Remifentanil, as a novel opioid drug of the 21st century, offers significant advantages including rapid onset, an ultrashort half-life, and metabolism largely independent of hepatic enzymes (Feldman, 2020; Zhu et al., 2025). It not only ensures intraoperative analgesia in general anesthesia but also promotes rapid awakening after surgery, making it a preferred agent in anesthetic management (Yang et al., 2021; Rocha et al., 2017). However, while exerting potent analgesic effects, remifentanil can also induce remifentanil-induced hyperalgesia (RIH), which occurs at a significantly higher rate compared to other opioids (Santonocito et al., 2018; Servin and Billard, 2008)and exhibits dose dependency (Koo et al., 2017). RIH not only increases postoperative analgesic requirements but is also closely associated with an elevated risk of transition from acute to chronic postsurgical pain (Luo et al., 2024; Rosenberger and Pogatzki-Zahn, 2022), seriously affecting patient recovery and quality of life (Jin et al., 2022). Nevertheless, effective strategies to prevent RIH or impede its progression to chronic pain are still lacking, primarily due to the fact that the underlying mechanisms of RIH remain incompletely elucidated.

Central sensitization plays a critical role in RIH (Zhang et al., 2024a), primarily involving synaptic plasticity and abnormal activation of the N-methyl-d-aspartate receptor (NMDAR) subunit NR2B (Yang et al., 2024; Zhuo, 2024). Activation of spinal dorsal horn microglia is a central event in the initiation and maintenance of central sensitization, Once activated, microglia will release pro-inflammatory cytokines (such as IL-1β and TNF-α) or reactive oxygen species (ROS), which indirectly regulate the membrane localization and phosphorylation levels of neuronal NR2B. Excessive activation of NR2B is key to amplifying nociceptive signaling and promoting central sensitization (Shan et al., 2024; Dhir et al., 2024; Chacur et al., 2009). However, no specific mechanism fully inhibiting RIH has yet been identified (Zhu et al., 2025) suggesting the existence of additional, unelucidated regulatory pathways. In pain mechanism research, phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) is a key signaling event regulating microglial activation (Wen et al., 2011). Previous studies have confirmed that p38 MAPK is persistently activated in spinal dorsal horn microglia across multiple pain models, and inhibiting its activity effectively alleviates pain sensitization (Deng et al., 2024; Li et al., 2023; Dai et al., 2020; Svensson et al., 2003). Our research group has further demonstrated that p38 MAPK in the spinal dorsal horn plays an important role in the development of RIH (Deng et al., 2016), though its upstream and downstream mechanisms remain unclear.

In recent years, the central role of mitochondrial dysfunction and oxidative stress in pain modulation has attracted increasing attention (Chen et al., 2025; Zhang et al., 2022a). Their association with RIH has been preliminarily confirmed: studies have shown that continuous remifentanil infusion leads to ROS accumulation in the spinal cord, accompanied by enhanced NR2B phosphorylation, while ROS scavengers can reverse hyperalgesia, suggesting the involvement of a ROS-NR2B positive feedback loop in RIH (Zhu et al., 2025). Furthermore, existing studies have demonstrated that p38 MAPK is not only involved in inflammatory regulation but can also influence energy metabolism and oxidative stress balance by regulating transcriptional coactivators (Coulthard et al., 2009). Based on our group's earlier findings (Deng et al., 2016), we hypothesize that p38 MAPK may modulate ROS levels in RIH by regulating mitochondrial antioxidant pathways. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), as a key regulator of mitochondrial biogenesis and antioxidant defense (Zhang et al., 2024b; Abu Shelbayeh et al., 2023; Halling and Pilegaard, 2020), has been validated in various pain models (Li et al., 2025; Shan et al., 2023; Ge et al., 2022; Fan et al., 2020). Under inflammatory conditions, p38 MAPK can phosphorylate and inhibit the transcriptional activity of PGC-1α, leading to mitochondrial dysfunction and exacerbated oxidative stress; administration of a p38 MAPK antagonist can restore PGC-1α levels and mitigate related pathological changes (Palomer et al., 2009). Therefore, we propose that PGC-1α may act as a critical downstream target of p38 MAPK and participate in the pathological process of RIH.

SIRT3, a member of the Sirtuin family, is a deacetylase primarily localized to mitochondria and serves as a key downstream target of PGC-1α (Ye et al., 2020; Kong et al., 2010). PGC-1α transcriptionally activates SIRT3 expression, which plays an important role in suppressing ROS and promoting mitochondrial biogenesis (Ilari et al., 2020; Liu et al., 2017). In chronic pain models, SIRT3 deficiency leads to ROS accumulation and exacerbates central sensitization (Deng et al., 2025; Yan et al., 2022; Gao et al., 2007). However, it remains unclear whether remifentanil increases ROS levels via the p38 MAPK/PGC-1α/SIRT3 signaling axis, thereby regulating neuronal NR2B activity and driving the development of RIH.

Based on the above evidence, this study proposes the following scientific hypothesis: remifentanil activates p38 MAPK in spinal dorsal horn microglia, inhibits the PGC-1α/SIRT3 signaling pathway, leads to ROS accumulation in spinal dorsal horn neurons, and subsequently causes overactivation of NR2B receptors, ultimately contributing to RIH. This mechanism provides a novel theoretical basis for the clinical prevention and treatment of RIH.