Mechanisms and Clinical Application Progress of Exercise in the Treatment of Neuropathic Pain

Xiangmiao Li; Jinzhu Bai

doi:10.1007/s10571-026-01678-x

. 2026 Jan 24;46:34. doi: 10.1007/s10571-026-01678-x

Mechanisms and Clinical Application Progress of Exercise in the Treatment of Neuropathic Pain

Xiangmiao Li ¹, Jinzhu Bai ^1,^2,^3,^✉

PMCID: PMC12894456 PMID: 41579232

Abstract

Neuropathic pain has a complex pathogenesis and poses significant treatment challenges. In recent years, exercise has garnered increasing attention as a nonpharmacological intervention for the management of neuropathic pain. This review systematically examines the research progress on the neurobiological mechanisms of exercise in the treatment of neuropathic pain, including its effects on improving neuroinflammation, alleviating oxidative stress, modulating neuroplasticity, influencing the descending pain modulation system, and regulating gene expression and epigenetic modifications. Additionally, this review summarizes the application and therapeutic effects of various exercise interventions in different types of neuropathic pain, such as neuropathic pain after spinal cord injury, chemotherapy-induced peripheral neuropathy, diabetic peripheral neuropathy, and neuropathic pain in multiple sclerosis, on the basis of current clinical research. It also explores future research directions and trends in this field. By integrating basic research and clinical evidence, this review aims to provide a theoretical basis and practical guidance for exercise therapy in patients with neuropathic pain. Although existing evidence supports the analgesic potential of exercise, future high-quality clinical studies are needed to optimize individualized exercise prescriptions and further explore its molecular and neural circuit mechanisms.

Graphical Abstract

Mechanism and clinical application of exercise therapy for neuropathic pain. Exercise exerts analgesic effects through multiple mechanisms, including modulation of neuroinflammation, oxidative stress, neuroplasticity, descending pain modulatory system, and epigenetics. For neuropathic pain of different etiologies, exercise programs can be customized to accurately regulate specific pathological links.

Keywords: Exercise, Exercise therapy, Neuropathic pain, Mechanism, Clinical evidence

Introduction

Neuropathic pain (NP) is a chronic pain condition directly caused by damage to or disease of the somatic nervous system. Its clinical manifestations are complex and diverse and include characteristic symptoms such as spontaneous pain, hyperalgesia, and allodynia (Burke et al. 2017; Cavalli et al. 2019). According to the definition by the International Association for the Study of Pain (IASP), neuropathic pain originates from lesions or diseases affecting the somatic sensory system. Its prevalence in the general population is approximately 7%-10% (Cavalli et al. 2019), and with the acceleration of population aging, the incidence rate has increased annually. Common types of NP include diabetic peripheral neuropathy (DPN), postherpetic neuralgia, trigeminal neuralgia, NP after spinal cord injury (SCI), and chemotherapy-induced peripheral neuropathy (CIPN) (Szok et al. 2019).

Exercise has demonstrated significant efficacy in chronic pain management (Ninneman et al. 2024). There are various forms of exercise, including aerobic exercise, resistance training, flexibility exercises, and the recently emerging neuromuscular control training and mind–body integration training. These interventions exert effects through different physiological and psychological mechanisms, providing personalized treatment options for patients with NP. Previous studies have shown that exercise can regulate the functions of multiple pain regulatory systems, including the descending inhibitory system, the endogenous opioid system, the endocannabinoid system, and the release of various neurotransmitters (such as serotonin, norepinephrine, and brain-derived neurotrophic factor (BDNF)) (Lesnak and Sluka 2020; Ghanbari 2025).

With advancements in neuroscience technologies, researchers have been able to more precisely analyze the specific mechanisms through which exercise affects NP. These basic research findings not only deepen our understanding of the principles of exercise-induced analgesia but also provide crucial evidence for optimizing clinical exercise intervention plans. Moreover, multimodal intervention strategies that combine exercise training with other therapeutic methods (such as transcranial magnetic stimulation and cognitive behavioral therapy) are becoming a new trend in the management of NP.

Therefore, this review aims to systematically examine the research progress on exercise in the treatment of neuropathic pain. Specifically, our objectives are threefold: (1) to synthesize current mechanistic insights from basic research on the neurobiological mechanisms of exercise, including its effects on neuroinflammation, oxidative stress, neuroplasticity, the descending pain modulatory system, and epigenetic modifications; (2) to summarize the application and therapeutic effects of various exercise interventions across different NP etiologies, such as NP after spinal cord injury, chemotherapy-induced peripheral neuropathy, and diabetic peripheral neuropathy, based on current clinical evidence; and (3) to identify current research limitations and translational gaps for future research.

Method

The PubMed database was searched for literature published from January 1, 2020 to August 23, 2025, and the following keywords were used in the search strategy and as selection criteria: neuropathic pain, exercise, exercise therapy and their related words. We used various combinations of the above search terms to assess the literature comprehensively. First, the relevance of the title and abstract to the content was reviewed. If they were deemed relevant, the entire paper was accessed. Priority was given to original research articles, recent high-impact studies, and reviews offering substantial insights into the topic. Eligible study designs encompassed preclinical and clinical randomized controlled trials (RCTs), pilot studies, and case reports. During screening, editorials, conference abstracts, non‑English publications, preclinical studies without exercise intervention, and clinical studies lacking pain‑related outcomes were excluded. To minimize selection bias, two authors independently reviewed the titles and abstracts of retrieved studies, with full‑text assessment conducted as needed. Any discrepancies were resolved through discussion. In addition, other relevant additional articles were identified from “similar articles” listed in the PubMed search results and from references in articles obtained from the search. These additional articles were used to provide background and other supporting information. A flowchart of the search and screening process is presented in Fig. 1.

Fig. 1 — Selection criteria for the literature included in this review

Preclinical Evidence on the Mechanisms of Exercise Therapy for NP

Exercise Improves Neuroinflammation

Neuroinflammation is a key factor in the occurrence and maintenance of NP, and exercise has been shown to significantly modulate this pathological process (Table 1). In the central nervous system (CNS), the activation of glial cells and the resulting neuroimmune cascade play pivotal roles in driving central sensitization and chronic pain (Meacham et al. 2017; Li et al. 2024; Ji et al. 2018; Finnerup et al. 2021).

Table 1.

The neuroinflammatory mechanism of exercise in the treatment of NP

Reference	Species	Model	Types	Program	Changes in related gene/cytokines/protein/ion after exercise	Involved in pathways	Mechanism
Cho et al. (2021)	Rat	SNI	Treadmill exercise	8 m/min, 20 min, no inclination, low-intensity walking exercise	DRG: Wnt3a↓, p-LRP6↓, β-catenin↓	DRG: Wnt/β-catenin	Inhibit the nuclear accumulation of β-catenin in DRG cells
Cho and Seo (2022)	Rat	SNI	Treadmill exercise	8 m/min, 30 min, no inclination, 14 days before and/or after SNI	DRG: Wnt3a↓, β-catenin↓, TNF-α↓, NF-κB↓	DRG: Wnt/β-catenin	Inhibit Wnt/β-catenin and proinflammatory cytokines in DRG
Wang et al. (2022)	Rat	thoracotomy	Treadmill exercise	First week: 20 m/min, 30 min. Second week: 30 m/min, 30 min. Third week to sixth week: 30 m/min, 60 min. 5 days a week for a total of 6 weeks	Spinal cord: TNF-α↓, IL-1β↓ IL-10↑		Regulate anti-inflammatory and proinflammatory cytokines in the spinal cord
Ma et al. (2020)	Rat	DPN	Treadmill exercise	4 days per week, for 5 weeks. Starting from 5 m/min, 10 min, it will be gradually increased to 10 m/min, 10 min in the third week	DRG: p-mTOR↓, p-S6K1↓, p-4E-BP1↓, IL-6↓	DRG: mTOR	Inhibit mTOR pathway and IL-6 in DRG
Sumizono et al. (2022)	Rat	CCI	Treadmill exercise	5 weeks, 20 m/min, 5 consecutive days per week, 15–30 min/d	SDH: IBA-1↓, CCR2↓, TRAF6↓	SDH: JNK/CCL2	Suppress microglial and astrocytic activation
Bai et al. (2022)	Mouse	SNI	Treadmill exercise	10 m/min, 60 min, no inclination	SDH: CD206↑, LC3-II/LC3-I↑, Beclin1↑ p62↓, BDNF↓, CD86↓	SDH: BDNF/AKT/mTOR	Enhance autophagy and promotes M2 microglial polarization
Sun et al. (2022)	Mouse	SNI	Treadmill exercise	10 m/min, 30 min, 5 consecutive days per week, 3 weeks	SDH: (LAP-)TGF-β1↓		Activate TGF-β1 and inhibit astrocyte reactivity
Wang et al. (2024)	Mouse	SNI	Treadmill exercise	10 m/min, 30 min, no inclination, 5 days per week, 4 weeks	SDH: GFAP↓, IL-1β↓, TNF-α↓, C3↓		Reduce astrocytic activation and C3 expression
Bai et al. (2023)	Mouse	SNI	Treadmill exercise	10 m/min, 60 min	SDH: Akt3↓, Atf2↓, Gsk3b↓, Pik3c3↓, Ppp2ca↓, Sqstm1↓ Pik3cb↑		Enhance autophagy
Cheng et al. (2022)	Rat	SCI	Voluntary wheel running exercise	3 weeks, free movement	SDH: CGRP↓, IBA-1↓		Suppress microglial activation
Hsieh et al. (2022)	Rat	brachial plexus avulsion	Swimming	Swim for five minutes twice every morning (7:00) and afternoon (17:00) for two consecutive weeks	SDH: SP↓, IBA-1↓		Suppress microglial activation Reduce inflammation and the formation of vacuoles in the damaged nerves
Dugan et al. (2020)	Rat	SCI	Treadmill exercise combined with NPCs transplantation	8 degree incline. 5 days a week. At the beginning, 10 m/min, 5 min. Then increase the speed (+ 1 m per week) and time (1–4 min per week). By the fourth week, increase to a maximum of 2 times per day, 20 min, 15 m/min each time	Spinal cord: TNF-α↓, IL-1β↓ IL-4↑, IL-10↑ CSF: TNF-α↓		Regulate cytokines and restore GABAergic inhibition
Lopes et al. (2020)	Rat	CCI	Treadmill exercise combined with tDCS	70% maximum oxygen uptake, 20 min, 8 consecutive days, no inclination	Spinal cord and brainstem: IL-4↑		Increase anti-inflammatory IL-4
Lopes et al. (2021)	Rat	CCI	Treadmill exercise combined with tDCS	70% maximum oxygen uptake, 20 min, 8 consecutive days, no inclination	Hippocampus: TNF-α↓ Sciatic nerve: IL-10↑		Regulate the levels of anti-inflammatory and proinflammatory cytokines
Cheng et al. (2023)	Mouse	SCI	Running training combined with ADSCs therapy	wheel running exercise	SDH: IBA-1↓, GFAP↓		Suppress glial cell activation

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↑, increase; ↓, decrease

SNI spared nerve injury, DRG dorsal root ganglia, Wnt wingless-related integration site, Wnt3a Wnt Family Member 3A, p-LRP6 phosphorylated low density lipoprotein receptor-related protein 6, TNF-α tumor necrosis factor-α, NF-κB nuclear factor kappa-B, IL-1β interleukin-1β, IL-10 interleukin-10, DPN diabetic peripheral neuropathy, p-mTOR phosphorylated mammalian target of rapamycin, p-S6K1 phosphorylated ribosomal protein S6 kinase beta-1, p-4E-BP1 phosphorylated eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1, IL-6 interleukin-6, mTOR mammalian target of rapamycin, CCI chronic constriction injury, SDH spinal dorsal horn, IBA-1 ionized calcium-binding adapter molecule 1, CCR2 C–C Motif Chemokine Receptor 2, TRAF6 tumor necrosis factor receptor-associated factor 6, JNK c-Jun N-terminal kinase, CCL2 C–C motif chemokine ligand 2, CD206 cluster of differentiation 206 (mannose receptor 1), LC3-II microtubule-associated protein 1A/1B-light chain 3-phosphatidylethanolamine conjugate, LC3-I microtubule-associated protein 1A/1B-light chain 3 (cytosolic form), Beclin1 BECN1 (coiled-coil, moesin-like BCL2-interacting protein), p62 sequestosome 1 (SQSTM1/p62), BDNF brain-derived neurotrophic factor, CD86 cluster of differentiation 86, AKT threonine kinase Akt, (LAP-)TGF-β1 latency-associated peptide-transforming growth factor-beta 1, TGF-β1 transforming growth factor-β1, GFAP glial fibrillary acidic protein, C3 complement component 3, Akt3 AKT serine/threonine kinase 3, Atf2 activating transcription factor 2, Gsk3b glycogen synthase kinase 3 beta, Pik3c3 phosphatidylinositol 3-kinase catalytic subunit type 3, Ppp2ca protein phosphatase 2 catalytic subunit alpha, Sqstm1 sequestosome 1, pik3cb phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta, SCI spinal cord injury, NPCs GABAergic neural progenitor cells, CGRP calcitonin gene related peptide, SP substance P, IL-4 interleukin-4, CSF cerebrospinal fluid, GABA γ-aminobutyric acid, tDCS transcranial direct current stimulation, ADSC adipose-derived stem cell

Role of Proinflammatory and Anti-inflammatory Cytokines

Exercise alleviates NP partly by restoring the balance of the cytokine milieu toward an anti-inflammatory state (Fig. 2). Evidence from multiple studies indicates that exercise interventions downregulate proinflammatory cytokines, while upregulating anti-inflammatory cytokines. For instance, Wang et al. (2022) reported that six weeks of treadmill exercise following rat thoracotomy reduced tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) expression and increased interleukin-10 (IL-10) expression in the spinal cord, thereby alleviating postoperative mechanical and cold allodynia. Similarly, in rat models of SCI and chronic constriction injury (CCI), two distinct combination therapies consistently lowered TNF-α and IL‑1β levels while elevating interleukin-4 (IL-4) and/or IL‑10 in the spinal cord, brainstem, or sciatic nerve (Lopes et al. 2020, 2021; Dugan et al. 2020). These regimens included intensive locomotor training (ILT) combined with GABAergic neural progenitor cell (NPC) transplantation, as well as aerobic exercise combined with transcranial direct current stimulation (tDCS). Beyond directly modulating cytokine expression, exercise can also inhibit upstream signaling pathways that drive inflammation. For example, in the rat model of diabetes induced by streptozotocin (STZ), Ma et al. (2020) reported that treadmill exercise could inhibit the excessive activation of the mammalian target of rapamycin (mTOR) pathway, downregulate the phosphorylation of mTOR (p-mTOR), phosphorylation of ribosomal protein S6 kinase beta-1 (p-S6K1), and phosphorylation of eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (p-4E-BP1) and reduce the expression of interleukin-6 (IL-6) in the DRG, thereby alleviating NP.

In studies of central neurodegenerative diseases and the spared nerve injury (SNI) model, the classical wingless-related integration site (Wnt) signaling pathway has been identified as a pain indicator. Studies demonstrated that treadmill exercise administered postoperatively or pre- and postoperatively significantly alleviated mechanical allodynia and hyperalgesia following SNI in rats (Cho et al. 2021; Cho and Seo 2022). Its analgesic mechanism involves a multitarget, synergistic process. During the early regenerative phase after injury, exercise directly affects DRG neurons. It synchronously downregulated the expression of the key initiator Wnt3a in the Wnt/β-catenin signaling pathway and its coreceptor phosphorylated low density lipoprotein receptor-related protein 6 (p-LRP6). This inhibited the accumulation of the core protein β-catenin and significantly reduced its translocation into the cell nucleus, thereby effectively blocking the activation of this pain signaling pathway at the transcriptional level. Furthermore, exercise significantly reduced the expression levels of key proinflammatory mediators in the DRGs, such as TNF-α and nuclear factor kappa-B (NF-κB), while decreasing their colocalization and interactions. These findings collectively indicate that treadmill exercise ameliorates NP by synergistically inhibiting the Wnt/β-catenin signaling pathway and downstream neuroinflammatory cytokine production in DRG neurons.

Role of Glial Cells

The modulation of microglial activation is a key aspect of the intervention of neuroinflammation through exercise (Fig. 2). In the context of NP, microglia in the spinal dorsal horn (SDH) undergo significant morphological and functional changes, characterized by hypertrophy with shortened processes and increased surface receptor expression (Tsuda et al. 2023). Studies have shown that exercise directly suppresses the activation of SDH microglia and downregulates the production of various pain-promoting mediators, such as calcitonin gene-related peptide (CGRP), substance P, CC chemokine receptor 2 (CCR2), and tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6), thereby alleviating neuroinflammation and central sensitization (Cheng et al. 2022; Sumizono et al. 2022; Hsieh et al. 2022). Bai et al. (2022) reported that treadmill exercise alleviated the inhibitory effect of the serine/threonine kinase Akt (AKT)/mTOR signaling pathway on the autophagic process in SDH microglia in SNI mice by downregulating BDNF expression and suppressing the activity of this pathway. Enhanced autophagy activity, manifested as an increased microtubule-associated protein 1A/1B-light chain 3-II/I (LC3-II/LC3-I) ratio, elevated coiled-coil, moesin-like BCL2-interacting protein (Beclin1/BECN1) expression, and decreased sequestosome 1 (SQSTM1/p62) levels, promoted the polarization of microglia from proinflammatory classical (M1) to anti-inflammatory alternative (M2) types, ultimately mediating the analgesic effect. These findings suggest that exercise alleviates NP not only by suppressing microglial activation but also by promoting their polarization toward an anti-inflammatory, reparative M2 phenotype.

Astrocyte activation, often secondary to microglial stimulation, is a central component in the maintenance of NP. This reactive state is characterized by upregulation of glial fibrillary acidic protein (GFAP), cellular hypertrophy, and proliferation. Activated astrocytes can release a variety of neuroactive substances including cytokines, chemokines, ATP, and glutamate. These responses enhance neuronal excitability, exacerbate neuroinflammation, and through interactions with neurons and microglia, promote central sensitization, thereby contributing to the persistence of NP (Li et al. 2025). Exercise counteracts this process via multiple mechanisms (Fig. 2). In mouse model of SNI, treadmill exercise reduces astrocyte activation and alleviates NP by promoting the spinal activation of transforming growth factor-β1 (TGF-β1) and by suppressing GFAP and complement 3 (C3) expression in the SDH (Sun et al. 2022; Wang et al. 2024).

Furthermore, running training can simultaneously reduce inflammatory responses in the SDH by modulating both microglial and astrocytic activation, thereby partially alleviating SCI-induced NP in mice (Cheng et al. 2023). Notably, the combination of running training with adipose-derived stem cell (ADSC) therapy further promotes early recovery of motor function and significantly improves pain-related behaviors (Cheng et al. 2023).

Role of Autophagy

Autophagy is a crucial process for maintaining intracellular homeostasis, and its role in the NP has garnered increasing attention. Exercise has also been shown to alleviate NP by regulating autophagy (Fig. 2). Bai et al. (2023) investigated the effects of exercise on SDH protein expression in NP mice via proteomics analysis and revealed that treadmill exercise significantly reduced hyperalgesic behavior in these mice. The study identified 270 differentially expressed proteins, comprising 221 downregulated and 49 upregulated proteins. The results of functional enrichment analysis indicated that these proteins participate primarily in pain-related biological processes such as autophagy, cAMP signaling, and calcium signaling. Key proteins, including AKT serine/threonine kinase 3 (Akt3), activating transcription factor 2 (Atf2), glycogen synthase kinase-3 beta (Gsk3b), phosphatidylinositol 3-kinase catalytic subunit type 3 (Pik3c3), protein phosphatase 2 catalytic subunit alpha (Ppp2ca), and sequestosome 1 (Sqstm1), were significantly downregulated after exercise, whereas phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta (Pik3cb) expression was upregulated. Further experiments confirmed that exercise improved hyperalgesia in NP mice through the modulation of these key proteins in the autophagy pathway. These findings suggest that treadmill exercise may alleviate NP through the regulation of autophagy, providing new molecular evidence for the mechanism of exercise in chronic pain management.

Collectively, the evidence presented demonstrates that exercise ameliorates neuroinflammation not by targeting a single molecule, but by orchestrating a network of responses across different cellular and molecular tiers. These mechanistic insights provide a rational basis for future clinical applications. This indicates that the assessment of inflammatory factors in NP patients, such as serum levels of IL-1β, TNF-α and IL-10, may be helpful in monitoring the effectiveness of exercise therapy. Furthermore, these mechanistic insights support the exploration of synergistic strategies that combine exercise with anti-inflammatory pharmacotherapies or targeted regulation of glial cells for patients with refractory NP. This integrated approach is particularly promising given the limitations of current pharmacotherapies. Many classic analgesics are constrained by single-target mechanisms, which may activate glial cells and lead to issues such as tolerance and off-target effects (Zhang et al. 2025). In contrast, exercise acts as a physiological, system-wide intervention that aligns with an ideal multi-target regulatory model, potentially circumventing the shortcomings of singular drug action. Therefore, future management of NP will likely rely on combined strategies that harness the complementary benefits of pharmacological agents and exercise.

The Alleviation of Oxidative Stress Through Exercise

The alleviation of oxidative stress is another important pathway through which exercise improves NP (Fig. 2). After nerve injury, mitochondrial dysfunction and weakened antioxidant defense systems lead to excessive accumulation of reactive oxygen species (ROS), causing oxidative damage to lipids, proteins, and DNA (Teixeira-Santos et al. 2020). ROS not only directly harm neurons and axons but also activate multiple pain-related signaling pathways, such as the mitogen-activated protein kinase (MAPK) and NF-κB pathways, exacerbating neuroinflammation and central sensitization (Teixeira-Santos et al. 2020). Green-Fulgham et al. (2022) showed that six weeks of voluntary wheel running (VWR) exercise pretreatment before CCI of the sciatic nerve in rats promoted the nuclear translocation of the transcription factor nuclear factor-erythroid 2 related factor 2 (Nrf2). This subsequently upregulated the expression of the superoxide dismutases superoxide dismutase 1 (SOD1) and superoxide dismutase 2 (SOD2) in DRGs, which effectively scavenges pro-pain reactive nitrogen/oxygen species such as peroxynitrite and maintains redox balance in neural tissue (Green-Fulgham et al. 2022). Similarly, in mice with experimental autoimmune encephalomyelitis (EAE), preconditioning with strength training significantly reduced ROS production in the spinal cord by inhibiting the rac family small GTPase 1 (Rac1)/nicotinamide adenosine dinucleotide phosphate (NADPH) oxidase axis, and also decreased malondialdehyde (MDA) levels while increasing total superoxide dismutase (SOD) activity, thereby mitigating oxidative stress-induced neuronal damage (Saffar Kohneh Quchan et al. 2025). In rat model of diabetic neuropathy, endurance exercise indirectly alleviated oxidative stress and improved mitochondrial function by inhibiting the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome and P38 mitogen-activated protein kinase (p38 MAPK) pathway in the spinal cord, which reduces the release of proinflammatory factors such as TNF-α and IL-1β (Habibi et al. 2022). Exercise and resveratrol (RES), either alone or in combination, enhanced neuroprotection by upregulating the silent information regulator 1 (SIRT1)/nerve growth factor (NGF)/growth-associated protein 43 (GAP-43) pathway, suppressing oxidative stress and apoptosis, modulating Na⁺/K⁺ ATPase function and reducing CGRP expression in sciatic nerves, thereby alleviating pain and sensory abnormalities caused by DPN in rats (Ghoweba et al. 2023). This combined treatment further promoted nerve regeneration and functional recovery through the activation of the Akt pathway and SOD activity in sciatic nerves (Ghoweba et al. 2023). Additionally, swimming can upregulate the expression of the myelin structural protein myelin protein zero (MPZ) in sciatic nerve, which protects myelin integrity to break the vicious cycle between inflammation and oxidative stress, ultimately improving NP in CCI rats (Ghanbari et al. 2023) The above research indicates that exercise can increase the activity of antioxidant enzymes and reduce the levels of oxidative stress markers, thereby exerting analgesic effects (Table 2).

Table 2.

The oxidative stress mechanism of exercise in the treatment of NP

Reference	Species	Model	Types	Program	Changes in related gene/cytokines/protein/ion after exercise	Involved in pathways	Mechanism
Green-Fulgham et al. (2022)	Rat	CCI	Voluntary wheel running exercise	Freely run on the running wheel for 3 or 6 consecutive weeks before CCI	Sciatic nerve: SOD1↑, SOD2↑		Activate Nrf2 to enhance antioxidant defenses
Saffar Kohneh Quchan et al. (2025)	Mouse	EAE	Strength training	1 × 0.18 m, 80° incline, ladder training. Complete 8–12 repetitions per set, with 2 min of rest between sets. Each session lasts approximately 30 min. 5 days per week for a total of 4 weeks	Spinal cord: TGF-β1↑ Rac1↓, IL-1β↓, TNF-α↓, MDA↓		Enhance SOD activity Inhibiting Rac1-mediated NADPH oxidase activity further reduces ROS production
Habibi et al. (2022)	Rat	DPN	Treadmill endurance training	Five times a week for six consecutive weeks. First week: 10 m/min, 10 min. Second week: 10 m/min, 20 min. Third week, 14-15 m/min, 20 min. Fourth week: 14-15 m/min, 30 min. Fifth and sixth week: 17-18 m/min, 30 min	Spinal cord: NLRP3↓, TNF-α↓, IL-1β↓	Spinal cord: P38 MAPK	Suppress NLRP3 inflammasome and oxidative stress Enhance mitochondrial function
Ghoweba et al. (2023)	Rat	DPN	Swimming combined with RES	5 days a week for a total of 4 weeks. Start with 15 min per session, increasing by 15 min each day until reaching one hour	Spinal cord: TNF-α↓, caspase-3↓ Sciatic nerve: CGRP↓ SIRT1↑, NGF↑, GAP-43↑, SOD↑, Bcl-2↑, Akt↑	Sciatic nerve: SIRT1/NGF/GAP-43, Akt	Activate SIRT1/NGF pathway and reduce oxidative stress Regulate mitochondrial function and axon regeneration
Ghanbari et al. (2023)	Rat	CCI	Swimming	20 min, 5 days a week, for 4 weeks	Sciatic nerve: MPZ↑		Upregulate MPZ to protect myelin integrity

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↑, increase; ↓, decrease

CCI chronic constriction injury, SOD1 superoxide dismutase 1, SOD2 superoxide dismutase 2, Nrf2 nuclear factor-erythroid 2 related factor 2, EAE experimental autoimmune encephalomyelitis, TGF-β1 transforming growth factor-β1, Rac1 rac family small GTPase 1, IL-1β interleukin-1β, TNF-α tumor necrosis factor-α, MDA malondialdehyde, SOD superoxide dismutase, NADPH nicotinamide adenine dinucleotide phosphate, ROS reactive oxygen species, SDH spinal dorsal horn, DPN diabetic peripheral neuropathy, NLRP3 NOD-like receptor thermal protein domain associated protein 3, P38 MAPK P38 mitogen-activated protein kinase, RES resveratrol, CGRP calcitonin gene related peptide, SIRT1 silent information regulator sirtuin 1, NGF nerve growth factor, GAP-43 growth-associated protein 43, Bcl-2 B-cell lymphoma 2, Akt AKT serine/threonine kinase, MPZ myelin protein zero

In summary, exercise alleviates oxidative stress by simultaneously enhancing the antioxidant defense mechanism and inhibiting the pro-oxidative process. It upregulates endogenous enzymes, such as SOD, through pathways like Nrf2, while inhibiting sources of ROS, such as the Rac1/NADPH oxidase axis and NLRP3 inflammasome. This oxidative regulation is also closely related to the anti-inflammatory effect of exercise. For example, inhibiting ROS can reduce the activation of pathways like NF-κB, thereby indirectly downregulating neuroinflammation. These mechanisms indicate that the detection of oxidative stress markers, such as MDA and SOD activity, in clinical settings can serve to identify patients who might derive particular benefit from exercise interventions. This mechanistic understanding also supports the potential of combining exercise with antioxidant supplementation in conditions like diabetic peripheral neuropathy.

The Regulation of Neuroplasticity by Exercise

Neuroplasticity refers to the ability of the nervous system to adapt its structure and function in response to changes in the internal and external environment. Current research indicates that neuroplasticity plays a central role in the treatment of NP through coordinated multilevel and multipathway regulation (Table 3; Fig. 3).

Table 3.

The neuroplasticity mechanism of exercise in the treatment of NP

Reference	Species	Model	Types	Program	Changes in related genes/cytokines/proteins/neurons after exercise	Involved in pathways	Mechanism
DRG and spinal cord
Guo et al. (2021)	Rat	CCI	Swimming	Starting on the third day after surgery, rest for one day every four consecutive days. Exercise for 30–60 min per day, gradually increasing the duration	DRG: miR-145-5p↑, miR-300-5p↑ miR-653-5p↓ miR-341↓, Atf3↓, Ctss↓, Cacna2d1↓, Gal↓		Improve synaptic transmission and plasticity of neurons Inhibit neuroinflammation and oxidative damage
Cho and Seo (2022)	Rat	SNI	Treadmill exercise	8 m/min, 30 min, no inclination, 14 days before and/or after SNI	DRG: GAP-43↑, BDNF↑		Promote the regeneration and functional recovery of sensory neurons Activate axonal regeneration-related pathways
Cho and Seo (2023)	Rat	SNI	Treadmill walking exercise	8 m/min, 30 min	DRG: GAP-43↑, BDNF↑ NF-κB↓, IL-6↓, TNF-α↓, CGRP↓, c-Fos↓		Promote the growth of neurites in the peripheral nerves Reduce inflammation
Ghanbari et al. (2024)	Rat	CCI	Swimming	25 min, 5 days per week	CSF: glutamate↓		Decrease the CSF glutamate level and its neurotransmission
Li et al. (2020)	Rat	SCI	BWSTT	6 m/min, 20 min. Twice a day, five days a week, for four consecutive weeks. The weight support range was set at 20% to 40% of the rats’ body weight	SDH: CREB↑, p-CREB↑, GAD-65/67↑	SDH: BDNF/TrkB	Increase the activation of the spinal sensorimotor neural circuit. Enhance neural plasticity Regulate the excitability of spinal cord neurons to reduce spasticity and abnormal pain after SCI
Saffar Kohneh Quchan et al. (2025)	Mouse	EAE	Strength training	1 × 0.18 m, 80° incline, ladder training. Complete 8–12 repetitions per set, with 2 min of rest between sets. Each session lasts approximately 30 min. 5 days per week for a total of 4 weeks	SDH: Rac1↓	SDH: Rac1/NF-κB	Suppress Rac1 to normalize synaptic structure
Yu et al. (2023)	Rat	SNI	Treadmill exercise combined with BMSC transplantation	8 m/min, 30 min, no inclination	Sciatic nerve: BDNF↑, TrkB↑, CNTF↑ DRG: NF-κB↓, IL-6↓, TNF-α↓		Upregulate neurotrophic factors, downregulate inflammation
Kiyomoto et al. (2024)	Mouse	CRPS	Weight load stimuli and rotarod training	Pull the tail with a 20 g force to apply pressure to the sole of the foot. 5 days a week, with 8 sets of load stimulation each time for 10 s, followed by a 5-s rest. The total duration is 2 min Perform rotational training on the rotating rod, 5 days a week, for 20 min each day	Spinal cord and DRG: NGF↓, TRPV1↓		Reduce the excitability of neurons and decrease the transmission of pain signals to the CNS
Encephalic region
Kami et al. (2020)	Mouse	PSL	VR	Free access to the treadmill for exercise	Amygdala: Increased activation of glutamate neurons Decreased activation of GABA neurons		Modulate amygdala neuronal subpopulations Promote positive emotions and suppress negative emotions
Sumizono et al. (2022)	Rat	CCI	Treadmill exercise	5 weeks, 20 m/min, for 5 consecutive days; after 1 day of exercise, the exercise duration was extended from 15 to 30 min	Hippocampus: DCX↑, PROX1↑		Promote hippocampal neurogenesis
Minami et al. (2023)	Mouse	PSL	VR	Free access to the treadmill for exercise	Hippocampus: FosB + cells↓ PV + and SOM + interneurones↑		Form "feedforward inhibition" on overly excited glutamatergic neurons Reduce the fear and anxiety associated with pain
Lopes et al. (2021)	Rat	CCI	Treadmill exercise combined with tDCS	70% maximum oxygen uptake, 20 min, 8 consecutive days, no inclination	Hippocampus and sciatic nerve: NGF↑, BDNF↑		Increase hippocampal and peripheral BDNF/NGF Promote regeneration process
Wang et al. (2025)	Mouse	CCI	Rotarod movement	10—19 rpm, acceleration of 0.06 rpm/s, each session lasts for 150 s, conducted twice, with an interval of 60 s each time	Primary sensorimotor cortex: SM1^PAG and SM1^RVM neuron calcium signals↑		Drive spinal NA/5-HTergic anti-nociceptive pathways and opioid analgesic pathways

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↑, increase; ↓, decrease

CCI chronic constriction injury, DRG dorsal root ganglia, Atf3 activating transcription factor 3, Ctss cathepsin S, Caena2d1 calcium voltage-gated channel auxiliary subunit alpha2delta 1, Gal galanin and GMAP prepropeptide, SNI spared nerve injury, GAP-43 growth-associated protein 43, BDNF brain-derived neurotrophic factor, NF-κB nuclear factor kappa-B, IL-6 interleukin-6, TNF-α tumor necrosis factor-α, CGRP calcitonin gene related peptide, c-Fos cellular FBJ osteosarcoma oncogene protein, CSF cerebrospinal fluid, SCI spinal cord injury, BWSTT body weight-supported treadmill training, SDH spinal dorsal horn, CREB cAMP-response element binding protein, p-CREB phosphorylated cAMP response element binding protein, GAD-65/67 glutamic acid decarboxylase-65/67, TrkB tyrosine kinase receptor B, EAE experimental autoimmune encephalomyelitis, Rac1 rac family small GTPase 1, BMSC bone marrow stromal cell, CNTF ciliary neurotrophic factor, CRPS complex regional pain syndrome, NGF nerve growth factor, TRPV1 transient receptor potential vanilloid 1, CNS central nervous system, PSL partial sciatic nerve ligation, VR voluntary running, GABA γ-aminobutyric acid, DCX doublecortin, PROX1 prospero homeobox protein 1, NP neuropathic pain, FosB + FBJ murine osteosarcoma viral oncogene homolog B-positive, PV + parvalbumin-positive, SOM + somatostatin-positive, tDCS transcranial direct current stimulation, SM1^PAG primary sensorimotor cortex neurons projecting to periaqueductal gray, SM1^RVM primary sensorimotor cortex neurons projecting to rostroventral medulla, 5-HT 5-hydroxytryptamine, NA norepinephrine

Fig. 3 — The neuroplasticity and descending pain modulatary mechanism of exercise in the treatment of neuropathic pain. Within supraspinal regions, exercise modulates amygdala circuitry by activating glutamatergic neurons and suppressing GABAergic activity, rebalances affective pain processing, enhances hippocampal neurogenesis via markers such as DCX and PROX1 and activation of PV + /SOM + interneurons to reduce pain-related anxiety, and engages the sensorimotor cortex to strengthen descending inhibition through SM1^PAG and SM1^RVM neuronal activation. Exercise also engages endogenous analgesic pathways, including the ACE2/Ang-(1‑7)/MasR axis and β‑endorphin release. At the spinal level, exercise promotes adaptive plasticity while suppressing pathological excitability via downregulation of Rac1, NGF, and TRPV1 and upregulation of GAD‑65/67 and BDNF/TrkB signaling. In the dorsal root ganglion (DRG), exercise enhances synaptic transmission and plasticity through modulation of miR‑145‑5p and *Atf3*, facilitates sensory neuron regeneration via GAP‑43 and BDNF upregulation, and reduces neuronal hyperexcitability by downregulating NGF and TRPV1. Within the sciatic nerve, exercise upregulates neurotrophic factors such as BDNF, TrkB, and CNTF to support axonal regeneration. *DCX* neurogenic markers doublecortin, *PROX1* prospero homeobox protein 1, *NGF* nerve growth factor, *BDNF* brain-derived neurotrophic factor, *ACE2* angiotensin-converting enzyme 2, *Ang* Angiotensin, *Rac1* Rac Family Small GTPase 1, *TRPV1* transient receptor potential vanilloid 1, *TrkB* tyrosine kinase receptor B, *Atf3* activating transcription factor 3, *GAP‑43* growth associated protein 43, *CNTF* ciliary neurotrophic factor, *DRG* dorsal root ganglia

DRG and the Spinal Cord

Exercise significantly affects gene expression and nerve regeneration in the DRG. Guo et al. (2021) employed RNA sequencing to reveal that swimming reversed the expression of differentially expressed microRNAs (miRNAs) and messenger RNAs (mRNAs) in the DRG of CCI rats. Among these genes, miR-145-5p, miR-341, miR-300-5p, and miR-653-5p and genes such as activating transcription factor 3 (Atf3), calcium voltage-gated channel auxiliary subunit alpha2delta 1 (Caena2d1), galanin and GMAP prepropeptide (Gal), and cathepsin S (Ctss) were enriched in pathways related to pain regulation. Swimming can reverse the downregulation of miR-145-5p and miR-300-5p after nerve injury, which may improve neuronal synaptic transmission and plasticity by targeting and regulating calcium channel subunits or neurotrophic factor signaling pathways. Additionally, changes in the expression of Atf3 (a marker of neuronal damage) are associated with synaptic remodeling. Moreover, the expression changes of miR-341 and miR-653-5p are associated with inflammation and oxidative stress. Swimming can inhibit their expression, thereby alleviating NP by suppressing neuroinflammation and oxidative damage. Both treadmill exercise and walking significantly increased the expression of GAP-43 and BDNF on the injured side of the DRG in SNI rats (Cho and Seo 2022, 2023). GAP-43 is a key marker of axonal regeneration, whereas BDNF supports neuronal survival and axonal growth. Specifically, postoperative treadmill exercise significantly increased GAP-43 colocalization with the sensory neuron marker neurofilament 200 (NF-200), promoting sensory neuron regeneration and functional recovery. Walking simultaneously reduced the expression of the inflammatory markers NF-κB, IL-6, TNF-α, CGRP, and cellular FBJ osteosarcoma oncogene protein (c-Fos), thereby suppressing the inflammatory response.

A pivotal mechanism through which exercise alleviates NP is the restoration of the excitatory-inhibitory balance in spinal pain processing circuits. Neurotransmitters such as γ-aminobutyric acid (GABA), glutamate, glycine, and endorphins play significant roles in pain signal transmission (Zimmermann 2001; Zeilhofer 2008; Kohno et al. 2005). Following nerve injury, as occurs in SCI, or after peripheral nerve injury, C fiber stimulation, or capsaicin injection, extracellular glutamate concentrations in the spinal cord increase markedly (Hulsebosch et al. 2009; Yezierski 2000). This excess glutamate overactivates its receptors on spinal dorsal horn neurons, leading to excessive excitation of neurons and glial cells, central sensitization, and the release of proinflammatory cytokines such as TNF-α and IL-1β, which further perpetuates NP (Hulsebosch et al. 2009). Critically, this pathological increase in central excitatory tone is systemically reflected in the cerebrospinal fluid (CSF). Ghanbari et al. (2024) demonstrated that moderate-intensity swimming exercise alleviated NP in CCI rats by reducing the level of glutamate in the CSF, indicating a downregulation of overall central nervous system excitability and glutamatergic neurotransmission. Li et al. (2020) demonstrated that early body weight-supported treadmill training (BWSTT) enhanced GABAergic inhibition in the SDH via BDNF/tyrosine kinase receptor B (TrkB) signaling and increased glutamic acid decarboxylase-65/67 (GAD-65/67) synthesis. This enhanced inhibition improves mechanical allodynia and thermal hyperalgesia in rats with incomplete SCI (Li et al. 2020). By suppressing the excessive activation of the Rac1 signaling pathway, four weeks of strength training reduced the abnormal proliferation of dendritic spines in WDR neurons of the SDH in EAE mice (Saffar Kohneh Quchan et al. 2025). This finding indicates that exercise directly mitigates the structural basis of aberrant synaptic plasticity. The restoration of synaptic structure and function subsequently reduces neuronal hyperexcitability and alleviates pain sensitivity.

The combined intervention of treadmill exercise and bone marrow stromal cell (BMSC) transplantation can accelerate nerve regeneration and effectively alleviate NP by synergistically regulating neurotrophic factors and inflammatory pathways. Yu et al. (2023) reported that during the early phase of nerve regeneration (1–2 weeks) after SNI in rats, both treadmill exercise alone and combined BMSC transplantation significantly upregulated the neurotrophic factors BDNF, TrkB, and ciliary neurotrophic factor (CNTF) in the sciatic nerve, which promotes axonal regeneration and alleviates pain. In the late phase (3–5 weeks), the combined intervention resulted in higher expression levels of these factors than either intervention alone, demonstrating superior efficacy. Furthermore, the combined therapy suppressed the expression of the proinflammatory cytokines IL-6 and TNF-α and the activity of NF-κB in the DRGs more effectively, thereby alleviating neuroinflammation and pain responses. Complex regional pain syndrome (CRPS) is a chronic pain disorder that typically occurs after limb injuries (such as fractures, surgeries, or traumas), and it is characterized by peripheral neuropathic pain (PNP). Central sensitization is the core feature of CRPS. Kiyomoto et al. (2024) simulated CRPS using a mouse model with a tibial fracture immobilized with cast fixation. Their study revealed that both weight load stimuli and rotarod training reduced the expression of NGF and transient receptor potential vanilloid 1 (TRPV1) in the spinal cord and DRG. This directly decreases neuronal excitability and pain signal transmission to the CNS, consequently alleviating central sensitization and improving mechanical and thermal hypersensitivity. However, weight load stimuli resulted in stronger TRPV1 inhibition, significantly outperforming rotarod training in reducing pain sensitivity and edema with more sustained effects.

Encephalic Region

Neuroimaging analyses in chronic pain patients have indicated that dysfunction of the mesocorticolimbic system, including the ventral tegmental area (VTA), amygdala (Amyg), hippocampus (Hipp), nucleus accumbens (NAc), and medial prefrontal cortex (mPFC), plays a critical role in the development and maintenance of chronic pain.

The amygdala is a limbic brain region that plays a crucial role in emotion processing, neuropsychiatric disorders, and the affective dimension of pain. Through synergistic or antagonistic interactions among its distinct subregions, the amygdala both encodes the negative affect of pain and participates in analgesic mechanisms. The basolateral nuclei of the amygdala (BLA)–nucleus accumbens (NAc) pathway promote positive emotions, whereas excessive activation of the central nuclei of the amygdala (CeA) intensifies the emotional component of pain (Cai et al. 2018). Targeting these circuits offers novel therapeutic strategies for chronic pain management. Exercise modulates neuronal activity in amygdala subregions to produce analgesic effects. Kami et al. (2020) demonstrated that voluntary running (VR) ameliorated heat hyperalgesia in mice with partial sciatic nerve ligation (PSL), with running distance positively correlated with analgesic effects. At the neuronal level, VR increased the activation of glutamatergic neurons in the medal basal amygdala (medBA), which project to the lateral shell of the NAc. This may enhance analgesia by promoting positive emotions. Simultaneously, VR reduced excessive activation of GABAergic neurons in the capsular division of the CeA (CeC), lateral division of the CeA (CeL) and medial division of the CeA (CeM) subdivision of the CeA, thereby alleviating pain-related negative emotions such as fear and anxiety. VR, by regulating neuronal activity in the subregions of the amygdala, synergistically promotes positive emotions and inhibits negative emotions, thereby generating the exercise-induced hypoalgesia (EIH) effect.

Exercise promotes hippocampal neurogenesis and modulates neuronal activity to alleviate pain. Sumizono et al. (2022) reported that regular treadmill training for 5 days per week over 5 weeks elevated the pain response threshold in CCI rats. The training also promoted the expression of the neurogenic markers doublecortin (DCX) and prospero homeobox protein 1 (PROX1) in the hippocampal dentate gyrus, which improves neurogenic dysfunction caused by NP. Collectively, these changes alleviate pain and improve associated cognitive dysfunction. Minami et al. (2023) further investigated the effects of VR on GABAergic interneurons in the ventral hippocampus (vHPC). The researchers found that VR specifically activated parvalbumin-positive (PV +) and somatostatin-positive (SOM +) GABAergic interneurons in the vHPC-CA1 region. This activation results in “feedforward inhibition” of overexcited glutamatergic neurons, thereby alleviating pain in PSL mice. Additionally, VR may reduce pain-related fear and anxiety by inhibiting neurons projecting from the vHPC-CA1 region to the basolateral amygdala (BLA). Aerobic exercise combined with tDCS also increases BDNF and NGF levels in the hippocampus and sciatic nerve of rats with NP (Lopes et al. 2021). These elevated neurotrophic factor levels promote nerve repair and plasticity, thereby alleviating NP (Lopes et al. 2021).

An imbalance of the sensorimotor cortical circuit is another important factor contributing to the persistence of chronic pain. The primary sensorimotor cortex (SM1), as a functional complex integrating the primary somatosensory cortex (S1) and the primary motor cortex (M1), is traditionally believed to process sensory input and motor output independently. However, new evidence indicates that SM1 regulates sensory and motor functions bidirectionally through descending projections. Wang et al. (2025) identified two distinct neuronal subpopulations within SM1: SM1^PAG and SM1^RVM. These proteins project to the midbrain periaqueductal gray (PAG) and rostroventral medulla (RVM), respectively, and independently and synergistically alleviate NP through the 5-hydroxytryptamine (5-HT)/norepinephrine (NA) system and the endogenous opioid system of the spine. Rotarod movement activates SM1^PAG and SM1^RVM neurons, driving spinal noradrenergic and serotonergic antinociceptive pathways as well as spinal opioid analgesic pathways to achieve analgesic effects. The specific mechanisms include the following. Rotarod movement induces enhanced calcium signals in SM1^PAG and SM1^RVM neurons, activating the projections of PAG glutamatergic neurons to the noradrenergic neurons of the locus coeruleus and the 5-HTergic neurons of the RVM, as well as the direct projections of RVM enkephalinergic neurons to the spinal cord. These effects mediate analgesia through α2A adrenergic receptors, 5-HT7/3 receptors, and μ-opioid receptors. Furthermore, SM1^PAG and SM1^RVM neurons participate in motor coordination and fine motor control, with their activation being essential for exercise-induced analgesia. These findings reveal the neural mechanism through which exercise achieves dual regulation of analgesia and motor function through the SM1 cortex-brainstem pathway.

The above results indicate that exercise has the ability to trigger adaptive neuroplasticity at multiple levels of the nervous system. Its functions include promoting axonal repair in the DRGs, restoring the excitation-inhibition balance in the SDH, regulating brain regions such as the Amyg and Hipp to improve the emotional and cognitive dimensions of pain, and activating the sensory-motor cortex to enhance descending inhibition. These functions lay the mechanistic foundation for its clinical application. For instance, objective indicators of neural reorganization can be utilized to evaluate therapeutic efficacy and optimize exercise prescriptions. Integrating exercise with neuromodulation techniques that target specific brain circuits may enhance outcomes by synergistically promoting beneficial plasticity.

Effects of Exercise on the Descending Pain Modulatory System

The descending pain modulatory system is a core component of endogenous analgesia and a key pathway through which exercise exerts its effects (Fig. 3). Originating in the cerebral cortex and limbic system, this system transmits signals through relay nuclei such as the PAG and the RVM of the medulla, ultimately reaching the SDH to regulate incoming nociceptive information. In the context of NP, descending inhibitory function is frequently impaired, whereas sensitization is enhanced, leading to hyperalgesia and allodynia. The regulation of exercise can enhance descending inhibition by activating endogenous analgesic systems (such as the midbrain PAG, amygdala and endogenous cannabinoid system), reduce the release of proinflammatory factors, and promote the expression of neurotrophic factors. This restores inhibitory/facilitative balance and alleviates pain (Lesnak and Sluka 2020; Ruimonte-Crespo et al. 2023).

Recent studies have revealed that the core mechanism through which exercise affects NP through activation of the descending pain modulatory system lies in its ability to specifically activate endogenous analgesic pathways in the brain and spinal cord. Echeverría-Rodríguez et al. (2021) revealed that swimming activated the nonclassical renin–angiotensin system ACE2/Ang-(1-7)/MasR axis in local tissues, including peripheral nerves, dorsal root ganglia (DRG), spinal cord, and/or brain. This pathway reversed tactile allodynia induced by spinal nerve ligation (SNL) in rats by increasing Ang-(1-7) levels and activating Mas receptors, independent of changes in the plasma Ang II/Ang-(1-7) ratio. Moreover, Sumizono et al. (2024) confirmed that treadmill exercise directly activates PAG, which increased the release of endogenous opioids such as β-endorphin. This enhances the descending inhibitory pathways from the brainstem to the spinal cord while simultaneously suppressing the activation of spinal microglia and astrocytes. By reducing pain sensitization and strengthening pain inhibition, it ultimately restores the balance of pain regulation and effectively alleviates NP.

The evidence that exercise engages and potentiates descending pain modulatory system underscores its role as a non-pharmacological modulator of endogenous pain control. The combination of exercise with non-invasive brain stimulation techniques targeted at key nodes of this system, such as the prefrontal cortex, may yield enhanced analgesic effects by concurrently engaging central and peripheral mechanisms. Optimizing exercise parameters to efficiently engage these endogenous systems is a key objective for clinical prescription.

Regulation of Gene Expression and Epigenetic Modifications by Exercise

Gene expression and epigenetic modifications are central mechanisms involved in the occurrence and maintenance of NP. Following nerve injury, specific gene expression profiles in peripheral and central nervous systems (such as the DRG, SDH, and prefrontal cortex) undergo significant alterations, primarily driven by epigenetic modifications, including DNA methylation, histone acetylation, and miRNA regulation. These modifications alter chromatin structure or interfere with transcriptional/translational processes, abnormally upregulating the expression of proinflammatory and proexcitatory cytokines, ion channels, and pain-related genes while downregulating the expression of anti-inflammatory and inhibitory neurotransmitter genes. This leads to central sensitization and hyperalgesia. Exercise, however, serves as an effective nonpharmacological regulatory approach, exerting analgesic effects by inducing opposite epigenetic reprogramming (Fig. 4).

Fig. 4 — The genetic regulatory mechanism of exercise in the treatment of neuropathic pain. Exercise can alleviate neuropathic pain (NP) by regulating the gene expression and epigenetic modifications in the central and peripheral nervous systems. At the spinal level, exercise downregulates the expression of pain‑associated genes, such as C3, *Sgk1*, and *Dnah7*, that are aberrantly elevated under pathological conditions. In the dorsal root ganglion (DRG), exercise reverses abnormal methylation patterns in differentially methylated regions (e.g., reducing methylation of the pain‑related gene *Ryr1*), while also downregulating the proinflammatory miR‑155. *DRG* dorsal root ganglia, *Ryr1* ryanodine receptor 1, *Sgk1* serum/glucocorticoid regulated kinase 1, *Dnah7* Dynein Axonemal Heavy Chain 7, C3 complement 3

As a crucial epigenetic modification mechanism, DNA methylation regulates gene expression patterns and maintains genomic stability without altering DNA sequences (Brandt et al. 2019; Jones and Takai 2001). Previous studies have indicated that DNA methylation participates in the regulation of PNP by modulating the expression levels of specific genes in the DRG (Chao et al. 2016; Zhao et al. 2017). Exercise can dynamically regulate DNA methylation (Cavalli and Heard 2019; Hunter et al. 2019). Using integrated transcriptome and whole-genome bisulfite sequencing analyses, Chen et al. (2025) revealed that six weeks of swimming pretraining significantly elevated the mechanical withdrawal threshold and thermal withdrawal latency in rats with CCI. They found this analgesic effect was mediated by the reversal of abnormal methylation patterns in differentially methylated regions (DMRs) within DRGs, which downregulated methylation of the pain-related gene ryanodine receptor 1 (Ryr1) and restored its normal expression, thereby exerting analgesia through calcium signaling pathways. Their data further suggested that methylation regulation of genes like Xin actin-binding repeat-containing protein 2 (Xirp2) holds potential as a therapeutic target for exercise-induced pain relief.

Beyond DNA methylation, exercise also regulates the expression of specific RNAs, thereby reshaping normal gene expression networks, suppressing neuroinflammation and glial cell activation, enhancing inhibitory pathways, and ultimately restoring the homeostatic balance of the pain modulatory system. Song et al. (2022) demonstrated that swimming significantly improved mechanical allodynia in CCI rats at 21 and 28 days post-surgery. RNA sequencing revealed that the pain-related genes C3, serum/glucocorticoid regulated kinase 1 (Sgk1), and dynein axonemal heavy chain 7 (Dnah7) were upregulated in the SDH in the CCI group but downregulated in the exercise group. Their analysis indicated that these genes primarily participate in muscle development, immune regulation, and peroxisome proliferator-activated receptor (PPAR) signaling pathways, and suggested that the cytokine-receptor interaction pathway may mediate the analgesic effect of exercise. These findings imply that swimming suppresses neuroinflammation and abnormal excitability by modulating long noncoding RNAs (lncRNA) and mRNA expression in the SDH, thereby alleviating NP. Another study by Kakavandi et al. (2025) demonstrated that both aerobic and resistance exercise alleviated NP in EAE mice through epigenetic regulation and signaling pathway intervention. Both types of exercise downregulated proinflammatory miR-155 in the DRGs, upregulated its target protein serum/glucocorticoid regulated kinase family member 3 (SGK3), and activated the phosphoinositide 3-kinase (PI3K)/Akt and adenosine 5’-monophosphate (AMP)-activated protein kinase (AMPK)/SIRT1 pathways. This coordinated regulation suppresses the release of inflammatory factors such as TNF-α, and enhances neuroprotection, offering a novel nonpharmacological intervention strategy for multiple sclerosis (MS)-induced pain.

The epigenetic modifications and gene expression regulated by exercise presents a novel perspective for managing NP. Identifying stable epigenetic signatures in accessible tissues could lead to biomarkers for predicting long-term exercise efficacy and personalizing treatment plans. At the same time, these mechanisms also indicate that exercise has the potential to permanently alter the expression of genes related to pain, thereby promoting sustained pain relief. Further research into these mechanisms may lead to new approaches for treating chronic pain conditions.

The Predictive Role of EIH Capability

Exercise, as an effective means of pain modulation, induces exercise-induced hypoalgesia (EIH), a phenomenon widely utilized to assess an individual’s pain regulation capacity (Black et al. 1979). Although the precise mechanisms underlying EIH remain incompletely understood, existing research suggests that it is involved in multiple pathways, including the endogenous opioid system, endocannabinoid system, norepinephrine, serotonin, adenosine signaling, and cardiovascular regulatory mechanisms (Lesnak and Sluka 2020; Stagg et al. 2011; Bement and Sluka 2005; Koltyn et al. 2014; Kami et al. 2017; Dietrich and McDaniel 2004; Bobinski et al. 2015; Martins et al. 2013; Lovick 1993). In recent years, the potential of EIHs in managing NP has garnered increasing attention. Research indicates that EIH not only provides palliative analgesia but also may influence pain progression by modulating inflammatory responses, immune responses, and cytokine expression (Ruimonte-Crespo et al. 2023; Bobinski et al. 2015; Chen et al. 2012; Detloff et al. 2016; Kuphal et al. 2007). Notably, EIH capacity exhibits significant interindividual variability, and this variability may hold predictive value for the development and severity of pain following nerve injury.

Khan et al. systematically investigated the predictive role and mechanisms of EIH capacity in NP through a series of studies (Khan et al. 2021a, 2023, 2021b). They reported that EIH performance in rats significantly predicted pain severity following nerve injury. Rats with low EIH exhibited more severe mechanical hyperalgesia after sciatic or infraorbital nerve injury, accompanied by elevated levels of the proinflammatory cytokine IL-1β and reduced levels of the anti-inflammatory cytokine IL-10. Conversely, rats with high EIH exhibited milder pain and higher IL-10 levels, suggesting enhanced endogenous anti-inflammatory and pain control capabilities. Mechanistically, the analgesic effect in high-EIH rats depended on the endocannabinoid system, particularly CB1 receptors, whereas the opioid pathway participated in regulation in both groups of rats. Additionally, EIH characteristics can guide drug selection. For instance, duloxetine and pregabalin demonstrate greater efficacy in rats with low EIH, even reversing their pain-suppressed phenotype to a high EIH state, whereas the anti-inflammatory drug diclofenac exhibits a limited effect. These findings consistently indicate that EIH capacity not only reflects the functional state of pain-suppression systems but also predicts inflammatory responses and pain susceptibility following nerve injury, providing crucial evidence for personalized treatment.

Clinical Exercise Programs and the Effects

A growing body of clinical evidence supports the efficacy of exercise in managing various types of NP. Across multiple studies, structured exercise interventions, including aerobic, resistance, and multimodal training, have consistently demonstrated clinically significant reductions in pain intensity. As summarized in Table 4, these improvements often manifest as substantial decreases on standardized pain scales, alongside enhancements in functional capacity, psychological well-being, and quality of life. The following sections detail these findings for specific NP etiologies.

Table 4.

Summary of clinical studies on exercise interventions for NP

Reference	Etiology	Study design	Exercise intervention	Pain assessment method	Key outcomes
Todd et al. (2021)	SCI	Pilot study	30 min of arm-crank aerobic exercise	modified version of the NPS	NP for patients with tetraplegics decreased by 60%, while for patients with paraplegics, it decreased by 16%
Yeh et al. (2021)	SCI	Double-blinded randomized controlled pilot trial	12 sessions of tDCS and moderate upper body exercises over 4–6 weeks	NRS NPSI PGIC	Significant pain reduction at 4-week follow-up
Trost et al. (2022)	SCI	Pilot feasibility study	Immersive interactive virtual walking for 2 weeks	NRS NPS PGIC with specified “pain status”	Significant reduction in NP
Lores-Peniche et al. (2024)	CIPN	Pilot study	9 weeks, with 3 PNE and 24 TE sessions	VAS scale DN4	A reduction in the frequency and intensity of pain NP decreased from the third week of treatment
Vigano et al. (2025)	CIPN	Clinical trial	two consecutive 2-month interventions: CBD (up to 300 mg/day) and CBD combined with MME	painDETECT questionnaire FACT-GOG-Ntx-13 questionnaire	Large improvements in CIPN neurotoxic symptoms and painDETECT scores were observed after combining CBD with MME. These improvements were also clinically meaningful in over 70% of the patients
Vigano et al. (2024)	CIPN	Case report	standard care (duloxetine) for 1 month (Phase 1), oral cannabidiol (CBD) for 2 months (Phase 2), and CBD plus multi-modal exercise (MME) for another 2 months (Phase 3)	painDETECT questionnaire FACT-GOG-Ntx-13 questionnaire	The combined CBD and multi-modal exercise (MME) intervention (Phase 3) was most beneficial and well tolerated The patient experienced the largest reduction in pain score and showed clinically meaningful improvements in CIPN symptoms
Yildirim and Gultekin (2022)	LDH	RCT	yoga exercise for one hour twice weekly for 12 weeks	DN4 LANSS VAS MPQ	Improved NP intensity (DN4, LANSS), low back pain, and disability
Reyhanıoglu et al. (2024)	DPN	RCT	BBS twice weekly for 8 weeks	DN4 MNSI	Decreased neuropathic pain and neuropathic symptoms
Adiguzel Tat et al. (2025)	MS	RCT	Bilateral NM of upper extremity and strengthening exercises of upper extremity/Bilateral strengthening exercises of upper extremity, 10 repetitions per day, 3 days per week for 6 weeks	VAS LANSS	NM combined with upper extremity strengthening reduces pain in patients with MS
Imaz et al. (2023)	SNPP	Case Report	6 weeks manual therapy for the upper limb and cervical spine and an exercise program for the scapular muscles, rotator cuff and wrist extensor muscles	DN4	Treatment helped relieve NP
Camerota et al. (2025)	SNPP	Case Report	three cycles of 12-week neurocognitive physiotherapy, with weekly 1 h sessions, interspersed with two cycles of 1-week therapy involving only fMV	NRS MPQ	During the treatment period, the pain symptoms were significantly improved

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SCI spinal cord injury, NPS neuropathic pain scale, NP neuropathic pain, tDCS transcranial direct current stimulation, NRS numeric rating scale, NPSI neuropathic pain symptom inventory, PGIC patient global impression of change, CIPN chemotherapy-induced peripheral neuropathy, PNE pain neuroscience education, TE therapeutic exercise, VAS visual analogue scale, DN4 douleur neuropathique 4 questions, CBD cannabidiol, MME multi-modal exercise, FACT-GOG-Ntx-13 Functional Assessment of Cancer Treatment/Gynecological Oncology-Neurotoxicity-13, LDH lumbar disc herniation, RCT randomized controlled trial, MPQ McGill pain questionnaire, LANSS leeds assessment of neuropathic symptoms and signs, DPN diabetic peripheral neuropathy, MNSI michigan neuropathy screening instrument, MS multiple sclerosis, NM neurodynamic mobilization, SNPP surgically induced neuropathic pain, fMV focal mechanical vibrations

Exercise Therapy for SCI-induced NP

NP is a common complication of SCI, with a prevalence of approximately 53% (Burke et al. 2017). The condition is described as burning, tingling, pricking, pins and needles, sharp, electric, stinging, pressing, shooting, squeezing, stabbing, painful cold, or electric shock-like sensations (Widerström-Noga 2023). Sensory dysfunction and pain should be present in an area that is consistent with the injury level and severity (Widerström-Noga 2023). Sensory dysfunctions include hypoesthesia, allodynia, or hyperalgesia (Widerström-Noga 2023). This significantly impairs patients’ quality of life and may trigger psychological issues such as anxiety and depression. Owing to the irreversibility of injury and the development of central sensitization, SCI-induced NP responds poorly to conventional pharmacological treatments, creating an urgent need for effective nonpharmacological interventions.

Current research indicates that exercise has promising potential for alleviating SCI-induced NP. Todd et al. (2021) reported that a single session of upper-limb submaximal aerobic training reduced pain by 60% in patients with tetraplegia. This effect showed moderate-to-high correlations with the synchronized upregulation of anti-inflammatory cascades (including IL-6 and interleukin-1RA [IL-1RA]) and the endocannabinoid-opioid system. Furthermore, IL-1RA levels may serve as a predictive biomarker for treatment efficacy. However, for patients with paraplegia, owing to the exercise intensity approaching the limit, the analgesic effect is delayed, and the coupling of inflammation and pain is more complex. In a double-blind randomized controlled trial by Yeh et al. (2021), 12 patients who performed exercise combined with 12 sessions of tDCS were not significantly different from those who performed exercise plus sham stimulation at the immediate follow-up. However, at the 4-week follow-up, the combined group exhibited more pronounced pain reduction, suggesting a potential delayed analgesic effect through the modulation of pain processing and emotional responses in the cortico-thalamic pathway. Trost et al. (2022) reported that compared with passive, noninteractive virtual walking, immersive interactive virtual walking significantly reduced pain intensity, decreased activity interference, and improved mood. The underlying mechanisms may involve visual-motor feedback reconstruction to restore embodied cognition, modulation of cortical reorganization, and activation of attentional distraction.

These studies collectively reveal that diverse exercise interventions, from traditional aerobic exercise to interactive virtual reality exercise, provide multidimensional evidence for the nonpharmacological management of SCI-induced NP. The underlying mechanisms include inflammation regulation, neural pathway modulation, and cortical functional remodeling, laying a crucial foundation for optimizing intervention protocols, exploring efficacy biomarkers, and conducting large-scale clinical trials.

Exercise Therapy for CIPN

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of cancer chemotherapy, with a prevalence of approximately 48% (Desforges et al. 2022). CIPN primarily manifests as symmetrical “glove and stocking” sensory disturbances, including pain, numbness, and tingling, significantly impairing patients’ quality of life and functional status (Desforges et al. 2022). Current treatment options for CIPN are limited. Opioids and serotonin and norepinephrine reuptake inhibitors (SNRIs), such as duloxetine, offer only modest benefits and are associated with notable side effects (Bae et al. 2021).

Breast cancer, which is the most common malignant tumor worldwide, often leaves survivors burdened by chronic pain, kinesiophobia, and loss of physical function as treatment sequelae (Sung et al. 2021; Bijker et al. 2018; Hong et al. 2019; Van der Gucht et al. 2020). With respect to this high-risk population, Lores-Peniche et al. (2024) reported that pain neuroscience education (PNE) combined with therapeutic exercise (TE) significantly improved NP, kinesiophobia, and upper limb function. The mechanism involves PNE reducing central sensitization by correcting pain-related cognitive distortions, whereas TE activates the endogenous analgesic system, improves local blood circulation, and enhances muscle strength. Together, these processes synergistically break the vicious cycle of “pain-dysfunction-kinesiophobia”. Furthermore, studies by Vigano et al. have further demonstrated that multimodal exercise (MME) combined with cannabidiol (CBD) has synergistic effects (Vigano et al. 2025, 2024). Compared with monotherapy, the combined program showed superior efficacy in alleviating CIPN symptoms, improving quality of life, and regulating the gut microbiota (e.g., promoting the enrichment of genera that produce short-chain fatty acids). The mechanism involves exercise upregulating neurotrophic factors and reducing systemic inflammation, whereas CBD exerts anti-inflammatory and neuroprotective effects by activating the endocannabinoid system (ECS). Exercise further enhances ECS activity, resulting in the formation of a positive “exercise-neuroplasticity-pain regulation” feedback loop.

These studies collectively demonstrate that exercise can alleviate CIPN through multiple pathways, including neuroimmune modulation, sensorimotor functional reorganization, and psychological and cognitive interventions. Future research should further explore the association between personalized exercise prescriptions and biomarkers to optimize multimodal combined intervention strategies.

Exercise Therapy for NP Caused by LDH

Lumbar disc herniation (LDH) is recognized as one of the most common causes of NP, resulting from compression of one or more spinal nerve roots and manifesting as radiating pain, paresthesia, and functional impairment (Hahne et al. 2010). Current research indicates that specific types of exercise can serve as effective nonpharmacological adjunct treatment strategies. For example, a study by Yildirim and Gultekin (2022) demonstrated that a 12-week yoga intervention based on stretching and strength exercises significantly improved NP intensity (as measured by DN4 and LANSS scores), low back pain, functional disability (Oswestry Disability Index), and flexibility in patients. These benefits remained stable at the 3- to 6-month follow-up. The underlying mechanisms may involve enhanced core muscle strength, improved spinal stability, increased neural mobilization, the modulation of inflammatory markers (such as IL-6 and IL-10), and the induction of neuroplastic adaptations. Moreover, the McKenzie method utilizes direction-specific exercise (e.g., repeated extension) to alleviate nerve root compression and the inflammatory response. Although its long-term effects are comparable to those of education alone, it more effectively enhances patients’ self-management abilities and reduces the need for additional treatments (Kilpikoski et al. 2024).

These exercise modalities exert synergistic effects through biomechanical, neuroinflammatory, and other mechanisms, providing an evidence-based foundation for individualized rehabilitation of LDH-related NP. However, future studies with larger sample sizes and standardized exercise protocols are still needed for further validation.

Exercise Therapy for DPN

Diabetic peripheral neuropathy (DPN) is among the most common chronic complications of diabetes, with a prevalence ranging from 6 to 51% (Abbott et al. 2011; Hicks and Selvin 2019; Tesfaye et al. 1996; Gregg et al. 2007). More than 50% of DPN patients experience intense NP, characterized by distal symmetric paresthesia, pain, and sensory loss, which severely interferes with daily activities and significantly reduces quality of life (Sadosky et al. 2015). Balance training is particularly important for individuals with DPN. Reyhanıoglu et al. (2024) evaluated the effects of computer-based balance training on DPN patients. After an 8-week intervention, compared with the control group, the experimental group showed significant improvements in balance ability (including postural stability and fall risk), NP (measured using the DN4 questionnaire), and clinical symptoms (assessed using the MNSI questionnaire). This training likely induced increased local blood flow and reduced oxidative stress, which may indirectly suppress neuroinflammatory cascades. Moreover, the increased expression of the neurotrophic factor BDNF and the promotion of synaptic reorganization, which are involved in the regulation of neuroplasticity, can alleviate symptoms by remodeling the pain perception pathway. This study demonstrated that computer-based balance training can effectively reduce DPN-induced pain and improve functional status; however, its ability to repair neural structures remains limited. These findings suggest that future interventions should incorporate multimodal strategies to achieve comprehensive management of DPN.

Exercise Therapy for MS-induced NP

Multiple sclerosis (MS) is a chronic disease characterized by demyelination of the CNS. Approximately 50% of MS patients experience pain at some point in their lives, with 20% reporting pain as one of their initial symptoms (Reynders et al. 2017; Foley et al. 2013). MS-induced NP may result from inflammation or upper motor neuron damage, negatively affecting patients’ physical and emotional functioning as well as quality of life (Foley et al. 2013; Reynders et al. 2017). Adiguzel Tat et al. (2025) investigated the effects of strength training combined with neurodynamic mobilization (NM) on upper extremity pain, muscle strength, and function in MS patients. After a 6-week intervention, both the bilateral strengthening exercise group and the NM group (bilateral upper extremity NM combined with strengthening exercises) demonstrated significant reductions in pain intensity and NP characteristics, along with marked improvements in shoulder flexor muscle strength. Further analysis revealed that the NM group demonstrated more pronounced improvements in shoulder extensor, elbow flexor, and elbow extensor muscle strength, along with significant gains in manual dexterity. Although no statistically significant differences were observed between the two groups, strength training combined with NM had positive effects on alleviating NP, enhancing the strength of specific muscle groups, and improving manual function. This effect was achieved through mechanisms such as facilitating movement between neural structures and their surroundings, reducing intraneural edema, improving intraneural fluid distribution, reducing thermal and mechanical hyperalgesia, and reversing increased immune responses following nerve injury. These findings suggest that this approach may serve as an effective adjunct for pain management and upper limb functional rehabilitation in MS patients.

Exercise Therapy for SNPP

Surgically induced neuropathic pain (SNPP) is a significant clinical problem, with persistent pain estimated to occur in 10–50% of individuals after common operations (Borsook et al. 2013). Postsurgical neuropathies may be a consequence of transection, contusion, stretching, or inflammation of the nerve (Borsook et al. 2013). Exercise has demonstrated targeted value in the intervention of SNPP, with existing research exploring the efficacy of diverse combined protocols for different types of SNPP. A case report by Imaz et al. (2023) on failed neck surgery syndrome (FNSS) demonstrated that a 6-week exercise program plus manual therapy significantly relieved pain, reduced neck disability and improved the function of the right upper quadrant. This approach achieved pain relief by optimizing motor control and activating descending pain inhibitory pathways. In a case of sciatic nerve injury following total hip arthroplasty (THA), Camerota et al. (2025) demonstrated that focal mechanical vibrations (fMV) led to reorganization of sensorimotor circuits and promoted cortical plasticity by enhancing proprioceptive feedback and modulating central sensory processing. When combined with neurocognitive exercise to modulate central pain processing, their synergistic effects not only immediately eliminated abnormal pain but also significantly improved gait function and quality of life.

These studies provide a mechanistic basis and practical reference for the nonpharmacological rehabilitation of SNPP, but larger-scale studies are still needed to validate the stability of therapeutic efficacy.

Overall, the exercise programs in the current research can be broadly categorized into several major types: aerobic exercise, resistance training, flexibility exercises, neuromuscular training, and integrative body-mind training (IBMT). Each type targets distinct pathophysiological mechanisms and functional objectives, and all have demonstrated efficacy in alleviating NP. Owing to variations in the etiology, severity, and functional status of patients with NP, the individualization of exercise prescriptions is a core principle in NP management. Clinical exercise interventions must be tailored to specific circumstances. An ideal exercise prescription should comprehensively consider factors such as exercise modality, intensity, frequency, duration, and progression rate while aligning with the patient’s preferences and lifestyle habits.

Conclusions and Outlook

In summary, exercise exerts significant analgesic effects through multiple pathways. At the pathophysiological level, it modulates neuroinflammation by suppressing proinflammatory factor release and inhibiting glial cell activation while mitigating oxidative stress damage. At the neural functional level, it enhances functional remodeling in the DRG, spinal cord, and multiple other brain regions and activates the descending pain modulatory system. Furthermore, it amplifies analgesic effects through molecular mechanisms such as the regulation of epigenetic modifications. In clinical practice, exercise has demonstrated positive outcomes across multiple types of NPs, including SCI-induced NP, CIPN, NP caused by LDH, DPN, MS-induced NP, and SNPP. Intervention modalities include aerobic exercise, resistance training, balance training, and comprehensive programs integrating neuromodulation technologies.

Although there is an increasing amount of preclinical and clinical research evidence indicating that exercise is an effective intervention for NP, there are still some key limitations in this field. Firstly, most of the mechanistic insights are derived from standardized rodent models, which may not fully simulate the complexity, heterogeneity, and psychological factors of human NP. There are differences in neuroanatomy, pain processing, and responses to exercise among different species, which pose challenges to the direct inference of these findings to clinical practice. Secondly, there is a widespread methodological inconsistency in research. Whether in animal studies or human studies, exercise prescriptions (methods, intensity, frequency, duration, progression) vary significantly, making it difficult to compare results, or determine the optimal parameters. Thirdly, clinical research often has some limitations, such as small sample sizes, short follow-up times, lack of control groups, and difficulties in achieving blinding, which all affect the reliability and generalizability of the conclusions. Additionally, the molecular mechanisms, such as specific cytokines, epigenetic changes, discovered are disconnected from their clinical applications. Currently, there is a lack of reliable and easily accessible biomarkers that can predict treatment efficacy, monitor therapeutic effects, or guide personalized exercise prescriptions. Therefore, addressing these limitations is crucial for promoting the development of this field towards precise and effective exercise-based pain management.

The translation of promising preclinical findings into effective, personalized exercise therapy for NP requires a concerted effort in future research. The possible future research directions are summarized in Box 1.

Box 1: Future Directions.

Key priorities for randomized clinical trials (RCTs) and mechanistic translation include:

Optimizing Prescriptions through Dose–Response RCTs: There is an urgent need for high-quality RCTs to move beyond simply proving efficacy and towards defining optimal exercise parameters (modality, intensity, frequency, and duration) for specific NP conditions. These studies should establish dose–response relationships to create precise, individualized, and standardized exercise prescriptions.
Translating Mechanisms into Biomarkers: Future clinical trials may integrate mechanistic insights from animal studies. This involves identifying and validating clinically accessible biomarkers (e.g., in blood or CSF) that reflect key exercise-induced changes, such as specific inflammatory cytokines (IL-10, TNF-α), neurotrophic factors (BDNF, NGF), or epigenetic markers. These biomarkers can serve as objective indicators for biomarker-guided prescriptions, predicting treatment response and tailoring therapy to the patient’s dominant pain pathophysiology. Advanced neuroimaging techniques (such as functional magnetic resonance imaging and magnetic resonance spectroscopy analysis) as well as quantitative sensory tests can also be employed to verify the mechanisms discovered in animals in humans, such as the restoration of cortical plasticity.
Developing Multimodal Strategies: Further exploration should investigate synergistic effects between exercise and nonpharmacological therapies such as neuromodulation and psychological interventions, in addition to pharmaceuticals, to develop multimodal pain management strategies that enhance comprehensive intervention outcomes.
Establishing Long-Term Efficacy: Implement long-term studies to track the effects of exercise on pain, quality of life, and functional recovery, providing evidence for its sustained benefits.

Acknowledgements

We want to express our gratitude for the drawing materials provided by Figdraw.com.

Author Contributions

Xiangmiao Li: Visualization, Writing-original draft, Writing-review and editing. Jinzhu Bai: Writing-review and editing. Both authors read and approved the final manuscript.

Funding

This work was supported by Beijing Science and Technology Planning Project (no. Z241100007724002).

Data Availability

No datasets were generated or analysed during the current study.

Declarations

Competing Interests

The authors declare no competing interests.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

No datasets were generated or analysed during the current study.

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PERMALINK

Mechanisms and Clinical Application Progress of Exercise in the Treatment of Neuropathic Pain

Xiangmiao Li

Jinzhu Bai

Abstract

Graphical Abstract

Introduction

Method

Fig. 1.

Preclinical Evidence on the Mechanisms of Exercise Therapy for NP

Exercise Improves Neuroinflammation

Table 1.

Role of Proinflammatory and Anti-inflammatory Cytokines

Fig. 2.

Role of Glial Cells

Role of Autophagy

The Alleviation of Oxidative Stress Through Exercise

Table 2.

The Regulation of Neuroplasticity by Exercise

Table 3.

Fig. 3.

DRG and the Spinal Cord

Encephalic Region

Effects of Exercise on the Descending Pain Modulatory System

Regulation of Gene Expression and Epigenetic Modifications by Exercise

Fig. 4.

The Predictive Role of EIH Capability

Clinical Exercise Programs and the Effects

Table 4.

Exercise Therapy for SCI-induced NP

Exercise Therapy for CIPN

Exercise Therapy for NP Caused by LDH

Exercise Therapy for DPN

Exercise Therapy for MS-induced NP

Exercise Therapy for SNPP

Conclusions and Outlook

Box 1: Future Directions.

Acknowledgements

Author Contributions

Funding

Data Availability

Declarations

Competing Interests

Footnotes

References

Associated Data

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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