• Junhua Wu, Meiling Jin, Quangdon Tran, Minwoo Kim, Song I Kim, Juhee Shin, Hyewon Park, Nara Shin, Hyunji Kang, Hyo Jung Shin, Sun Yeul Lee, Song-Biao Cui, C Justin Lee, Won Hyung Lee, and Dong Woon Kim.
• Department of Medical Science, Chungnam National University School of Medicine, Daejeon, Republic of Korea; Department of Anatomy and Cell Biology, Brain Research Institute, Chungnam National University School of Medicine, Daejeon, Republic of Korea; Department of Neurology, Yanji Hospital, Yanji, China.
• Transl Res. 2024 Jan 1; 263: 537253-72.

AbstractNeuropathic pain is caused by injury or disease of the somatosensory system, and its course is usually chronic. Several studies have been dedicated to investigating neuropathic pain-related targets; however, little attention has been paid to the persistent alterations that these targets, some of which may be crucial to the pathophysiology of neuropathic pain. The present study aimed to identify potential targets that may play a crucial role in neuropathic pain and validate their long-term impact. Through bioinformatics analysis of RNA sequencing results, we identified Slc9a1 and validated the reduced expression of sodium-hydrogen exchanger 1 (NHE1), the protein that Slc9a1 encodes, in the spinal nerve ligation (SNL) model. Colocalization analysis revealed that NHE1 is primarily co-localized with vesicular glutamate transporter 2-positive neurons. In vitro experiments confirmed that poly(lactic-co-glycolic acid) nanoparticles loaded with siRNA successfully inhibited NHE1 in SH-SY5Y cells, lowered intracellular pH, and increased intracellular calcium concentrations. In vivo experiments showed that sustained suppression of spinal NHE1 expression by siRNA-loaded nanoparticles resulted in delayed hyperalgesia in naïve and SNL model rats, whereas amiloride-induced transient suppression of NHE1 expression yielded no significant changes in pain sensitivity. We identified Slc9a1, which encodes NHE1, as a key gene in neuropathic pain. Utilizing the sustained release properties of nanoparticles enabled us to elucidate the chronic role of decreased NHE1 expression, establishing its significance in the mechanisms of neuropathic pain.Copyright © 2023 Elsevier Inc. All rights reserved.

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