Towards precision pain management-the case for targeting DRP1 in remifentanil-induced hyperalgesia.

short-acting opioid analgesic, remifentanil also causes opioid-induced hyperalgesia (OIH), as opioids paradoxically can increase sensitivity to painful stimuli [1]. The exact mechanisms behind remifentanil-induced hyperalgesia (RIH) are not entirely understood but have been attributed to various factors. Prevention and treatment for RIH are not easy and unpredictable. Tapering or discontinuation is not universally effective and may not be applicable in acute settings where remifentanil is often used [2]. And while adjuvant therapies such as N-methylD-aspartate (NMDA) receptor antagonists or alpha-2 agonists may have a role in managing OIH, more evidence is required [3,4]. In the last issue of the Korean Journal of Pain, the research of Zhou et al. [5] provided insight into a potential therapeutic strategy for RIH and reinforced the importance of the dynamin-related protein 1 (DRP1)mitochondria-reactive oxygen species (ROS) pathway in pain modulation. Upregulation of DRP1, a key protein involved in mitochondrial fission, can lead to excessive mitochondrial fission, which may contribute to mitochondrial dysfunction [6]. Dysfunctional mitochondria may produce excessive ROS, activating pain pathways [7]. DRP1-mediated mitochondrial fission has been shown to play a role in synaptic plasticity [8]. Given that neural plasticity is one of the essential factors in the development of chronic pain and possibly OIH [9], DRP1 upregulation could be a contributing factor. In this study, antisense oligodeoxynucleotides against DRP1 (AS-DRP1), administered intrathecally, relieved pain behavior due to RIH via downregulation of the DRP1-mitochondria-ROS pathway. By reducing DRP1 expression, hyperactivity of the spinal NR2B subunit of the NMDA receptor associated with neural hyperexcitability was reduced [10,11]. These findings emphasize the role of the DRP1-mitochondria-ROS-NMDA pathway in the development of RIH. Inhibiting DRP1 in the spinal cord with AS-DRP1 may offer an effective treatment or prevention of RIH. Interestingly, the authors used antisense oligodeoxynucleotide (ASO) drug delivery methods. ASOs are short, synthetic strands of DNA or RNA that specifically bind to a designated RNA target [12]. By binding to target mRNA, they can modulate post-transcriptional gene expression, preventing the mRNA from being translated into a pro-