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Abstract

Neuropathic pain affects approximately 7%–10% of the global population, significantly impairing patients’ quality of life and placing a substantial burden on public health systems. Current pharmacological treatments have limited efficacy and are often accompanied by notable side effects, highlighting the urgent need for novel therapeutic targets. Increasing evidence supports the important role of chemokines and their receptors in neuro-immune interactions underlying pain sensitization. Among these pathways, the CXCL12/CXCR4 axis has emerged as an important regulator of both the initiation and maintenance of neuropathic pain. Beyond its canonical function in immune cell trafficking, the CXCL12/CXCR4 axis modulates neuronal excitability, glial activation, synaptic plasticity, and nociceptive sensitization. Notably, this axis is frequently upregulated in both peripheral and central neurons, as well as in multiple glial populations, including astrocytes, microglia, and satellite glial cells, across diverse neuropathic pain models. Importantly, CXCR4 is one of the few chemokine receptors with a clinically approved antagonist, highlighting its unique translational potential. This review systematically summarizes the expression patterns, biological functions, and pain-related mechanisms of the CXCL12/CXCR4 axis in preclinical models of neuropathic pain and discusses current limitations and potential future therapeutic strategies targeting this pathway.

Keywords

Chemokine CXCL12 CXCR4 neuropathic pain nociceptive sensitization

Introduction

Pain is defined as an unpleasant sensory and emotional experience typically associated with actual or potential tissue damage.¹ As a subjective sensation, pain perception is influenced by biological, psychological, and social factors.² Acute pain is generally regarded as a protective mechanism, serving as a defense response to harmful stimuli, infections, or secondary injuries.^3,4 It typically occurs suddenly and lasts for a short duration. In contrast, chronic pain is characterized by persistent or recurrent pain lasting for more than 3 months.⁵ Neuropathic pain (NP) is a common type of chronic pain that arises from lesions or diseases affecting the peripheral nervous system (PNS) or central nervous system (CNS). Classic causes of peripheral NP include painful peripheral neuropathies induced by metabolic diseases (such as diabetes), inflammatory diseases (such as herpes zoster), and traumatic nerve injuries. In contrast, central NP is often caused by conditions such as spinal cord injury, stroke, and multiple sclerosis.⁶ The prevalence of NP in the general population is estimated to be approximately 7%–10%, accounting for 20%–25% of all patients with chronic pain,⁷ thereby imposing a substantial burden on both individuals and healthcare systems.^8,9 Compared with other types of chronic pain, NP is typically more severe and represents a major contributor to the global burden of disease.¹⁰ NP significantly impairs patients’ quality of life and may lead to psychological comorbidities, including anxiety, depression, and sleep disorders.^11,12 At present, analgesic drugs remain the cornerstone of pain management; however, their efficacy is often limited, and long-term use is associated with risks of drug dependence and adverse effects.¹³ Therefore, there is an urgent need to develop novel analgesic strategies to provide safer and more effective therapeutic options.

Extensive interactions between neurons, immune cells, and glial cells form the fundamental basis for the maintenance of chronic pain.¹⁴ During nociceptive transmission, neurotransmitters and cytokines released by primary sensory neurons act on immune and glial cells. In turn, the activated immune and glial cells promote the release of various inflammatory mediators, including pro-inflammatory cytokines and chemokines, which further sensitize sensory neurons. In chronic pain conditions, chemokines and their receptors function as modulators of neural plasticity and play a critical role in the amplification of nociceptive transmission, making them an emerging focus in pain research.¹⁵ Chemokines, as key signaling molecules, mediate interactions among neurons, glial cells, and immune cells and actively contribute to both peripheral and central sensitization processes. The chemokine CXCL12 and its receptor CXCR4 have been shown to be pathologically upregulated in various NP models, while inhibition of the CXCL12/CXCR4 axis significantly alleviates pain progression.¹⁶ Based on this evidence, further elucidation of the mechanisms underlying the CXCL12/CXCR4 axis may provide novel insights and therapeutic targets for NP.

Background of the CXCL12/CXCR4 axis pathway

Biological characteristics

Chemokines are a large family of highly conserved small proteins that regulate systemic immune responses and cell migration. Based on the positioning and spacing of two conserved N-terminal cysteine residues, chemokines are classified into four subfamilies: CXC, CC, CX3C, and C. CXCL12, also known as stromal cell-derived factor-1 (SDF-1), belongs to the CXC chemokine family and plays critical roles in angiogenesis, cell migration, stem cell maintenance, and neurogenesis. CXCR4, a transmembrane G protein-coupled receptor (GPCR), serves as the principal receptor for CXCL12 and participates in various biological processes, including organogenesis, immune responses, and hematopoiesis.

The intracellular signaling mediated by CXCR4 follows the classical activation mechanism of GPCRs. Upon CXCL12 binding to CXCR4, the receptor couples with heterotrimeric G proteins composed of Gαi, Gβ, and Gγ subunits. This interaction induces the exchange of GDP for GTP on the Gαi subunit, resulting in the dissociation of the G protein complex into a Gαi subunit and a Gβγ dimer. These components then activate several downstream signaling pathways, including the MAPK, PI3K, and PLC pathways. Additionally, the dissociated Gαi subunit can inhibit cyclic AMP (cAMP) production. Beyond G protein-dependent pathways, the CXCL12/CXCR4 interaction can also activate G protein-independent signaling cascades, such as the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway and the β-arrestin pathway. Through these diverse signaling mechanisms, the CXCL12/CXCR4 axis regulates key cellular processes including chemotaxis, cell survival, proliferation, transcription, and gene expression.^17,18 The specific downstream signaling events can vary depending on the cell type involved.

Unique features and translational relevance

CXCL12 and CXCR4 are widely expressed in both the PNS and CNS, providing an anatomical basis for their involvement in pain modulation. Knockout of either the CXCL12 or CXCR4 gene results in abnormal nervous system development in animal models,¹⁹ strongly suggesting their essential roles in neural function. In fact, dysregulation of the CXCL12/CXCR4 axis pathway has been implicated in various neurological disorders.²⁰ The CXCL12/CXCR4 axis participates in multiple key stages of nociceptive processing and coordinates pain signaling at both peripheral and central levels. In the PNS, it modulates the excitability of dorsal root ganglion (DRG) neurons and mediates neuron-glial interactions.²¹ At the spinal level, it contributes to the development and maintenance of central sensitization by enhancing neuronal excitability and promoting glial activation.^22–24 Through the integration of neuronal activity, glial responses, and inflammatory signaling, the CXCL12/CXCR4 axis may act as a central hub in neuro-immune interactions and contribute to the initiation and persistence of chronic pain.

From a translational perspective, CXCR4 is one of the few chemokine receptors with clinically approved antagonists. The CXCR4 antagonist AMD3100 (plerixafor) has been widely used for hematopoietic stem cell mobilization, supported by clinical data demonstrating a relatively well-characterized safety profile.^25–27 This provides a rationale for therapeutic targeting and potential drug repurposing. In contrast, several antagonists targeting other chemokine receptors, such as CCR2, have failed to achieve primary analgesic endpoints in randomized controlled trials involving patients with NP,^28,29 indicating that not all chemokine pathways engaged during inflammation and pain possess equivalent therapeutic potential. In this context, CXCR4 antagonists may represent potential therapeutic targets for NP.

Furthermore, the CXCL12/CXCR4 axis is highly conserved across species. The amino acid sequence identity of CXCR4 between humans and mice is approximately 89%, while the major CXCL12 isoforms (α and β) share approximately 92% sequence similarity.³⁰ In addition, downstream signaling pathways, including Gi protein-mediated PI3K and MAPK cascades, are largely conserved between humans and rodents.^31,32 This structural and functional conservation enhances the translational relevance of preclinical findings and provides a basis for the extrapolation of animal data to human pain biology.

Cell-type-specific expression landscape of CXCL12/CXCR4 revealed by single-cell transcriptomics

Although accumulating evidence supports the involvement of CXCL12/CXCR4 axis in NP, its precise cellular localization in the nervous system under physiological conditions remains incompletely defined. Previous studies have reported inconsistent findings regarding the distribution of CXCL12 and CXCR4 in the spinal cord and DRG,^33–37 which may be attributed to methodological differences, antibody specificity, and the limited resolution of conventional techniques. Recent advances in single-cell RNA sequencing (scRNA-seq) provide an opportunity to systematically characterize cell-type-specific expression patterns of this signaling axis. To address this issue, we analyzed publicly available scRNA-seq datasets from naïve mouse DRG (GSE298412) and spinal cord (GSE281205) to characterize the physiological distribution of CXCL12 and CXCR4.^38,39

After quality control, 16,600 cells from the mouse DRG were retained for downstream analysis. Unsupervised clustering identified 14 distinct clusters, which were further annotated into eight major cell types based on established marker genes: satellite glial cells (SGCs), myelinating Schwann cells (MSCs), non-myelinating Schwann cells (NMSCs), mural cells, fibroblasts, macrophages, endothelial cells, and neurons (Figure 1(a)). In parallel, 24,001 cells from the mouse spinal cord were included after quality control. These cells were grouped into 25 clusters and annotated into 11 major cell types, including microglia, ependymal cells, endothelial cells, oligodendrocytes, pericytes, neurons, dendritic cells, astrocytes, fibroblasts, T cells, and oligodendrocyte precursor cells (OPCs) (Figure 1(e)).

Figure 1.

Single-cell RNA sequencing analysis of the DRG and spinal cord from naïve mice: (a, e) t-distributed stochastic neighbor embedding (t-SNE) plots of cells derived from the DRG (a) and spinal cord (e), cell types were manually annotated based on previously reported marker genes,^38,39 (b, f) t-SNE feature plots showing the expression patterns of CXCL12 and CXCR4 across cell clusters in the DRG (b) and spinal cord (f), (c, g) dot plots illustrating the expression of CXCL12 and CXCR4 across different cell types in the DRG (c) and spinal cord (g), the color of the dots represents the average expression level, and the size of the dots indicates the percentage of cells expressing the gene, and (d, h) violin plots showing the expression levels of CXCL12 and CXCR4 across different cell types in the DRG (d) and spinal cord (h).

Analysis of gene expression patterns (Figure 1(b)–(d)) revealed that CXCL12 is predominantly expressed in endothelial cells, fibroblasts, and mural cells in the DRG, whereas its expression in SGCs and neurons is minimal. In contrast, CXCR4 is primarily enriched in SGCs and macrophages, with only low expression in neurons. In the spinal cord (Figure 1(f)–(g)), CXCL12 is primarily expressed in endothelial cells, fibroblasts, and pericytes, while showing relatively low expression in astrocytes, neurons, and microglia. Conversely, CXCR4 expression is mainly observed in ependymal cells, dendritic cells, and T cells, with limited expression in astrocytes and microglia, and minimal expression in neurons.

Collectively, these findings provide an overview of the baseline cell-type-specific expression landscape of CXCL12 and CXCR4 under physiological conditions. CXCL12 is predominantly expressed by vascular and stromal cells, whereas CXCR4 is mainly expressed in SGCs and immune-related populations, with minimal neuronal involvement. This baseline provides a critical reference for understanding how pathological upregulation and cellular redistribution of the CXCL12/CXCR4 axis may drive aberrant neuro-immune and neuro-glial interactions in NP.

CXCL12/CXCR4 axis in NP: Evidence from preclinical models

Traumatic nerve injury models

Spared nerve injury (SNI)

The SNI model is established by selectively transecting specific branches of the sciatic nerve, mimicking chronic pain conditions following peripheral nerve injury. In this model, plasma levels of CXCL12 are persistently elevated, and its concentration is positively correlated with pain intensity.^40,41 Although direct expression of CXCL12 has not been detected in the injured nerve tissue, the site exhibits a robust release of pro-inflammatory cytokines, chemokines, and adhesion molecules, which may contribute to the increased plasma CXCL12 levels.⁴⁰ Studies have demonstrated that a single intravenous injection of exogenous CXCL12 induces mechanical hypersensitivity in naïve mice, whereas repeated injections lead to persistent pain-like behaviors.⁴⁰ Furthermore, SNI induces upregulation of CXCL12 and its receptor CXCR4 in both neurons and satellite glial cells within the DRG, and a similar trend has also been reported in the spinal dorsal horn (SDH). Notably, in the spinal cord, CXCL12 is predominantly expressed in neurons and microglia, whereas CXCR4 is mainly found in neurons and astrocytes.⁴² These findings suggest that the CXCL12/CXCR4 axis is involved in SNI-induced pain hypersensitivity through coordinated actions in both the PNS and CNS. SNI also leads to sustained upregulation of TNF-α in the DRG and spinal cord. Treatment with the TNF-α synthesis inhibitor thalidomide significantly attenuates pain behaviors and suppresses CXCL12 expression in both regions,⁴² implying a key role for inflammatory cytokines in the upregulation of CXCL12. Additionally, SNI activates the ERK pathway in the spinal cord. Inhibition of the upstream MEK pathway effectively alleviates CXCL12-induced mechanical allodynia, highlighting ERK as a critical downstream effector of CXCL12 signaling.⁴²

Moreover, therapeutic strategies targeting the CXCL12/CXCR4 axis-such as administration of neutralizing antibodies against CXCL12, the CXCR4 antagonist AMD3100, or CXCR4-specific siRNA-have been reported to significantly alleviate SNI-induced pain hypersensitivity.^40,42,43

Spinal nerve ligation (SNL)

The SNL model is a classical paradigm for studying peripheral nerve injury-induced NP. In rats subjected to SNL, astrocytes and microglia in the SDH become activated, accompanied by upregulation of the CXCL12/CXCR4 axis and increased expression of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6.^44–46 Immunofluorescence analysis reveals that CXCL12 is predominantly expressed in neurons, while its receptor CXCR4 is significantly upregulated in both neurons and astrocytes. Intrathecal injection of CXCL12 induces mechanical hypersensitivity in naïve rats, and co-administration of CXCL12 with fluorocitrate, an astrocyte inhibitor, partially alleviates this effect, indicating that the pro-nociceptive effects of CXCL12 are partially mediated through astrocyte-dependent mechanisms.⁴⁵

Furthermore, administration of a neutralizing antibody against CXCL12 significantly reduces pain behaviors in SNL rats by suppressing the activation of both astrocytes and microglia. Similarly, intrathecal delivery of the CXCR4 antagonist AMD3100 has been shown to inhibit glial and neuronal activation and downregulates the expression of pro-inflammatory cytokines including TNF-α, IL-1β, and IL-6.⁴⁵ In addition, CXCR4 contributes to pain sensitization after SNL by downregulating the inhibitory glycine receptor subunit GlyRα3, thereby impairing inhibitory neurotransmission.⁴⁴

Partial sciatic nerve ligation (pSNL)

The pSNL model is another widely used paradigm for studying NP. In this model, both astrocytes and microglia are activated on the ipsilateral side of the spinal cord, and CXCR4 expression is significantly upregulated in the sciatic nerve tissue and spinal glial cells.^37,47 The CXCR4 antagonist effectively alleviates pain behaviors in pSNL mice.^22,37,47,48 Moreover, various pain-associated molecules, including TNF-α, IL-6, substance P (SP), and calcitonin gene-related peptide (CGRP), are elevated in the ipsilateral spinal cord following pSNL, while AMD3100 treatment reduces the expression of some of these inflammatory mediators, including TNF-α and IL-6.²² However, some discrepancies have been reported. For example, Luo et al.⁴⁸ found that under their experimental conditions, AMD3100 did not alter spinal TNF-α or IL-6 levels but significantly suppressed SP expression. Additionally, AMD3100 was shown to inhibit the expression of phosphorylated JNK1 (p-JNK1), p-p38, and p65 in the spinal cord, while having little effect on the activation of ERK1, ERK2, and JNK2. Notably, microRNAs (miRNAs), as important post-transcriptional regulators, also play a role in modulating CXCR4 expression in the pSNL model. Pan et al.³⁷ demonstrated that miR-23a targets CXCR4 and regulates the TXNIP/NLRP3 signaling pathway in glial cells, thereby contributing to pain modulation.

Chronic constriction injury (CCI)

The CCI model is a well-established paradigm for investigating the mechanisms of NP. Multiple studies have confirmed that the expression of CXCL12 and its receptor CXCR4 is significantly upregulated in the spinal cord of CCI rats,^49–53 where these molecules colocalize with neurons, astrocytes, and microglia.⁵⁰ After CCI, the expression of CXCR4 is notably elevated in DRG neurons and satellite glial cells (SGCs). In contrast, CXCL12 expression in the DRG exhibits a biphasic expression pattern: it decreases markedly during the early stage (days 1–3) but partially recovers by day 14.³³ However, another study reported a continuous increase of CXCL12 in the DRG post-CCI.⁴⁹ Additionally, serum levels of CXCL12 are also elevated after CCI.⁵⁴

The enhanced CXCL12/CXCR4 axis activates downstream pathways such as NLRP3 and RhoA/ROCK2, which in turn promote the release of pro-inflammatory cytokines and exacerbate pain sensitization.^24,50,53 Epigenetic regulation also influences CXCR4 expression. For instance, miR-130a-5p, by interacting with the long non-coding RNA MEG3 to form a competing endogenous RNA (ceRNA) network, suppresses CXCL12/CXCR4 expression and inhibits activation of the Rac1/NF-κB pathway.⁵¹ Similarly, miR-185-5p and miR-381 target CXCR4 to reduce neuroinflammation and neuronal apoptosis, thereby alleviating NP.^52,53 Furthermore, administration of the CXCR4 antagonist AMD3100 has been shown to alleviate CCI-induced pain hypersensitivity. However, one study reported that although AMD3100 effectively reversed thermal hyperalgesia, its effect on mechanical allodynia was limited, suggesting that the CXCL12/CXCR4 axis may play differential roles in distinct pain modalities.³³

Other traumatic nerve injury models

In the chronic compression of DRG (CCD) model, the expression levels of both CXCL12 and CXCR4 are significantly upregulated in the DRG, with CXCR4 predominantly localized in small- and medium-diameter neurons.⁵⁵ CCD also induces marked increases in voltage-gated sodium channels Nav1.8 and Nav1.9 in DRG neurons. These changes can be effectively suppressed by AMD3100 administration, leading to attenuation of NP behaviors.⁵⁶

In the spinal cord injury (SCI) model, sustained upregulation of CXCL12 has been observed in the spinal cord.⁵⁷ Intravenous administration of a miR-130a-5p mimic significantly downregulates CXCL12 expression and inhibits the activation of its downstream pathways, thereby effectively alleviating SCI-induced NP.⁵⁸ However, some studies have reported a decrease in CXCL12 expression within spinal neurons following SCI,⁵⁹ suggesting that the increased CXCL12 levels may derive mainly from non-neuronal sources.

In the complete sciatic nerve transection (CSNT) model, the expression of both CXCL12 and CXCR4 in the DRG is also upregulated. Intrathecal injection of AMD3100 suppresses STAT3 expression, while exogenous administration of IL-6 promotes the expression of CXCR4, indicating that the CXCL12/CXCR4 axis may be involved in IL-6/STAT3-mediated neuroinflammatory responses.⁶⁰

In the focal demyelination model of the sciatic nerve, CXCR4 expression is elevated in DRG neurons.⁶¹ Moreover, CXCL12 has been shown to induce intracellular calcium increases in these neurons,^61,62 suggesting a potential role in sensitization and pain signaling.

Overall, the CXCL12/CXCR4 axis is consistently dysregulated across multiple traumatic nerve injury models. Through modulation of neuron–glia interactions, inflammatory cytokine networks, and epigenetic mechanisms, this pathway appears to contribute to the development and maintenance of NP. Although pharmacological targeting of the CXCL12/CXCR4 axis has shown analgesic effects in preclinical studies, further investigation is warranted to determine its translational potential in clinical settings.

Central neuropathic pain models

Central post-stroke pain (CPSP) is a challenging and treatment-resistant form of NP that typically arises following damage to the thalamus or other central structures after a stroke. In an animal model of CPSP induced by the injection of type IV collagenase into the thalamus, both CXCL12 and CXCR4 are significantly upregulated in the hemorrhagic area, and CXCL12 expression is positively correlated with the severity of pain hypersensitivity. Local blockade of CXCR4 in the thalamus effectively prevents both the development and maintenance of CPSP.⁶³ Furthermore, even in naïve rats, direct thalamic injection of CXCL12 is sufficient to induce mechanical hypersensitivity, which can be suppressed by the CXCR4 antagonist AMD3100.⁶³ Notably, thalamic hemorrhage also induces secondary neuroinflammatory responses in distant regions such as the SDH, leading to activation of the spinal CXCL12/CXCR4 axis. Intrathecal administration of AMD3100 significantly alleviates bilateral mechanical hypersensitivity following thalamic hemorrhagic stroke (THS), suggesting that CXCL12/CXCR4 is also involved in the modulation of CPSP via spinal mechanisms.⁶⁴ Collectively, these findings indicate that the CXCL12/CXCR4 axis contributes to CPSP through a dual mechanism – local activation in the thalamus and distant regulation within the spinal cord. These findings suggest that targeting this pathway may offer a potential therapeutic approach for CPSP, although further validation is required.

Diabetic neuropathic pain (DNP)

DNP, a common chronic complication of diabetes, primarily results from diabetes-induced damage to the nervous system, especially peripheral neuropathy. Various DNP animal models have been established using high-fat diet (HFD) induction, streptozotocin (STZ) administration, or genetically modified mice (e.g. C57BLKS db/db mice). Across these models, the CXCL12/CXCR4 axis consistently appears to play an important role.^65–71 In HFD-induced DNP mice, the CXCL12/CXCR4 pathway is markedly upregulated in DRG neurons, and exposure to CXCL12 elicits a pronounced calcium influx response in these neurons.⁶⁷ Knockout of the CB2 gene suppresses the upregulation of CXCR4 and the development of hyperalgesia, suggesting a modulatory role of CB2 in peripheral sensitization.⁷² Additionally, studies have shown that Nav1.8-positive DRG neurons are closely associated with mechanical hypersensitivity and small fiber degeneration in DNP mice. Selective deletion of CXCR4 in these neurons reverses both pain behavior and fiber degeneration.⁶⁶ In STZ-induced DNP rat models, CXCR4 expression is increased in both the DRG and SDH, with changes in the DRG preceding those in the SDH, indicating that peripheral sensitization may initiate central sensitization.⁷¹ High-mobility group box 1 (HMGB1) indirectly enhances CXCR4-mediated inflammatory responses in both DRG and SDH, whereas administration of the HMGB1 inhibitor glycyrrhizin (GLC) significantly reduces CXCR4 expression and increases pain threshold (i.e. reduces pain sensitivity).⁶⁹ These findings suggest that CXCL12/CXCR4 axis contributes to DNP pathogenesis at both peripheral and central levels. Furthermore, CXCL12/CXCR4 axis in the brain is also implicated in DNP. In the anterior cingulate cortex (ACC) of DNP mice, activated microglia upregulate CXCL12/CXCR4, leading to hyperactivity of ACC glutamatergic neurons and exacerbation of pain perception.⁶⁸

Therapeutic studies targeting the CXCL12/CXCR4 pathway further support its analgesic potential. Intraperitoneal injection of the CXCR4 antagonist AMD3100 effectively alleviates DNP-associated pain behavior in animal models.^65,67,70 However, in advanced stages of DNP, despite sustained high expression of CXCR4, the analgesic efficacy of AMD3100 diminishes, likely due to a cascade amplification of inflammatory mediators (such as CXCL12 and TNF-α) driven by chronic CXCR4 activation.⁷⁰ Moreover, whole blood analysis reveals that expression levels of MALAT1 and CXCR4 are significantly correlated with the presence of NP in diabetic patients, suggesting that targeting MALAT1 and CXCR4 may offer a novel therapeutic strategy for DNP.⁷³

In summary, current evidence suggests a multilayered involvement of the CXCL12/CXCR4 axis in the pathogenesis of DNP, spanning peripheral nerve injury, central sensitization, and neuro-glial network imbalance. Targeted interventions against this pathway have demonstrated analgesic effects in preclinical models; however, their efficacy may vary depending on disease stage, underscoring the need for further investigation to optimize therapeutic strategies.

HIV-associated neuropathic pain (HIV-NP)

HIV-NP is a common complication in people living with HIV, primarily resulting from peripheral nerve injury induced by HIV infection or antiretroviral drugs such as didanosine (ddC). Both mechanisms contribute to sensory deficits and NP. In animal models, HIV gp120 is used to mimic viral injury, while ddC represents antiretroviral drug toxicity. Studies have demonstrated that the CXCL12/CXCR4 axis plays a key role in both gp120- and ddC-induced NP. In both models, TNF-α, CXCL12, and CXCR4 are significantly upregulated in the spinal cord and DRG. Blocking TNF-α significantly alleviates mechanical allodynia and reverses the upregulation of CXCL12/CXCR4 in the spinal cord and DRG.^74,75 Similarly, viral vector-mediated overexpression of the anti-inflammatory cytokine IL-10 alleviates pain hypersensitivity and concurrently downregulates spinal cord and DRG levels of p-p38, TNF-α, CXCL12, and CXCR4.^76,77 In the gp120 model, SGCs in the DRG exhibit specific and pronounced upregulation of CXCL12. CXCR4 expression appears to be cell type-dependent. Some studies report its upregulation in both neurons and SGCs,⁷⁸ while others have observed increased CXCR4 expression restricted to small- and medium-diameter neurons.⁷⁹ Administration of the CXCR4 antagonist AMD3100 significantly reduces pain behaviors in both gp120- and ddC-induced models, further supporting the involvement of the CXCL12/CXCR4 axis in HIV-NP.^75,78,79 These findings highlight the interplay between neuroinflammatory processes and chemokine signaling in HIV-associated neuropathy and suggest that the CXCL12/CXCR4 pathway may represent a potential therapeutic target. Future studies are needed to further elucidate downstream effectors of this signaling axis to enable more precise analgesic strategies.

Intervertebral disc degeneration-associated low back pain

Intervertebral disc degeneration (IVDD) is a common cause of low back pain, and during disease progression, it can lead to nerve root compression and nerve injury, with some patients exhibiting features of NP. In degenerated intervertebral disc tissues, the expression of CXCL12 and its receptor CXCR4 is significantly upregulated.^80–82 Studies have shown that stimulation of degenerated nucleus pulposus cells with CXCL12 induces increased apoptosis and elevated phosphorylation of p65 in the NF-κB signaling pathway, whereas transfection with CXCR4 siRNA can inhibit these changes.⁸¹ Furthermore, CXCL12 promotes CXCR4 expression and upregulates matrix metalloproteinases (MMPs) at both the mRNA and protein levels in cartilage endplate cells, thereby accelerating extracellular matrix (ECM) degradation.⁸³ Interfering with CXCL12/CXCR4 axis can effectively inhibit the production of pro-inflammatory mediators, delay ECM breakdown and disc degeneration, and alleviate pain symptoms.^83–87 Angiogenesis is a hallmark pathological feature of IVDD and is closely correlated with the severity of degeneration.⁸⁸ CXCL12 participates in this process via binding to either CXCR4 or CXCR7.^89,90 Notably, CXCL12 also plays a positive role in disc regeneration. Its chemotactic signaling with CXCR4 enhances the recruitment and chondrogenic differentiation potential of nucleus pulposus–derived stem cells (NPSCs).⁹¹ In addition, CXCL12 promotes the proliferation of nucleus pulposus cells (NPCs) via cartilage endplate stem cells (CESCs), an effect that is significantly inhibited by AMD3100.⁹² Although CXCL12 contributes to ECM degradation, moderate matrix remodeling may facilitate the migration of endogenous stem cells toward degenerated regions, thus promoting tissue repair and regeneration.⁸³ In summary, the CXCL12/CXCR4 axis plays critical roles in both the pathogenesis and regeneration of IVDD, exerting dual regulatory effects and representing a potential therapeutic target for IVDD-associated low back pain.

Chemotherapy-induced peripheral neuropathy (CIPN)

CIPN represents a significant clinical challenge during cancer treatment, often leading to dysesthesia and abnormal pain sensations. Chemokine signaling has been implicated as an important mediator in CIPN pathogenesis.⁹³ Studies have shown that intraperitoneal administration of paclitaxel or vincristine activates the STAT3 signaling pathway in SDH neurons. This activation enhances histone acetylation at the CXCL12 gene promoter, thereby increasing CXCL12 mRNA and protein expression. Blocking CXCR4 attenuates mechanical allodynia induced by paclitaxel or vincristine.⁹⁴ Similarly, repeated intraperitoneal injections of oxaliplatin activate STAT3 and upregulate CXCL12 expression in the DRG; inhibition of STAT3 expression prevents CXCL12 elevation in the DRG and attenuates oxaliplatin-induced chronic pain.⁹⁵ Paclitaxel also activates spinal astrocytes, promoting the release of pro-inflammatory mediators such as TNF-α and CXCL12. Administration of TNF-α or CXCL12 neutralizing antibodies reverses paclitaxel-induced mechanical allodynia.⁹⁶ Oxaliplatin treatment also induces elevated serum levels of TNF-α and CXCL12.⁹⁷ Bioinformatic analyses further reveal a strong association between CXCR4 expression and the incidence, severity, and susceptibility of CIPN.⁹⁸ However, a single intraperitoneal injection of AMD3100 failed to effectively relieve cisplatin- or paclitaxel-induced mechanical or cold hypersensitivity within a short-term (3-hour) window.⁹⁹ Collectively, these findings suggest that the CXCL12/CXCR4 axis is involved in the initiation and progression of CIPN. Nonetheless, its precise mechanisms and therapeutic efficacy remain to be fully elucidated, highlighting the need for further studies to develop more reliable therapeutic strategies for CIPN management.

Conclusions and future perspectives

This review systematically summarizes the biological functions, cellular distribution, and roles of the CXCL12/CXCR4 axis in pain signal transmission, with a particular focus on its potential involvement in the initiation and maintenance of NP. Although initially characterized in the context of immune cell trafficking, CXCL12/CXCR4 axis has also been implicated in broader neurobiological processes, including neurodevelopment, neuronal survival, synaptic plasticity, and CNS homeostasis.¹⁰⁰ These broader roles suggest that CXCL12/CXCR4 axis may extend beyond physiological functions to influence pathological processes, including pain modulation.¹⁰¹ In multiple NP models, upregulation of the CXCL12/CXCR4 axis has been observed in both peripheral and central neurons, as well as in various types of glial cells, including astrocytes and microglia in the CNS and SGCs in the PNS (Table 1). Together, these observations indicate that CXCL12/CXCR4 axis may act as an active contributor to pain processing, rather than merely reflecting injury-associated changes.

Table 1.

Cellular distribution of the CXCL12/CXCR4 axis in preclinical models of neuropathic pain.

Tissue type	Model type	Cell type	Colocalized with	References
Anterior cingulate cortex	DNP (C57BL/6 mice, male)	Microglia	CXCL12	Song et al.⁶⁸
Anterior cingulate cortex	DNP (C57BL/6 mice, male)	Glutamatergic neuron	CXCR4	Song et al.⁶⁸
Dorsal root ganglion	SNI (SD rat, male)	Neuron SGCs	CXCL12/CXCR4 CXCL12/CXCR4	Bai et al.⁴²
	CCI (Wistar rat, male)	SGCs	CXCL12/CXCR4	Dubový et al.³³
		Neuron	CXCR4	Dubový et al.³³
	DNP (C57BL/6 mice, male)	Neuron	CXCL12/CXCR4	Menichella et al.⁶⁷
	DNP (Transgenic mice)	Na_v1.8⁺ neuron	CXCR4	Jayaraj et al.⁶⁶
	DNP (ZDF rats, male)	Neuron	CXCR4	Thakur et al.⁶⁹
	HIV-NP (SD rat, female)	SGCs	CXCL12/CXCR4	Bhangoo et al.⁷⁸
	HIV-NP (SD rat, female)	Neuron	CXCR4	Bhangoo et al.⁷⁸
	HIV-NP (SD rat, female)	Neuron	CXCR4	Bhangoo et al.⁷⁹
	CSNT (Wistar rat, male)	Neuron	CXCL12	Dubový et al.⁶⁰
	Sciatic nerve demyelination (SD rat, female)	Neuron	CXCR4	Bhangoo et al.⁶¹
Spinal cord	SNI (SD rat, male)	Microglia	CXCL12	Bai et al.⁴²
		Astrocyte	CXCR4
		Neuron	CXCL12/CXCR4
	SNL (SD rat, male)	Neuron	CXCL12/CXCR4	Liu et al.⁴⁵
	SNL (SD rat, male)	Astrocyte	CXCR4	Liu et al.⁴⁵
	CCI (SD rat, male)	NeuronAstrocyteMicroglia	CXCL12/CXCR4CXCL12/CXCR4CXCL12/CXCR4	Cheng et al.⁵⁰
	DNP (SD rat, male)	NeuronAstrocyte	CXCR4CXCR4	Zhu et al.⁷⁰
	CIPN (SD rat, male)	Neuron	CXCL12	Xu et al.⁹⁴
	CIPN (CD1 mice, male and female)	Astrocyte	CXCL12	Liu et al.⁹⁶
	SCI (Long Evans rats, male)	AstrocyteMicrogliaSP⁺ fibersCGRP⁺ fibers	CXCL12/CXCR4CXCL12/CXCR4CXCL12/CXCR4CXCL12/CXCR4	Knerlich-Lukoschus et al.⁵⁷
	pSNL (C57BL/6 mice, male)	AstrocyteMicroglia	CXCR4CXCR4	Pan et al.³⁷

CCI: chronic constriction injury; CGRP: calcitonin gene-related peptide; CIPN: chemotherapy-induced peripheral neuropathy; CSNT: complete sciatic nerve transection; DNP: diabetic neuropathic pain; HIV-NP: HIV-associated neuropathic pain; pSNL: partial spinal nerve ligation; SCI: spinal cord injury; SGCs: satellite glial cells; SNI: spared nerve injury; SNL: spinal nerve ligation; SP: substance P.

In recent years, a growing number of preclinical studies have evaluated the effects of CXCR4 antagonists across diverse NP models (summarized in Table 2). Across these studies, CXCR4 blockade has generally been associated with reductions in mechanical allodynia and/or thermal hyperalgesia. Mechanistic investigations suggest that the CXCL12/CXCR4 axis may contribute to the development and maintenance of peripheral and central sensitization through coordinated regulation of neuronal excitability, glial activation, and neuroinflammatory responses (Figure 2). However, the relative contribution of these mechanisms likely varies depending on the injury context and disease stage.

Table 2.

Preclinical evidence for the analgesic effects of CXCR4 antagonists in neuropathic pain.

Antagonist	Target	Model type	Effects	References
AMD3100	CXCR4	SNL (SD rat, male)	Attenuated mechanical allodynia and thermal hyperalgesia.	Liu et al.⁴⁵
AMD3100	CXCR4	SNL (SD rat, male)	Alleviated mechanical allodynia.	Liu et al.⁴⁴
AMD3100	CXCR4	pSNL (C57BL/6 mice, male)	Attenuated mechanical allodynia.	Luo et al.²²
AMD3465	CXCR4	pSNL (C57BL/6 mice, male)	Attenuated mechanical allodynia.	Luo et al. ²²
AMD3100	CXCR4	pSNL (C57BL/6 mice, male)	Reversed mechanical allodynia and thermal hyperalgesia.	Pan et al.³⁷
AMD3100	CXCR4	pSNL (C57BL/6 mice, male)	Attenuated mechanical allodynia.	Luo et al.⁴⁸
AMD3100	CXCR4	CCI (C57BL/6 mice, male)	Reversed EphA1-induced mechanical allodynia and thermal hyperalgesia.	Li et al.²⁴
AMD3100	CXCR4	CCI (Wistar rat, male)	Reversed thermal hyperalgesia but failed to significantly attenuate mechanical allodynia.	Dubový et al.³³
AMD3100	CXCR4	DNP (C57BL/6 mice, male)	Reversed mechanical allodynia in two type II diabetic models.	Menichella et al.⁶⁷
AMD3100	CXCR4	DNP (Wistar rat, unspecified)	Attenuated mechanical allodynia.	da Silva Junior et al.⁶⁵
AMD3100	CXCR4	DNP (SD rat, male)	Reversed mechanical allodynia and thermal hyperalgesia.	Zhu et al.⁷⁰
AMD3100	CXCR4	HIV-NP (SD rat, female)	Attenuated mechanical allodynia.	Bhangoo et al.⁷⁸
AMD3100	CXCR4	HIV-NP (SD rat, female)	Reversed mechanical allodynia induced by combined gp120 and antiretroviral drug treatment.	Bhangoo et al.⁷⁹
AMD3100	CXCR4	HIV-NP (SD rat, male)	Attenuated gp120-induced mechanical allodynia.	Huang et al.⁷⁴
AMD3100	CXCR4	HIV-NP (SD rat, male)	Attenuated mechanical allodynia.	Huang et al.⁷⁵
AMD3100	CXCR4	CIPN (SD rat, male)	Failed to attenuate cisplatin- or paclitaxel-induced mechanical allodynia and cold allodynia.	Deng et al.⁹⁹
AMD3100	CXCR4	CCD (SD rat, male)	Attenuated mechanical allodynia.	Yang et al.⁵⁶
FC131	CXCR4	pSNL (ICR mice, male)	Attenuated mechanical allodynia and thermal hyperalgesia.	Kiguchi et al.⁴⁷

CCI: chronic constriction injury; CIPN: chemotherapy-induced peripheral neuropathy; DNP: diabetic neuropathic pain; HIV-NP: HIV-associated neuropathic pain; pSNL: partial spinal nerve ligation; SNL: spinal nerve ligation.

Figure 2.

CXCL12/CXCR4 axis-mediated neuron-glia crosstalk in peripheral and central sensitization of neuropathic pain.

Notably, the availability of clinically approved CXCR4 antagonists provides a practical basis for exploring the translational potential of targeting this pathway. AMD3100 (plerixafor), originally developed for hematopoietic stem cell mobilization, has accumulated clinical evidence supporting its pharmacokinetic and safety profiles.^25–27 However, despite these advantages, CXCR4-targeted therapies have not yet been systematically evaluated in clinical pain trials, and their efficacy in human NP remains uncertain.

Despite encouraging preclinical findings, several important limitations should be considered. First, current studies on the CXCL12/CXCR4 axis largely rely on global interventions, with limited cell-specific genetic evidence. As complete deficiency of CXCL12 or CXCR4 results in perinatal lethality, the use of conventional knockout models is restricted.^102,103 Therefore, the development of cell-specific genetic approaches will be important for clarifying its roles in distinct cellular contexts. Second, it is now recognized that pain circuits exhibit sex-based differences,¹⁰⁴ and the CXCL12/CXCR4 axis may also demonstrate sex-specific patterns in pain modulation. Although women account for the majority of chronic pain patients, preclinical studies have predominantly utilized male animal models. Therefore, inclusion of both sexes in future studies will be important to improve translational relevance. Third, the spatiotemporal dynamics of CXCL12/CXCR4 axis during different stages of NP remain incompletely understood. Given the dynamic activation of glial cells under pathological conditions,¹⁰⁵ further studies are needed to delineate how this axis is regulated across disease progression. Such investigations may help clarify stage-dependent mechanisms underlying pain initiation and maintenance and provide a basis for temporally targeted therapeutic strategies.

In addition, the long-term safety of targeting CXCR4 warrants careful consideration. The CXCL12/CXCR4 axis plays essential roles in immune homeostasis, cardiovascular function, neurogenesis, and tumor biology. Prolonged systemic blockade of this pathway may therefore interfere with immune regulation or tissue repair processes. Although clinical studies in oncology have shown that CXCR4 antagonists are generally well tolerated, with adverse event rates comparable to control treatments,¹⁰⁶ their safety profile in the context of chronic pain, where long-term or repeated administration may be required, remains insufficiently characterized. In particular, the potential effects on immune function, neural plasticity, and central reward circuits require further systematic evaluation. Although no evidence currently suggests that CXCR4 antagonists possess addictive properties, the possible functional overlap between chemokine signaling and dopaminergic or affective regulatory pathways warrants further investigation of long-term neurobehavioral outcomes.¹⁰⁷

Based on current evidence, several directions may help advance the clinical translation of CXCL12/CXCR4-targeted interventions. First, drug repurposing may represent a feasible approach. Leveraging the existing clinical safety data for AMD3100, further exploration of its localized or short-term application in specific NP subtypes may help accelerate translational progress. Second, gene- and RNA-based therapeutic approaches, such as siRNA, shRNA, or CRISPR systems targeting CXCL12 or CXCR4, may provide promising strategies for region- and cell-specific modulation of this signaling axis, potentially preserving analgesic efficacy while minimizing systemic side effects.¹⁰⁸ Third, nanoparticle-based targeted delivery systems may offer an innovative technical avenue for CXCL12/CXCR4 modulation.¹⁰⁹ By directing CXCR4 antagonists to the DRG or spinal cord, such approaches may help enhance local analgesic effects while reducing required doses.

Overall, the CXCL12/CXCR4 axis may represent an important component of neuroimmune signaling in NP. However, its precise cellular contributions, temporal dynamics, and clinical utility remain to be fully clarified. Addressing these gaps will be critical for determining whether targeting this pathway can be effectively translated into clinically meaningful pain therapies.

Footnotes

Author contributions

Ming Li and Xiaoxiao Lu contributed to the literature review and drafting of the manuscript. Luyao Cai and Tao Zhu participated in manuscript revision and editing. Jin Cui supervised the study and revised the manuscript critically for important intellectual content. All authors read and approved the final manuscript.

Data availability

No new data were generated or analyzed in support of this review. All information discussed is based on previously published literature.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The present project is supported by the Graduate Research Funding Program of Guizhou Province (2024YJSKYJJ351).

ORCID iDs

Ming Li

Jin Cui

References

Raja

Carr

Cohen

Finnerup

N.B

Flor

Gibson

Keefe

Mogil

Ringkamp

Sluka

Song

Stevens

Sullivan

Tutelman

Ushida

Vader

. The revised International Association for the Study of Pain definition of pain: concepts, challenges, and compromises. Pain 2020; 161: 1976–1982.

Gatchel

Peng

Peters

Fuchs

Turk

. The biopsychosocial approach to chronic pain: scientific advances and future directions. Psychol Bull 2007; 133: 581–624.

Julius

Basbaum

. Molecular mechanisms of nociception. Nature 2001; 413: 203–210.

Yang

Jacobson

Meerschaert

Sifakis

Chen

Yang

Zhou

Anekal

Rucker

Sharma

Sontheimer-Phelps

Deng

Anderson

Choi

Neel

Lee

Kasper

Jabri

Huh

Johansson

Thiagarajah

Riesenfeld

Chiu

. Nociceptor neurons direct goblet cells via a CGRP-RAMP1 axis to drive mucus production and gut barrier protection. Cell 2022; 185: 4190–4205.e4125.

Treede

Rief

Barke

Aziz

Bennett

Benoliel

Cohen

Evers

Finnerup

First

Giamberardino

Kaasa

Kosek

Lavand’homme

Nicholas

Perrot

Scholz

Schug

Smith

Svensson

Vlaeyen

JWS

Wang

. A classification of chronic pain for ICD-11. Pain 2015; 156: 1003–1007.

Rosner

de Andrade

Davis

Gustin

Kramer

JL.K

Seal

Finnerup

. Central neuropathic pain. Nat Rev Dis Prime 2023; 9: 73.

Bouhassira

. Neuropathic pain: definition, assessment and epidemiology. Rev Neurol 2019; 175: 16–25.

Zou

Guo

Han

Fan

Zang

Huang

. Global burden of low back pain and its attributable risk factors from 1990 to 2021: a comprehensive analysis from the global burden of disease study 2021. Front Public Health 2024; 12: 1480779.

Stubhaug

Hansen

Hallberg

Gustavsson

Eggen

Nielsen

. The costs of chronic pain-long-term estimates. Eur J Pain (Lond, Engl) 2024; 28: 960–977.

10.

Baskozos

Hébert

Pascal

Themistocleous

Macfarlane

Wynick

Bennett

Smith

. Epidemiology of neuropathic pain: an analysis of prevalence and associated factors in UK Biobank. Pain Rep 2023; 8: e1066.

11.

Vieira

Coelho

DR.A

Litwiler

McEachern

Clancy

Morales-Quezada

Cassano

. Neuropathic pain, mood, and stress-related disorders: a literature review of comorbidity and co-pathogenesis. Neurosci Biobehav Rev 2024; 161: 105673.

12.

Wang

Zhang

Duan

Zhang

Liu

Yang

Liu

. Association between mental disorders and trigeminal neuralgia: a cohort study and Mendelian randomization analysis. J Headache Pain 2025; 26: 74.

13.

Nwankwo

Koyyalagunta

Huh

D’Souza

Javed

. A comprehensive review of the typical and atypical side effects of gabapentin. Pain Pract 2024; 24: 1051–1058.

14.

Zhang

Cui

Liang

Jia

Guo

Zhang

. The core of maintaining neuropathic pain: crosstalk between glial cells and neurons (neural cell crosstalk at spinal cord). Brain Behav 2023; 13: e2868.

15.

Pawlik

Mika

. Targeting members of the chemokine family as a novel approach to treating neuropathic pain. Molecules (Basel, Switz) 2023; 28:155766.

16.

Chen

Xia

Liu

Fang

. The CXCL12/CXCR4 axis: an emerging therapeutic target for chronic pain. J Pain Res 2025; 18: 2583–2603.

17.

Yang

Lei

Wang

Liu

Yan

Tian

Wang

Yang

Wang

. CXCL12-CXCR4/CXCR7 Axis in Cancer: from Mechanisms to Clinical Applications. Int J Biol Sci 2023; 19: 3341–3359.

18.

Yen

Chang

Hsu

Yang

Mani

Liou

. C-X-C motif chemokine ligand 12-C-X-C chemokine receptor type 4 signaling axis in cancer and the development of chemotherapeutic molecules. Tzu Chi Med J 2024; 36: 231–239.

19.

Zou

Kottmann

Kuroda

Taniuchi

Littman

. Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature 1998; 393: 595–599.

20.

Yan

Zhang

. The CXCL12/CXCR4/ACKR3 response axis in chronic neurodegenerative disorders of the central nervous system: therapeutic target and biomarker. Cell Mole Neurobiol 2022; 42: 2147–2156.

21.

Yang

Sun

Yang

Wang

Yang

Chen

. SDF1-CXCR4 signaling contributes to persistent pain and hypersensitivity via regulating excitability of primary nociceptive neurons: involvement of ERK-dependent Nav1.8 up-regulation. J Neuroinflam 2015; 12: 219.

22.

Luo

Tai

Sun

Pan

Xia

Chung

Cheung

. Crosstalk between astrocytic CXCL12 and microglial CXCR4 contributes to the development of neuropathic pain. Mole Pain 2016; 12: 6385.

23.

Zhang

Chen

Cui

Yang

Shen

. Chemokine receptor CXCR4 regulates CaMKII/CREB pathway in spinal neurons that underlies cancer-induced bone pain. Sci Rep 2017; 7: 4005.

24.

Zhu

Chu

Chen

Zhang

Gao

Chen

. EphA1 aggravates neuropathic pain by activating CXCR4/RhoA/ROCK2 pathway in mice. Human Cell 2023; 36: 1416–1428.

25.

De Clercq

. Mozobil^® (Plerixafor, AMD3100), 10 years after its approval by the US Food and Drug Administration. Antiviral Chem Chemother 2019; 27: 829382.

26.

McDermott

Velez

Cho

Cowen

DiGiovanna

Pastrana

Buck

Calvo

Gardner

Rosenzweig

Stratton

Merideth

Kim

Brewer

Katz

Kuhns

Malech

Follmann

Fay

Murphy

. A phase III randomized crossover trial of plerixafor versus G-CSF for treatment of WHIM syndrome. J Clin Invest 2023; 133: 164918.

27.

Sidana

Bankova

Hosoya

Kumar

Holmes

Tamaresis

Muffly

Maysel-Auslender

Johnston

Arai

Lowsky

Meyer

Rezvani

Weng

Frank

Shiraz

Maecker

Miklos

Shizuru

. Phase II study of novel CXCR2 agonist and Plerixafor for rapid stem cell mobilization in patients with multiple myeloma. Blood Cancer J 2024; 14: 173.

28.

Kalliomäki

Attal

Jonzon

Bach

Huizar

Ratcliffe

Eriksson

Janecki

Danilov

Bouhassira

. A randomized, double-blind, placebo-controlled trial of a chemokine receptor 2 (CCR2) antagonist in posttraumatic neuralgia. Pain 2013; 154: 761–767.

29.

Kalliomäki

Jonzon

Huizar

O’Malley

Andersson

Simpson

. Evaluation of a novel chemokine receptor 2 (CCR2)-antagonist in painful diabetic polyneuropathy. Scandinav J Pain 2013; 4: 77–83.

30.

Döring

Pawig

Weber

Noels

. The CXCL12/CXCR4 chemokine ligand/receptor axis in cardiovascular disease. Front Physiol 2014; 5: 212.

31.

Delgado-Martín

Escribano

Pablos

Riol-Blanco

Rodríguez-Fernández

. Chemokine CXCL12 uses CXCR4 and a signaling core formed by bifunctional Akt, extracellular signal-regulated kinase (ERK)1/2, and mammalian target of rapamycin complex 1 (mTORC1) proteins to control chemotaxis and survival simultaneously in mature dendritic cells. J Biol Chem 2011; 286: 37222–37236.

32.

Tian

Yin

Deng

Tang

Ren

Jiang

. CXCL12 induces migration of oligodendrocyte precursor cells through the CXCR4-activated MEK/ERK and PI3K/AKT pathways. Mole Med Rep 2018; 18: 4374–4380.

33.

Dubový

Klusáková

Svízenská

Brázda

. Spatio-temporal changes of SDF1 and its CXCR4 receptor in the dorsal root ganglia following unilateral sciatic nerve injury as a model of neuropathic pain. Histochem Cell Biol 2010; 133: 323–337.

34.

Wilson

Jung

Ripsch

Miller

White

. CXCR4 signaling mediates morphine-induced tactile hyperalgesia. Brain Behav Immun 2011; 25: 565–573.

35.

Reaux-Le Goazigo

Rivat

Kitabgi

Pohl

Melik Parsadaniantz

. Cellular and subcellular localization of CXCL12 and CXCR4 in rat nociceptive structures: physiological relevance. Eur J Neurosci 2012; 36: 2619–2631.

36.

Shen

Liu

Han

Chen

Wang

Song

. CXCL12 in astrocytes contributes to bone cancer pain through CXCR4-mediated neuronal sensitization and glial activation in rat spinal cord. J Neuroinflam 2014; 11: 75.

37.

Pan

Shan

Wang

Tai

Sun

Luo

Sun

Cheung

. miRNA-23a/CXCR4 regulates neuropathic pain via directly targeting TXNIP/NLRP3 inflammasome axis. J Neuroinflam 2018; 15: 29.

38.

Feng

Rosen

Ansari

John

Thomsen

Avraham

Geoffroy

Cavalli

. Endothelin B receptor inhibition rescues aging-dependent neuronal regenerative decline. eLife 2025; 13: 100217.

39.

Kong

Song

Yan

Calderazzo

Saddala

De Labastida Rivera

Cherry

Eckman

Appel

Velenosi

Swarup

Kawaguchi

Kwon

Gate

Engwerda

Zhou

Di Giovanni

. Clonally expanded, targetable, natural killer-like NKG7 T cells seed the aged spinal cord to disrupt myeloid-dependent wound healing. Neuron 2025; 113: 684–700.e688.

40.

Leng

Fang

Wang

Lin

Mai

Wan

Wei

Zheng

Zhang

Wang

Zhou

Tan

Zhang

. Elevated plasma CXCL12 leads to pain chronicity via positive feedback upregulation of CXCL12/CXCR4 axis in pain synapses. J Headache Pain 2024; 25: 213.

41.

Mai

Tan

Zhang

Huang

Wang

Zhang

Gui

Zhang

Lin

Meng

Wei

Jie

Grace

Zhou

Liu

. CXCL12-mediated monocyte transmigration into brain perivascular space leads to neuroinflammation and memory deficit in neuropathic pain. Theranostics 2021; 11: 1059–1078.

42.

Bai

Wang

Kong

Zhao

Qian

Kan

Zhang

. Upregulation of chemokine CXCL12 in the dorsal root ganglia and spinal cord contributes to the development and maintenance of neuropathic pain following spared nerve injury in rats. Neurosci Bull 2016; 32: 27–40.

43.

Yang

Sun

Luo

Yang

Wang

Chen

. SDF1-CXCR4 signaling contributes to the transition from acute to chronic pain state. Mole Neurobiol 2017; 54: 2763–2775.

44.

Liu

Dai

. CXCR4 antagonist AMD3100 elicits analgesic effect and restores the GlyRα3 expression against neuropathic pain. J Pain Res 2017; 10: 2205–2212.

45.

Liu

Song

Guo

Wang

Zhu

Yang

Liu

. CXCL12/CXCR4 signaling contributes to neuropathic pain via central sensitization mechanisms in a rat spinal nerve ligation model. CNS Neurosci Ther 2019; 25: 922–936.

46.

Zou

Cao

Liu

Zhang

Xiong

. The role of dorsal root ganglia PIM1 in peripheral nerve injury-induced neuropathic pain. Neurosci Lett 2019; 709: 134375.

47.

Kiguchi

Kobayashi

Kadowaki

Fukazawa

Saika

Kishioka

. Vascular endothelial growth factor signaling in injured nerves underlies peripheral sensitization in neuropathic pain. J Neurochem 2014; 129: 169–178.

48.

Luo

Tai

Sun

Qiu

Xia

Chung

Cheung

. Central administration of C-X-C chemokine receptor type 4 antagonist alleviates the development and maintenance of peripheral neuropathic pain in mice. PLoS One 2014; 9: e104860.

49.

Chen

Park

Xie

. Intrathecal bone marrow stromal cells inhibit neuropathic pain via TGF-β secretion. J Clin Investig 2015; 125: 3226–3240.

50.

Cheng

Chen

Hsu

Cheng

Chang

Lee

Yeh

Dai

. Loganin prevents CXCL12/CXCR4-regulated neuropathic pain via the NLRP3 inflammasome axis in nerve-injured rats. Phytomed Int J Phytother Phytopharmacol 2021; 92: 153734.

51.

Dong

Xia

Zhang

. LncRNA MEG3 aggravated neuropathic pain and astrocyte overaction through mediating miR-130a-5p/CXCL12/CXCR4 axis. Aging 2021; 13: 23004–23019.

52.

Huang

. miR-185-5p alleviates CCI-induced neuropathic pain by repressing NLRP3 inflammasome through dual targeting MyD88 and CXCR4. Int Immunopharmacol 2022; 104: 108508.

53.

Zhan

Lei

Zhang

Wang

Zhao

Cui

Ding

Huang

. Overexpression of miR-381 relieves neuropathic pain development via targeting HMGB1 and CXCR4. Biomed Pharmacother 2018; 107: 818–823.

54.

Hamed

Mohamed Farghaly

Abdel Mola

Fahmi

Makhlouf

Balfas

. Role of monocyte chemoattractant protein-1, stromal derived factor-1 and retinoic acid in pathophysiology of neuropathic pain in rats. J Basic Clin Physiol Pharmacol 2016; 27: 411–424.

55.

Huang

Fan

. Effect of CXCL12/CXCR4 signaling on neuropathic pain after chronic compression of dorsal root ganglion. Sci Rep 2017; 7: 5707.

56.

Yang

Zou

Luo

Chen

. Intervertebral foramen injection of plerixafor attenuates neuropathic pain after chronic compression of the dorsal root ganglion: possible involvement of the down-regulation of Nav1.8 and Nav1.9. Eur J Pharmacol 2021; 908: 174322.

57.

Knerlich-Lukoschus

von der Ropp-Brenner

Lucius

Mehdorn

Held-Feindt

. Spatiotemporal CCR1, CCL3 (MIP-1α), CXCR4, CXCL12 (SDF-1α) expression patterns in a rat spinal cord injury model of posttraumatic neuropathic pain. J Neurosurg Spine 2011; 14: 583–597.

58.

Dong

Xia

Zhang

. Upregulating miR-130a-5p relieves astrocyte over activation-induced neuropathic pain through targeting C-X-C motif chemokine receptor 12/C-X-C motif chemokine receptor 4 axis. Neuroreport 2021; 32: 135–143.

59.

Chen

Huang

Liu

Peng

. CXCL12 promotes spinal nerve regeneration and functional recovery after spinal cord injury. Neuroreport 2021; 32: 450–457.

60.

Dubový

Hradilová-Svíženská

Brázda

Jambrichová

Svobodová

Joukal

. The intrinsic neuronal activation of the CXCR4 signaling axis is associated with a pro-regenerative state in cervical primary sensory neurons conditioned by a sciatic nerve lesion. Int J Mole Sci 2024; 26: 010193.

61.

Bhangoo

Ren

Miller

Henry

Lineswala

Hamdouchi

Monahan

Chan

Ripsch

White

. Delayed functional expression of neuronal chemokine receptors following focal nerve demyelination in the rat: a mechanism for the development of chronic sensitization of peripheral nociceptors. Mole Pain 2007; 3: 38.

62.

Foster

Jung

Farooq

McClung

Ripsch

Fitzgerald

White

. Sciatic nerve injury induces functional pro-nociceptive chemokine receptors in bladder-associated primary afferent neurons in the rat. Neuroscience 2011; 183: 230–237.

63.

Yang

Luo

Sun

Wang

Yang

Wei

Wang

Guan

Chen

. SDF1-CXCR4 signaling maintains central post-stroke pain through mediation of glial-neuronal interactions. Front Mole Neurosci 2017; 10: 226.

64.

Liang

Chen

Yang

Wang

Sun

Chen

. Secondary damage and neuroinflammation in the spinal dorsal horn mediate post-thalamic hemorrhagic stroke pain hypersensitivity: SDF1-CXCR4 signaling mediation. Front Mole Neurosci 2022; 15: 911476.

65.

da Silva Junior

de Castro Junior

Pereira

EM.R

Binda

da Silva

do Nascimento Cordeiro

Diniz

Cecilia

Ferreira

Gomez

. The inhibitory effect of Phα1β toxin on diabetic neuropathic pain involves the CXCR4 chemokine receptor. Pharmacol Rep 2020; 72: 47–54.

66.

Jayaraj

Bhattacharyya

Belmadani

Ren

Rathwell

Hackelberg

Hopkins

Gupta

Miller

Menichella

. Reducing CXCR4-mediated nociceptor hyperexcitability reverses painful diabetic neuropathy. J Clin Investig 2018; 128: 2205–2225.

67.

Menichella

Abdelhak

Ren

Shum

Frietag

Miller

. CXCR4 chemokine receptor signaling mediates pain in diabetic neuropathy. Mole Pain 2014; 10: 42.

68.

Song

Yang

Cao

Mao

Jin

Wang

Zhu

Wang

Zhang

Tao

. Up-regulation of microglial chemokine CXCL12 in anterior cingulate cortex mediates neuropathic pain in diabetic mice. Acta Pharmacol Sinica 2023; 44: 1337–1349.

69.

Thakur

Sadanandan

Chattopadhyay

. High-mobility group box 1 protein signaling in painful diabetic neuropathy. Int J Mole Sci 2020; 21: e030881.

70.

Zhu

Fan

Chen

Huo

Liu

Cai

Cheung

Tang

Cui

Xia

. CXCR4/CX43 regulate diabetic neuropathic pain via intercellular interactions between activated neurons and dysfunctional astrocytes during late phase of diabetes in rats and the effects of antioxidant N-acetyl-L-cysteine. Oxidat Med Cell Longev 2022; 1: 8547563.

71.

Zhu

Fan

Huo

Cui

Cheung

Xia

. Progressive increase of inflammatory CXCR4 and TNF-alpha in the dorsal root ganglia and spinal cord maintains peripheral and central sensitization to diabetic neuropathic pain in rats. Mediat Inflam 2019; 1: 4856156.

72.

Hosoki

Asahi

Nozaki

. Cannabinoid CB2 receptors enhance high-fat diet evoked peripheral neuroinflammation. Life Sci 2024; 355: 123002.

73.

Ashjari

Karamali

Rajabinejad

Hassani

Afshar Hezarkhani

Afshari

Gorgin Karaji

Salari

Rezaiemanesh

. The axis of long non-coding RNA MALAT1/miR-1-3p/CXCR4 is dysregulated in patients with diabetic neuropathy. Heliyon 2022; 8: e09178.

74.

Huang

Zheng

Liu

Zeng

Levitt

Candiotti

Lubarsky

Hao

. HSV-mediated p55TNFSR reduces neuropathic pain induced by HIV gp120 in rats through CXCR4 activity. Gene Ther 2014; 21: 328–336.

75.

Huang

Zheng

Ouyang

Liu

Zeng

Levitt

Candiotti

Lubarsky

Hao

. Mechanical allodynia induced by nucleoside reverse transcriptase inhibitor is suppressed by p55TNFSR mediated by herpes simplex virus vector through the SDF1α/CXCR4 system in rats. Anesth Analges 2014; 118: 671–680.

76.

Zheng

Huang

Liu

Levitt

Candiotti

Lubarsky

Hao

. Interleukin 10 mediated by herpes simplex virus vectors suppresses neuropathic pain induced by human immunodeficiency virus gp120 in rats. Anesth Analges 2014; 119: 693–701.

77.

Zheng

Huang

Liu

Levitt

Candiotti

Lubarsky

Hao

. IL-10 mediated by herpes simplex virus vector reduces neuropathic pain induced by HIV gp120 combined with ddC in rats. Mole Pain 2014; 10: 49.

78.

Bhangoo

Ren

Miller

Chan

Ripsch

Weiss

McGinnis

White

. CXCR4 chemokine receptor signaling mediates pain hypersensitivity in association with antiretroviral toxic neuropathy. Brain Behav Immun 2007; 21: 581–591.

79.

Bhangoo

Ripsch

Buchanan

Miller

White

. Increased chemokine signaling in a model of HIV1-associated peripheral neuropathy. Mole Pain 2009; 5: 48.

80.

Abdel Fattah

Nasr El-Din

. Granulocyte-colony stimulating factor improves intervertebral disc degeneration in experimental adult male rats: a microscopic and radiological study. Anatomic Rec (Hob NJ 2007) 2021; 304: 787–802.

81.

Liu

Shen

Wang

Hao

. SDF-1/CXCR4 axis induces apoptosis of human degenerative nucleus pulposus cells via the NF-κB pathway. Mole Med Rep 2016; 14: 783–789.

82.

Zhang

Chen

. Stromal cell-derived factor-1 and its receptor CXCR4 are upregulated expression in degenerated intervertebral discs. Int J Med Sci 2014; 11: 240–245.

83.

Zhang

Zhu

Zhang

. Stromal cell-derived factor-1 induces matrix metalloproteinase expression in human endplate chondrocytes, cartilage endplate degradation in explant culture, and the amelioration of nucleus pulposus degeneration in vivo. Int J Mole Med 2018; 41: 969–976.

84.

Guo

Cheng

Song

Liu

Cai

Chen

Mei

Zhou

Gao

Wang

Liu

. Mechanisms of inhibition of nucleus pulposus cells pyroptosis through SDF1/CXCR4-NFkB-NLRP3 axis in the treatment of intervertebral disc degeneration by Duhuo Jisheng Decoction. Int Immunopharmacol 2023; 124: 110844.

85.

Liu

Wang

Huang

Liu

Wei

Liu

Shen

Duan

. Duhuo Jisheng Decoction inhibits SDF-1-induced inflammation and matrix degradation in human degenerative nucleus pulposus cells in vitro through the CXCR4/NF-κB pathway. Acta Pharmacol Sinica 2018; 39: 912–922.

86.

Sun

Tang

Wang

Sun

Chu

Sun

Tian

. LncRNA H19 aggravates intervertebral disc degeneration by promoting the autophagy and apoptosis of nucleus pulposus cells through the miR-139/CXCR4/NF-κB axis. Stem Cells Dev 2021; 30: 736–748.

87.

Yang

Liu

Sun

Liu

. Needle-scalpel therapy inhibits the apoptosis of nucleus pulposus cells via the SDF-1/CXCR4 axis in a rat degenerative cervical intervertebral disc model. Aging 2024; 16: 10868–10881.

88.

Rätsep

Minajeva

Asser

. Relationship between neovascularization and degenerative changes in herniated lumbar intervertebral discs. Eur Spine J 2013; 22: 2474–2480.

89.

Zhang

. SDF1/CXCR4 axis plays a role in angiogenesis during the degeneration of intervertebral discs. Mole Med Rep 2019; 20: 1203–1211.

90.

Zhang

Wang

Zhang

Zhao

Ren

. SDF1/CXCR7 signaling axis participates in angiogenesis in degenerated discs via the PI3K/AKT pathway. DNA Cell Biol 2019; 38: 457–467.

91.

Ying

Wen

Pei

Ruan

. Stromal cell-derived factor-1α promotes recruitment and differentiation of nucleus pulposus-derived stem cells. World J Stem Cells 2019; 11: 196–211.

92.

Jia

Yuan

Wang

. Roles of SDF-1/CXCR4 axis in cartilage endplate stem cells mediated promotion of nucleus pulposus cells proliferation. Biochem Biophys Res Commun 2018; 506: 94–101.

93.

Zhou

Yan

Fang

. The therapeutic potential of chemokines in the treatment of chemotherapy-induced peripheral neuropathy. Curr Drug Targets 2020; 21: 288–301.

94.

Zhang

Ou-Yang

Liu

Huang

Wei

Nie

Xin

. Epigenetic upregulation of CXCL12 expression mediates antitubulin chemotherapeutics-induced neuropathic pain. Pain 2017; 158: 637–648.

95.

Liu

Qiu

Zeng

Yang

Zhang

. Activation of STAT3-mediated CXCL12 up-regulation in the dorsal root ganglion contributes to oxaliplatin-induced chronic pain. Mole Pain 2017; 13: 47425.

96.

Liu

Tonello

Ling

Gao

Berta

. Paclitaxel-activated astrocytes produce mechanical allodynia in mice by releasing tumor necrosis factor-α and stromal-derived cell factor 1. J Neuroinflam 2019; 16: 209.

97.

Zeng

Chen

Wang

Xiao

Zhang

. Mechanism of analgesic effect of fire needle on peripheral sensitization in rats with neuropathic pain induced by chemotherapy. Acupunc Res 2023; 48: 1095–1102.

98.

Zhou

Chen

Jin

Zhou

. Co-expression gene modules involved in cisplatin-induced peripheral neuropathy according to sensitivity, status, and severity. J Peripher Nerv Syst 2020; 25: 366–376.

99.

Deng

Guindon

Vemuri

Thakur

White

Makriyannis

Hohmann

. The maintenance of cisplatin- and paclitaxel-induced mechanical and cold allodynia is suppressed by cannabinoid CB₂ receptor activation and independent of CXCR4 signaling in models of chemotherapy-induced peripheral neuropathy. Mole Pain 2012; 8: 71.

100.

Luchetta

Nash

Festa

Johnson

Sacan

Jackson

Sanz-Clemente

Brandimarti

Meucci

. CXCL12 engages cortical inhibitory neurons to enhance dendritic spine plasticity and structured network activity. J Neurosci 2025; 45: 2213.

101.

Jiang

Bai

. CXCR4/CXCL12 axis: “old” pathway as “novel” target for anti-inflammatory drug discovery. Med Res Rev 2024; 44: 1189–1220.

102.

Nagasawa

Hirota

Tachibana

Takakura

Nishikawa

Kitamura

Yoshida

Kikutani

Kishimoto

. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 1996; 382: 635–638.

103.

Tachibana

Hirota

Iizasa

Yoshida

Kawabata

Kataoka

Kitamura

Matsushima

Yoshida

Nishikawa

Kishimoto

Nagasawa

. The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract. Nature 1998; 393: 591–594.

104.

Mogil

Parisien

Esfahani

Diatchenko

. Sex differences in mechanisms of pain hypersensitivity. Neurosci Biobehav Rev 2024; 163: 105749.

105.

Gwak

Kang

Unabia

Hulsebosch

. Spatial and temporal activation of spinal glial cells: role of gliopathy in central neuropathic pain following spinal cord injury in rats. Experim Neurol 2012; 234: 362–372.

106.

Huynh

Dingemanse

Meyer

Schwabedissen

Sidharta

. Relevance of the CXCR4/CXCR7-CXCL12 axis and its effect in pathophysiological conditions. Pharmacol Res 2020; 161: 105092.

107.

Gipson

Rawls

Scofield

Siemsen

Bondy

Maher

. Interactions of neuroimmune signaling and glutamate plasticity in addiction. J Neuroinflam 2021; 18: 56.

108.

Zhong

Weng

Peng

Huang

Zhao

Liang

. Therapeutic siRNA: state of the art. Signal Transduct Target Ther 2020; 5: 101.

109.

Jackson

Gigliobianco

Casadidio

Di Martino

Censi

. MicroRNA-based delivery systems for chronic neuropathic pain treatment in dorsal root ganglion. Pharmaceutics 2025; 17: e070930.

CXCL12/CXCR4 axis in neuropathic pain: Insights from preclinical models and translational implications

Abstract

Keywords

Introduction

Background of the CXCL12/CXCR4 axis pathway

Biological characteristics

Unique features and translational relevance

Cell-type-specific expression landscape of CXCL12/CXCR4 revealed by single-cell transcriptomics

CXCL12/CXCR4 axis in NP: Evidence from preclinical models

Traumatic nerve injury models

Spared nerve injury (SNI)

Spinal nerve ligation (SNL)

Partial sciatic nerve ligation (pSNL)

Chronic constriction injury (CCI)

Other traumatic nerve injury models

Central neuropathic pain models

Diabetic neuropathic pain (DNP)

HIV-associated neuropathic pain (HIV-NP)

Intervertebral disc degeneration-associated low back pain

Chemotherapy-induced peripheral neuropathy (CIPN)

Conclusions and future perspectives

Footnotes

Author contributions

Data availability

Declaration of conflicting interests

Funding

ORCID iDs

References