 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.

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