Oxidative stress contributes to persistent pain and central sensitization in a repeated PGE2-induced hyperalgesic priming model

Chronic pain is a global health concern that impairs physical and psychological well-being. Recently, nociplastic pain, characterized by the absence of overt inflammation or nerve injury, has gained attention as a distinct chronic pain condition. Central sensitization is considered a primary mechanism underlying nociplastic pain and the persistence of chronic pain states.

Emerging evidence suggests that oxidative stress contributes to central sensitization, through increased neuronal excitability and glial activation; however, its role in nociplastic pain remains unclear. In this study, we investigated the involvement of oxidative stress in a prostaglandin E2 (PGE2)-induced hyperalgesic priming mouse model with features resembling nociplastic pain. Additionally, we examined the effects of modulating oxidative stress on pain progression using a silicon (Si)-based antioxidant agent.

Repeated PGE2 administration induced mechanical allodynia and increased circulating reactive oxygen metabolites (d-ROMs), effects that were attenuated in mice treated with the Si-based agent. In the spinal dorsal horn, neuronal activity and astrocyte activation increased in the chronic pain model but not in mice treated with the Si-based agent. These findings support an association between systemic oxidative stress and spinal sensitization in this repeated PGE2-induced hyperalgesic priming model and provide insight into mechanisms underlying persistent pain that may share features with nociplastic pain.

This research was supported by the Center of Innovation Program (COI Program, Grant Number JPMJCE1310) and JST SPRING (Grant Number JPMJSP2138, JST Japan). We would like to thank Editage (www.editage.com) for English language editing and the Center for Medical Research and Education, Graduate School for Medicine, Osaka University, for technical support. This work was supported by Center of Innovation Program (COI Program) Grant Number JPMJCE1310 and JST SPRING Grant Number JPMJSP2138, JST Japan.

Department of Anesthesiology and Intensive Care Medicine, Graduate School of Medicine, The University of Osaka, Suita, 565-0871, Osaka, Japan Yukiko Arai, Ayako Takahashi & Takeshi Yoshida Department of Neuroscience and Cell Biology, Graduate School of Medicine, The University of Osaka, 2-2 Yamadaoka, Suita, 565-0871, Osaka, Japan Yukiko Arai, Yoshihisa Koyama & Shoichi Shimada Addiction Research Unit, Osaka Psychiatric Research Center, Osaka Psychiatric Medical Center, Osaka, 541-8567, Japan SANKEN, The University of Osaka, Osaka, 567-0047, Japan United Graduate School of Child Development, The University of Osaka, Suita, Japan The authors declare no competing interests. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Below is the link to the electronic supplementary material.

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