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3092 ｜NEURAL REGENERATION RESEARCH｜Vol 21｜No. 7｜July 2026NEURAL REGENERATION RESEARCHwww.nrronline.orgResearch Art i cleTrans-spinal magnet i c st i mulat i on upregulates microglial SOCS3 to at t enuate neuroinf l ammat i on in chronic constrict i on injury–induced neuropathic painAbstract Current treatments for neuropathic pain are suboptimal, necessitating the search for more effective therapeutics. Our previous study showed that inhibition of neuroinflammation in the spinal cord induced analgesic effects, and focal repetitive trans-spinal magnetic stimulation showed an anti-neuroinflammatory effect in spinal cord injury rat models. Here, we speculated that repetitive trans-spinal magnetic stimulation might induce an anti-inflammatory effect to alleviate neuropathic pain by upregulating calmodulin-dependent protein kinase kinase beta (CaMKKβ)/adenosine 5′-monophosphate-activated protein kinase (AMPK)/suppressor of cytokine signaling-3 (SOCS3) signaling in microglia. Experiments have found that non-invasive focal repetitive trans-spinal magnetic stimulation effectively alleviates mechanical allodynia and spinal neuroinflammation in rats with neuropathic pain induced by chronic sciatic nerve ligation. Further research found that repetitive trans-spinal magnetic stimulation upregulated the expression of SOCS3 in spinal microglia, which subsequently inhibited the phosphorylation of p38 mitogen-activated protein kinase and signal transducer and activator of transcription 3 and nuclear factor-kappa B p65 nuclear translocation in rats with neuropathic pain, thereby suppressing neuroinflammation. The upregulation of SOCS3 by repetitive trans-spinal magnetic stimulation may be achieved through the activation of the CaMKKβ/AMPK signaling pathway in microglia. The results suggested that focal repetitive trans-spinal magnetic stimulation inhibits spinal neuroinflammation and alleviates neuropathic pain by activating the CaMKKβ/AMPK/SOCS3 signaling pathway in spinal microglia. This mechanism provides an effective noninvasive treatment for neuropathic pain caused by peripheral nerve injury.Key Words: CaMKKβ/AMPK/SOCS3 signaling; chronic constriction injury; mechanical pain sensitivity; microglia; neuropathic pain; neuroinflammation; nuclear factor-κB p65; repetitive trans-spinal magnetic stimulation; STAT3ht t ps://doi.org/10.4103/NRR.NRR-D-24-00912Date of submission: August 11, 2024 Date of decision: January 19, 2025 Date of acceptance: March 17, 2025 Date of web publicat i on: April 29, 2025 Introduct i on Neuropathic pain (NP), a devastat i ng form of chronic pain, imposes considerable social and economic burdens on patients and society worldwide (Bouhassira, 2019). The management of NP is challenging as currently available drugs have poor efficacy and are associated with severe adverse effects and addiction. It is generally believed that neuroinflammation in the dorsal horn, involved in immune cell recruitment and the release of mediators, plays a central role in the chronification and central sensitization of NP (Sommer et al., 2018). In the last decade, preclinical studies of NP have explored neuroinf l ammat i on and glial act i vity in the dorsal horn, fi nding that NP is at t enuated by neuroinf l ammat i on inhibit i on and glial act i vat i on (Hu et al., 2020; Yu et al., 2020a; Sun et al., 2021). Systemic inhibit i on of neuroinf l ammat i on and glial act i vat i on may have serious side effects, and there is currently no effective means of targeted drug delivery to the dorsal horn for clinical treatment of NP. Therefore, a novel noninvasive targeted therapy to suppress neuroinf l ammat i on in the dorsal horn is a promising therapeut i c strategy for NP.Neuroinf l ammat i on is a major cause of chronic pain (Wu et al., 2025). Neuroinf l ammat i on in the spinal cord drives chronic pain via neuron–glial interact i ons (Yi et al., 2021). Peripheral nerve injury promotes de novo expression of colony-stimulating factor 1, inducing microglial proliferat i on and act i vat i on in the dorsal horn of the spinal cord. The dif f usion of neuroinf l ammat i on in the central nervous system is underpinned by microglial act i vat i on (Guan et al., 2016). The activated microglia release the majority of proinflammatory cytokines, such as interleukin-1 beta (IL-1β), interleukin (IL)-6, and tumor necrosis factor-alpha (TNF-α), which further activate the adjacent glia to induce neuroinflammation dif f usion and contribute to chronic pain states (Chen et al., 2018). This fi nding suggests that target i ng neuroinf l ammat i on may be a therapeut i c strategy for chronic pain. 1 Department of Rehabilitat i on, Hengyang Medical School, The First Af f i liated Hospital, University of South China, Hengyang, Hunan Province, China; 2 Rehabilitat i on Medicine Center, The First Af f i liated Hospital of Nanjing Medical University (Jiangsu Province Hospital), Nanjing, Jiangsu Province, China; 3 Department of Rehabilitat i on, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China; 4 Department of Rehabilitat i on Medicine, The Af f i liated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu Province, China; 5 Jiangsu Key Laboratory of Neurodegenerat i on, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu Province, China*Correspondence to: Liang Hu, PhD, lianghu@njmu.edu.cn; Tong Wang, MD, PhD, wangtong60621@163.com; Ying Shen, MD, PhD, shenying@njmu.edu.cn; Wentao Liu, PhD, painresearch@njmu.edu.cn.ht t ps://orcid.org/0000-0002-0013-7440 (Liang Hu); ht t ps://orcid.org/0000-0001-6516-4397 (Tong Wang); ht t ps://orcid.org/0000-0001-8308-9562 (Ying Shen); ht t ps://orcid.org/0000-0001-8732-7927 (Wentao Liu)#These authors contributed equally to this work and share fi rst authorship.Funding: This study was supported by the Nat i onal Natural Science Foundat i on of China, Nos. 82302877 (to QW), 82172541 (to TW); the Natural Science Foundat i on of Hunan Province, No. 2023JJ30549 (to QW); and the Clinical Medical Technology Innovat i on Guidance Project of Hunan Provincial Science and Technology Department, No. 2021SK51815 (to QW).How to cite this article: Wu Q, Xu X, Zhai C, Cai J, Wang Z, Fang L, Wang Y, Qian Y, Dong M, Hu L, Wang T, Shen Y, Liu W (2026) Trans-spinal magnet i c st i mulat i on upregulates microglial SOCS3 to at t enuate neuroinf l ammat i on in chronic constrict i on injury–induced neuropathic pain. Neural Regen Res 21(7):3092-3102. Graphical AbstractrTSMS activates CaMKK β /AMPK–SOCS3 signaling in microglia to suppress neuroinflammation and relieve neuropathic painFrom the ContentsIntroductionMethodsResultsDiscussionQi Wu 1, 2, # , Xingjun Xu 3, # , Chenyuan Zhai 4, # , Jili Cai 2 , Zun Wang 2 , Lu Fang 2 , Yu Wang 2 , Yilun Qian 2 , Manyu Dong 2 , Liang Hu 5, * , Tong Wang 2, * , Ying Shen 2, * , Wentao Liu 5, *