Multifaceted Astrocyte-Neuron Cross-Talk in Neuropathic Pain: Potential Mechanisms and Functional Implications

Songchao Xu,¹ Chenghui Cai,¹ Peiqi Shao,¹ Yue Zhao,¹ Yun Guan,² Yanbing Zhu,³ Yun Wang¹

¹Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China; ²Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA; ³Beijing Clinical Research Institute, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China

Correspondence: Yun Wang, Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, No. 95, Yong’an Road, Beijing, People’s Republic of China, Email [email protected]

Abstract: Neuropathic pain is a prevalent and debilitating chronic condition with complex and incompletely understood mechanisms. Growing evidence has uncovered astrocytes as active and dynamic regulators in both the initiation and persistence of neuropathic pain. Beyond their classical supportive roles, astrocytes undergo profound morphological and functional remodeling following nerve injury and engage in extensive bidirectional communication with neurons. Through direct physical contacts, gliotransmitter release, and complex intercellular signaling networks, astrocytes critically shape synaptic plasticity, neuroinflammatory cascades, and neuronal excitability, ultimately driving maladaptive pain processing. In this review, we provide an updated and integrative overview of astrocyte-neuron cross-talk in neuropathic pain, with a particular focus on the molecular and cellular mechanisms by which astrocytic signaling modulates synaptic remodeling and pain sensitization. A deeper understanding of these astrocyte-mediated interactions may open new avenues for the development of precise and targeted therapeutic strategies for neuropathic pain.

Keywords: neuropathic pain, astrocytes, neuron, cross talk, mechanisms

Introduction

Neuropathic pain is a chronic pain condition caused by a lesion or disease of the somatosensory nervous system.¹ Clinically, neuropathic pain is characterized by spontaneous pain, allodynia and hyperalgesia.^2,3 It is frequently accompanied by chronic comorbidities such as depression and anxiety, which profoundly impair quality of life.^4–6 Current therapeutic strategies, including pharmacological treatments and neuromodulation, remain unsatisfactory due to limited efficacy, drug tolerance, and challenges in long-term management, highlighting the urgent need to identify new therapeutic targets and underlying mechanisms.^6–8

Glial activation represents a fundamental cellular process underpinning the pathophysiology of neuropathic pain.⁹ Under physiological conditions, astrocytes in the central nervous system (CNS) are responsible for maintaining ion homeostasis, providing metabolic support, regulating synaptic function, and clearing neurotransmitters, thereby contributing to neural network stability and information processing.^10,11 By forming tripartite synapses with neurons, astrocytes actively participate in the regulation of synaptic plasticity.^12–14 In addition, astrocytes influence synaptic plasticity by releasing modulators such as D-serine and ATP, and they sustain neuronal metabolic demands by supplying lactate via monocarboxylate transporters.^15,16 However, following nerve injury or under chronic pain conditions, astrocytes become activated and release pro-inflammatory cytokines, exosomes, and metabolites, which modulate synaptic transmission, neuronal excitability, and network remodeling, thereby promoting the propagation and maintenance of pain signaling.^17,18 Intriguingly, a recent study demonstrated that targeted activation of astrocytes in the primary somatosensory cortex reversed mechanical hypersensitivity by inducing synaptic plasticity and reducing aberrant synapse formation after injury, leading to long-lasting pain relief.¹⁹ In contrast, another study in a diabetic neuropathic pain model revealed that activation of motor cortex astrocytes enhanced neuronal excitability via the release of inflammatory mediators, thereby facilitating pain maintenance.²⁰ These findings suggest a bidirectional role of astrocytes in pain regulation: depending on brain region and mode of activation, astrocytes may exert analgesic effects under certain conditions or exacerbate pain hypersensitivity in pathological states.

Astrocyte-neuron interactions are reciprocal and dynamic, encompassing neurotransmitter regulation, inflammatory signaling, metabolic support, synaptic plasticity modulation, and ion homeostasis. Astrocytes maintain neuronal hyperexcitability via these mechanisms, driving the progression of nociceptive sensitivity.^21,22 Deciphering the diverse forms of intercellular communication is crucial for understanding the underlying pathological processes. Here, we review current insights into these interactions, examine their regulatory mechanisms, and evaluate their potential as targets for precision therapies.

Potential Mechanisms of Astrocyte-Neuron Crosstalk in Neuropathic Pain

Direct Astrocyte-Neuron Interactions

Astrocytes form direct interactions with neurons through the tripartite synapse, which comprises the presynaptic terminal, postsynaptic dendritic spine, synaptic cleft, and perisynaptic astrocytic processes (PAPs).^23,24 Unlike conventional bidirectional communication between pre- and postsynaptic neurons, astrocytes detect synaptic activity and actively modulate synaptic transmission through the release of gliotransmitters and regulation of ionic homeostasis.²⁵ In addition, astrocytic processes tightly enwrap synapses, providing mechanical support to synaptic structures, reducing spatial drift of synaptic sites, and enhancing long-term synaptic stability.¹² Astrocytes, along with perineuronal nets, create a physical scaffold that constrains neurotransmitter spread, optimizes synaptic signaling accuracy, reduces neural circuit interference, and stabilizes local synaptic function.²⁶ Baldwin et al demonstrated that astrocytes rely on hepatocyte cell adhesion molecule-mediated interactions to compete for neuronal synaptic territories and regulate their morphogenesis and gap junction coupling.²⁷ In spinal cord injury models, hyperreflexia has been closely associated with increased formation of tripartite synapses involving the astrocytic glutamate transporter (GLT-1) and neuronal PSD-95, suggesting that astrocytes promote central hyperexcitability by regulating synaptic plasticity.²⁸ In a trigeminal nerve chronic constriction injury model, PAPs in the dorsal medullary horn were markedly elevated, exhibiting enhanced envelopment of presynaptic terminals and postsynaptic dendrites.²⁹ Via tripartite synapses, astrocytes engage directly with neurons to sense and fine-tune synaptic activity, preserve structural integrity, and maintain precise signal transmission. Astrocytic control via tripartite synapses is crucial for synaptic homeostasis, and its disruption drives neuropathic pain.

Cytokine and Chemokines

Astrocyte activation in the spinal cord and brain is accompanied by the release of pro-inflammatory cytokines that critically modulate neuronal excitability and synaptic plasticity (Table 1). Among these, IL-1β is a key inflammatory mediator that not only enhances excitatory glutamatergic synaptic transmission by binding to IL-1 receptors on neuronal surfaces, but also induces phosphorylation of NMDARs in spinal neurons, thereby amplifying synaptic transmission and pain signaling.³⁰ In the motor cortex, activated astrocytes release TNF-α and IL-1β, which in turn enhance the excitability of neurons within the same region, contributing to the modulation and exacerbation of diabetic neuropathic pain.²⁰ Moreover, IL-6 can promote astrocyte activation via the JAK2/STAT3 signaling axis, enhance neuronal electrical excitability, and maintain central sensitization under conditions of spinal cord injury or chronic inflammatory pain.^31,32

Table 1 Potential Cytokine and Chemokines Mechanisms in Different Neuropathic Pain Models

Other inflammatory mediators also play a role. For instance, IL-17 enhances CaMKII/CREB activity in spinal neurons, modulating synaptic transmission and sustaining chronic pain induced by chemotherapy or peripheral nerve injury.⁵⁰ IFN-γ activates astrocytes and increases neuronal activity in trigeminal nerve injury models.⁴⁵ Nerve injury can epigenetically downregulate miR-214-3p in astrocytes, leading to upregulation of secreted colony-stimulating factor-1 (CSF-1), which enhances neuronal excitability and exacerbates neuropathic pain.⁵¹ Furthermore, the IL-33/ST2 signaling pathway in the spinal cord promotes neuropathic pain development through a dual mechanism involving neuronal CaMKII–CREB and astrocytic JAK2–STAT3 pathways.⁴⁴

Similarly, astrocytes release chemokines, including CXCL1 and CCL2. These molecules act on neuronal receptors CXCR2 and CCR2, activating downstream signaling and enhancing neuronal excitability in pain pathways.⁵⁶ For example, CXCL1 is upregulated and released from spinal astrocytes, and acts on CXCR2-expressing spinal neurons to activate ERK and CREB signaling, enhance neuronal excitability, and induce immediate early gene expression, thereby promoting central sensitization and persistent pain.^34,57 Following inflammation or nerve injury, activated spinal astrocytes secrete CCL2, which binds to CCR2 expressed on neurons, modulating synaptic transmission and enhancing NMDA receptor function, thus facilitating central sensitization.^58,59 In addition, CXCL10 expression is upregulated in spinal neurons and astrocytes after nerve injury. CXCL10 enhances spontaneous excitatory postsynaptic currents and potentiates NMDA- and AMPA-induced currents in spinal neurons, further amplifying neuronal responsiveness to pain stimuli.⁴⁰ Collectively, Cytokines and chemokines mediate neuron-astrocyte signaling, forming a positive feedback loop that enhances neuronal excitability and sustains neuropathic pain.

Extracellular Vesicles

Extracellular vesicles(EVs), particularly exosomes, are key mediators of intercellular communication. Exosomes are nanoscale vesicles, approximately 30–150 nm in diameter, capable of carrying diverse bioactive cargos, including miRNAs, mRNAs, proteins, and lipids, which can be internalized by target cells via endocytosis to modulate gene expression and cellular functions. While studies of exosomes in neuropathic pain remain scarce, accumulating evidence highlights their roles in various neurodegenerative conditions.⁶⁰

miRNAs packaged within astrocyte-derived exosomes have emerged as critical regulators of neuronal gene expression and synaptic plasticity. For instance, exosomes enriched in miR-26a-5p exert neuroprotective effects by inhibiting neuronal apoptosis and promoting dendritic development.⁶¹ Mechanistically, miR-26a-5p targets neural cell adhesion molecule and activates the AKT/GSK3-β/CRMP2 signaling pathway, thereby enhancing neuronal function.⁶¹ Similarly, miR-378a-5p carried by astrocyte-derived exosomes mitigates NLRP3-mediated pyroptosis and neuroinflammation, conferring neuroprotection in cerebral ischemia.⁶² Neurons also release exosomes to transfer miR-124-3p to microglia and astrocytes, suppressing M1 microglia and A1 astrocyte activation through modulation of MYH9 and the PI3K/AKT/NF-κB signaling axis, which facilitates functional recovery following spinal cord injury.⁶³

Beyond miRNAs, exosomes transport specific proteins that critically regulate neuronal functions. Astrocytic processes release exosomes containing neuroglobins, contributing to noncanonical CNS signaling and selectively targeting neurons to exert protective effects.⁶⁴ Following mild cortical spreading depolarization, stressed neurons release small HMGB1-enriched exosomes that are internalized by astrocytic processes, activating NF-κB p65 signaling and eliciting inflammatory responses.⁶⁵ Interestingly, astrocyte-derived exosomes (ADEVs) exhibit stimulus-dependent protein cargos: ATP or IL-10 stimulation enriches proteins promoting neurite outgrowth, dendritic branching, synaptic transmission, and neuronal survival, whereas IL-1β-stimulated ADEVs are enriched in proteins that modulate peripheral immune responses and recruit immune cells into the CNS.⁶⁶ Collectively, these findings highlight exosomes as key mediators of astrocyte-neuron communication and suggest their potential as therapeutic targets for chronic pain intervention.

Synapse-Associated Molecules

Astrocytes orchestrate neuronal plasticity via synapse-associated molecules, thereby influencing synaptic transmission and promoting neuropathic pain (Table 2). D-serine, a key NMDAR co-agonist released by astrocytes, enhances excitatory synaptic transmission.^15,67,68 Members of the Hevin/SPARC protein family exert opposing effects on synaptic remodeling: Hevin promotes postsynaptic dendritic spine formation, potentially enhancing nociceptive signaling, whereas SPARC inhibits synaptic remodeling, reducing pain hypersensitivity.⁶⁹ Astrocyte-derived Hevin has been shown to sustain neuropathic and inflammatory pain by upregulating spinal GluN2B expression.⁷⁰ In addition, astrocytes secrete Chordin-like 1, which promotes synapse maturation and constrains plasticity by increasing GluA2 receptor expression at synapses.⁷¹

Table 2 Potential Synapse-Associated Molecules Mechanisms in Different Neuropathic Pain Models

Matrix metalloproteinases (MMPs) are key regulators of the extracellular synaptic matrix and play pivotal roles in neuropathic pain. MMP-9 degrades chondroitin sulfate proteoglycans (CSPGs), influencing synaptic stability and facilitating synaptic remodeling.⁷⁷ CSPGs form perisynaptic barriers that limit synaptic plasticity and maintain synaptic stability.⁷⁸ Abnormal CSPG accumulation after nerve injury may impede repair, whereas its degradation promotes plasticity and modulates pain signal transmission.⁷⁹ Furthermore, the Sema3A/Neuropilin-1 signaling pathway regulates synaptic plasticity, with astrocyte-derived Sema3A mediating axonal retraction and synaptic functional changes via Neuropilin-1 receptor.⁷⁹

Connexins (Cxs) modulate astrocyte–neuron interactions and inter-astrocytic coupling, driving synaptic abnormalities and pain sensitization. Neuronal potassium channel activity downregulation leads to upregulation of neuronal Cx36 and astrocytic Cx43, enhancing synaptic transmission and glial activation.⁷⁶ In chemotherapy-induced neuropathic pain, increased astrocytic Cx43 mediates aberrant intercellular communication, facilitating pain hypersensitivity.⁷⁴ Following spinal cord injury, Sigma-1 Receptor activation further elevates astrocytic Cx43 expression and coupling, accelerating central sensitization and mechanical allodynia.⁷⁵ Collectively, astrocytes influence neuronal synaptic plasticity and excitatory transmission through the secretion and regulation of multiple synapse-associated molecules.

Ion Homeostasis

Astrocytes engage in bidirectional interactions with neurons through diverse mechanisms of ionic homeostasis, which play crucial roles in the initiation and maintenance of neuropathic pain⁸⁰ (Table 3). Astrocytes regulate extracellular K⁺ buffering via Kir4.1 potassium channels, thereby modulating neuronal excitability.⁸¹ In chronic constriction injury models, impaired K⁺ channel function in dorsal horn astrocytes increases astrocytic excitability, alters neuronal firing patterns, and enhances neuronal excitability.⁸² Aberrant Ca²⁺ signaling also represents a key factor in pain modulation. Astrocytic Ca²⁺ fluctuations directly influence synaptic function and neurotransmitter release, while Ca²⁺ signals mediated via P2Y receptor activation further potentiate pain signal transmission.⁸³ Notably, electroacupuncture has been reported to modulate Ca²⁺ dynamics in rostral ventromedial medulla astrocytes, activating downstream signaling pathways to achieve analgesic effects.⁸⁴

Table 3 Potential Ion Homeostasis and Energy Metabolism Mechanisms in Different Neuropathic Pain Models

Astrocytes also modulate neuronal excitability through Na⁺/K⁺-ATPase. In migraine, Na⁺/K⁺-ATPase dysfunction leads to elevated extracellular Na⁺, concomitant with reduced perisynaptic glutamate transporter density, slowing glutamate clearance, and increasing cortical susceptibility to spreading depolarization, thereby enhancing nociceptive responses to migraine triggers.⁹⁴ Astrocytic regulation of Cl⁻ homeostasis further influences neuronal excitability; impaired Cl⁻ efflux raises intracellular Cl⁻ in neurons, weakening GABAergic inhibition and promoting hyperexcitability.⁹⁵ Activation of astrocytic BDNF-TrkB signaling downregulates Cl⁻ extrusion transporters while enhancing the release of pro-inflammatory cytokines and neurotrophic factors, establishing a positive feedback loop that sustains pain signaling.⁹⁶ In spared nerve injury models, differential target multiplexed programming of spinal cord stimulation modulates a broader array of ion homeostasis-related proteins compared with low-frequency stimulation. Regulation of proteins controlling Ca²⁺, Na⁺, K⁺, and Cl⁻ homeostasis leads to reduced intracellular Ca²⁺, enhanced GABAergic inhibition, and restored K⁺ and Cl⁻ balance, thereby reversing ion dysregulation and neuronal hyperexcitability in pain states.⁹⁷ Overall, astrocytes regulate neuronal excitability and synaptic transmission via ion homeostasis, critically contributing to the onset and maintenance of chronic pain.

Energy Metabolism

Reciprocal metabolic coupling, via astrocytic lactate and ATP release and mitochondrial transfer, shapes neuronal excitability and perpetuates pain signaling (Table 3). Among these mechanisms, lactate shuttling is particularly critical. During inflammatory pain, astrocytes generate lactate through glycogenolysis and transport it to neurons via monocarboxylate transporters. Lactate serves as an energy substrate, facilitating synaptic plasticity and heightened excitability in spinal neurons, thereby sustaining pain states.^88,98 In the spinal cord, lactate shuttling enhances C-fiber-induced long-term potentiation, exacerbating mechanical hypersensitivity.^87,99 In higher brain regions such as the anterior cingulate cortex and hippocampus, astrocyte-derived lactate modulates synaptic plasticity, augments pain sensitization, and influences pain-associated cognitive and emotional processes.^100,101 ATP also regulates neuronal activity. Astrocyte activation triggers ATP release, which enhances neuronal excitability and pain hypersensitivity, effects that can be reversed upon blockade of ATP receptors.¹⁰² Conversely, dorsal horn neurons in neuropathic pain states release ATP via vesicular nucleotide transporter-mediated vesicular exocytosis, sustaining pain signaling.⁹³

Mitochondrial transfer mediated by astrocytes has emerged as a novel form of intercellular communication, essential for maintaining neuronal function and metabolic homeostasis. Although its role in neuropathic pain remains unclear, extensive studies in various neurodegenerative and injury models provide insights. For instance, the Tak1 signaling pathway promotes mitochondrial transfer from astrocytes to hypothalamic proopiomelanocortin neurons, maintaining glucose and cholesterol homeostasis.¹⁰³ In Rett Syndrome models, astrocytic mitochondrial dysfunction and excessive reactive oxygen species (ROS) production impair their neuronal support capacity.¹⁰⁴ Acupuncture interventions in acute stroke models enhance astrocyte-to-neuron mitochondrial transfer, conferring neuroprotection.¹⁰⁵ Recent studies also show that LRP1-mediated mitochondrial transfer from astrocytes mitigates cerebral ischemic injury through inhibition of ADP-ribosylation factor 1 myristoylation,¹⁰⁶ and reactive astrocytes with abnormal mitochondrial dynamics are closely associated with neuronal damage in multiple pathological conditions.¹⁰⁷ These findings suggest that astrocytic mitochondrial transfer can be protective or harmful depending on context and may modulate neuronal metabolism, synaptic plasticity, and ROS to influence pain pathways, warranting further study.

Neurotransmitter Regulation

Astrocytes regulate neurotransmitter signaling to sustain neuronal excitability and modulate pain (Table 4). In key pain-processing regions such as the spinal dorsal horn and hypothalamus, astrocytes maintain the balance of excitatory and inhibitory synaptic transmission by clearing excess glutamate from the synaptic cleft via GLT-1.²⁸ When astrocytic function is impaired or GLT-1 expression is downregulated, glutamate clearance is compromised, leading to elevated extracellular glutamate levels, enhanced excitatory synaptic plasticity, and central sensitization, thereby exacerbating chronic pain phenotypes.^108,109 Moreover, astrocytes can sense synaptic glutamate through metabotropic glutamate receptor 5, triggering intracellular Ca²⁺-dependent responses that further disrupt excitatory signaling.¹¹⁰

Table 4 Potential Neurotransmitter and Other Molecule Mechanisms in Different Neuropathic Pain Models

Beyond glutamate, norepinephrine also participates in astrocyte–neuron cross talk. Norepinephrine released from locus coeruleus neurons in the midbrain acts on astrocytes to suppress pro-inflammatory activation, thereby reducing astrocyte-mediated neuroinflammation, limiting glutamate-driven neuronal hyperexcitability, and alleviating pain transmission.¹¹¹ Pharmacological studies indicate that upregulating GLT-1 in astrocytes enhances glutamate clearance, suppresses neuronal hyperexcitability, and significantly improves pain behaviors in spinal cord injury or neuropathic pain models.¹³¹ Together, astrocytes orchestrate neurotransmitter signaling to modulate synaptic transmission and central sensitization.

Conclusions and Future Directions

In this review, we summarized the multifaceted mechanisms by which astrocyte-neuron interactions contribute to the initiation and maintenance of neuropathic pain. These interactions occur both through direct cell-cell contacts and via indirect pathways, including cytokine/chemokine signaling, extracellular vesicle release, synapse-associated molecules, ion homeostasis, energy metabolism, and neurotransmitter regulation (Figure 1). These mechanisms are highly interconnected, collectively shaping central sensitization and synaptic plasticity.

Figure 1 Astrocyte-Neuron Crosstalk Mechanisms and Molecular Mediators in Neuropathic Pain. Activated astrocytes regulate neuronal activity and synaptic plasticity via multiple interconnected mechanisms. These include direct structural modulation of the tripartite synapse, release of proinflammatory cytokines (eg, IL-1β, TNF-α, IL-6, IL-17, IFN-γ, IL-33, CSF-1) and chemokines (eg, CCL2, CXCL1, CXCL13), and secretion of gliotransmitters such as ATP, D-serine, and glutamate. In addition, astrocyte-derived factors, including Hevin and MMPs, orchestrate excitatory synapse formation, while exosomes and metabolic signals further contribute to central sensitization and the maintenance of neuropathic pain. The red box marks the tripartite synapse composed of astrocytes, presynaptic membrane and postsynaptic membrane, with its detailed magnified diagram shown inside the box. Black dashed arrows indicate the transport, paracrine secretion and transcellular signal regulatory pathways of various molecules and extracellular vesicles. The upward solid arrow denotes enhanced postsynaptic excitation.

In the central nervous system, astrocytes are not merely supportive cells for neurons but are pivotal regulators of neural network function. Through the formation of tripartite synapses and the envelopment of presynaptic terminals and postsynaptic dendrites by PAPs, astrocytes are capable of sensing neuronal activity and modulating synaptic transmission, thereby contributing to the regulation of synaptic plasticity.^23–25 Via gap junctions and an extensive astrocytic network, they facilitate lateral signal propagation, enabling local neuronal activity to be coordinated across broader neural circuits. In addition, astrocytes provide essential metabolic support, including the release of lactate and ATP as well as mitochondrial transfer, ensuring neuronal energy supply and the maintenance of activity-dependent plasticity.^88,102,103 Astrocytes also play a central role in maintaining ion homeostasis, including Ca²⁺, K⁺, and Cl⁻, thereby regulating neuronal excitability and preventing aberrant firing.^81,83,95 Under inflammatory or chronic pain conditions, astrocytes release gliotransmitters, cytokines, and chemokines, participating in bidirectional neuron-glia signaling that amplifies central sensitization and synaptic plasticity.^31,56

Accumulating evidence suggests that astrocyte-neuron communication in neuropathic pain is mediated by an integrated signaling network rather than independent pathways. Following nerve injury, excessive neuronal activity and the release of neurotransmitters activate astrocytes and trigger multiple downstream responses, including the production of cytokines and chemokines, extracellular vesicles, synapse-associated molecules, and alterations in ion homeostasis and metabolic coupling.¹³² Importantly, these pathways exhibit substantial functional crosstalk. For example, astrocyte-derived TNF-α and IL-1β not only directly enhance neuronal excitability but also impair glutamate homeostasis and facilitate NMDA receptor activation, while IL-6 amplifies inflammatory signaling through the JAK2/STAT3 pathway.

These signaling pathways further interact to reinforce maladaptive neuron-astrocyte communication. Extracellular vesicles can propagate inflammatory signals by transferring regulatory miRNAs and proteins, whereas synapse-associated molecules such as Hevin and D-serine directly promote excitatory synaptic remodeling.⁶⁹ Meanwhile, disturbances in ion homeostasis and energy metabolism further potentiate cytokine production and glutamatergic transmission, establishing a feed-forward loop that sustains neuronal hyperexcitability. Despite their molecular diversity, these mechanisms ultimately converge on common downstream events, including enhanced excitatory synaptic plasticity, central sensitization, and persistent neuropathic pain.

Despite significant progress in recent years, several challenges remain. First, most studies have been conducted in rodent models, with limited evidence from human patients. Although rodent models provide important mechanistic insights, species differences may limit the direct translatability of findings. Second, astrocyte functions are highly context- and region-dependent, and may exhibit distinct roles across different brain regions, disease stages, or physiological states.^133,134 Moreover, astrocyte-neuron interactions involve multiple inflammatory mediators, metabolites, neurotrophic factors, and ion channels, which may act synergistically or antagonistically.^9,17,135 Future studies combining single-cell sequencing, multi-omics analyses, and systems biology approaches, along with advanced neuroimaging techniques, are needed to comprehensively map these molecular networks and dynamically monitor astrocyte function in vivo.^136–138 Astrocytes involved in neuropathic pain are increasingly recognized as a heterogeneous population with distinct functional phenotypes. Rather than representing a uniform cell type, astrocytes exhibit marked region-specific and state-dependent characteristics. In particular, homeostatic astrocytes preserve synaptic homeostasis by maintaining glutamate uptake, ion balance, and metabolic support, whereas reactive astrocytes acquire diverse phenotypes that differentially regulate neuroinflammation, synaptic remodeling, and neuronal excitability following nerve injury. Consequently, distinct astrocyte subpopulations are likely to contribute to different stages of neuropathic pain, including its initiation, maintenance, and resolution. Future studies integrating single-cell multi-omics and spatial transcriptomics are needed to define the molecular and functional characteristics of these astrocyte subsets and their dynamic interactions with neurons. Such advances will facilitate the development of precision therapies that selectively target pathogenic astrocyte populations while preserving their essential homeostatic functions. In addition, it is also worth noting that the bidirectional communication between microglia and astrocytes represents another critical regulatory axis in neuropathic pain and other CNS disorders.^139,140 Microglia-derived factors such as complement component C1q, TNF-α, and IL-1α can drive the conversion of astrocytes into the neurotoxic A1 phenotype, thereby exacerbating neuronal dysfunction.^141,142 However, this aspect is beyond the scope of the present discussion.

From a translational perspective, while glia-targeted therapeutic strategies have shown promising results in preclinical models, their clinical application remains challenging. Current approaches targeting astrocyte-neuron signaling primarily focus on restoring glutamate homeostasis, inhibiting astrocyte-derived synaptogenic factors, modulating astrocytic inflammatory signaling pathways, regulating connexin-mediated gliotransmission, and interfering with extracellular vesicle-mediated neuron-glia communication. These strategies aim to normalize aberrant synaptic transmission and attenuate central sensitization. A major obstacle is the selective modulation of astrocyte function without inadvertently affecting other glial populations, such as microglia or oligodendrocytes. Enhancing astrocytic glutamate clearance has emerged as a promising strategy for pain modulation. β-lactam antibiotics such as ceftriaxone and cefadroxil reduce extracellular glutamate, suppress neuronal hyperexcitability, and produce significant antinociceptive effects in neuropathic and inflammatory pain models.¹⁴³ Similarly, clavulanic acid has been shown to alleviate neuropathic pain through GLT-1 dependent mechanisms.¹⁴⁴ Increased transporter activity also dampens spinal astrocyte activation and synaptic hyperexcitability.¹⁰⁸ However, clinical evidence directly demonstrating therapeutic efficacy remains limited. Furthermore, the intimate association of astrocytes with the blood-brain barrier necessitates that therapeutics are designed to efficiently penetrate this barrier while minimizing systemic side effects.^145,146 With advances in nanomedicine, bioengineered materials, and gene editing technologies, more precise and effective intervention strategies may be developed, offering new therapeutic options for patients with neuropathic pain.^147–149

While most studies have focused on the pronociceptive functions of reactive astrocytes after nerve injury, recent evidence suggests that homeostatic astrocytes are integral components of spinal non-neuronal pain-gating mechanisms. Activation of low-threshold Aβ afferents recruits spinal astrocytes to suppress nociceptive transmission through endogenous adenosine signaling and long-term depression of neurokinin-1 receptor-positive (NK1R⁺) projection neurons, thereby contributing to endogenous antinociception.¹⁵⁰ This context-dependent functional transition may provide a more comprehensive framework for understanding astrocyte-neuron interactions in neuropathic pain. Under physiological conditions, astrocytes maintain synaptic homeostasis and limit nociceptive transmission, whereas following nerve injury they undergo reactive remodeling and acquire pronociceptive properties that facilitate central sensitization.

In summary, astrocytes play a critical role in the development and maintenance of neuropathic pain. Through inflammatory mediators, metabolic pathways, and synaptic regulation, they form a complex interactive network with neurons. Although key pathways have been partially elucidated, further investigation is required to understand their dynamic changes and molecular mechanisms under different pathological conditions. Targeting astrocytes may provide a novel strategy for the treatment of neuropathic pain and pave the way for more effective, individualized therapeutic approaches.

Acknowledgments

The authors express gratitude to Home for Researchers (https://www.home-for-researchers.com) for their English language editing assistance. The figure was created with BioRender.com (License No. DB29YM6SFN; https://app.biorender.com).

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

This work was supported by the National Natural Science Foundation of China (82171217) and the Natural Science Foundation of Beijing Municipality (7252025, 7252029, 7254332).

Disclosure

The authors declare no conflicts of interest in this work.

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