Research Progress on Zoster-Associated Pain and Its Pain Mechanisms

Abstract

Herpes zoster (HZ) is an acute infectious disease caused by varicella-zoster virus (VZV) reactivation, and zoster-associated pain (ZAP), including acute HZ pain and postherpetic neuralgia (PHN), severely impairs patients’ quality of life. The Chinese Guidelines (2025) define PHN as pain persisting over 1 month after lesion healing and advocate integrated ZAP management. ZAP’s pathogenesis is complex, involving VZV replication, neuronal sensitization, neuro-immune-inflammatory interactions, abnormal ion channels, genetic variations, and sympathetic dysfunction. Clarifying these mechanisms is crucial for optimizing treatment and developing targeted interventions, to further elucidate its pathogenic mechanisms.

Graphical abstract

Keywords

zoster-associated pain / postherpetic neuralgia / neuropathic pain

Introduction

Herpes zoster (HZ) is an acute infectious skin disease caused by the reactivation of the varicella‑zoster virus (VZV). The global incidence is approximately 3–5 per 1000 person-years, and that of the general population in the Asia‑Pacific region is 3–10 per 1000 person‑years. The most distressing manifestation for patients is the associated severe neuralgia, namely zoster‑associated pain (ZAP), including acute pain and postherpetic neuralgia (PHN). Patients with ZAP typically present with intense unilateral spontaneous cutaneous pain, often described as burning or stabbing, and may also involve itching, aching, and paroxysmal pain. Persistent (spontaneous) pain is usually accompanied by hyperalgesia and allodynia. PHN is the most common and severe complication and sequela of HZ. It may be persistent or intermittent, with a clinical course ranging from several months to years, and in some cases persists for a lifetime, severely impairing patients’ quality of life[1].

Some definitions characterize PHN as persistent neuralgia lasting more than 3 months after HZ skin lesions heal. In fact, from a holistic perspective, acute HZ pain and PHN represent two phases of a continuous disease process, without a sharp temporal boundary between them. Furthermore, early pain control helps reduce the risk of PHN. Accordingly, the Pain Medicine Branch and Dermatology and Venereology Branch of the Chinese Medical Association jointly issued the Chinese Guidelines for the Whole‑Course Management of Herpes Zoster‑Associated Pain (2025 Edition) in 2025. These guidelines recommend that ZAP—encompassing HZ pain and PHN (defined as pain persisting for 1 month or longer after lesion healing)—should be recognized and managed as an integrated entity to achieve more effective and timely control of ZAP, thereby supporting the standardized whole‑course management of ZAP[2].

Unfortunately, the pathogenesis of ZAP is extremely complex and has not been fully elucidated. It arises from the interplay of multiple mechanisms, including direct viral injury, neuronal sensitization, and inflammatory responses. Moreover, different mechanisms may predominate or coexist across distinct clinical stages, thereby influencing clinical manifestations and therapeutic strategies. Before skin lesions appear, pain is mainly driven by neuritis; after lesion onset, nociceptive pain emerges and gradually intensifies; whereas pain following lesion healing is again predominantly neuropathic. The pain mechanisms differ across clinical phases of ZAP. Clarifying the core pain mechanisms underlying ZAP is crucial for optimizing clinical diagnosis and treatment regimens, developing novel targeted interventions, and represents a key prerequisite for addressing current challenges in ZAP management (e.g., unsatisfactory efficacy in refractory PHN).

Mechanisms of pain in acute HZ

It is currently recognized that the pathogenesis of acute neuralgia in HZ involves complex interactions between viral replication within sensory ganglia and immune-mediated inflammatory responses, which collectively contribute to tissue damage and functional impairment[3]. Following primary infection, VZV invades sensory ganglia and establishes latent infection in neurons. During the acute phase of HZ, reactivated VZV replicates extensively in ganglia (predominantly sensory ganglia) and adjacent cells, and can spread along sensory nerve fibers, resulting in peripheral neuritis corresponding to cutaneous lesions. In affected neural tissues, this process induces the infiltration of a variety of inflammatory mediators, chemokines, and immune cells, leading to local nerve tissue injury (including nerve demyelination, axonal degeneration, and necrosis of sensory nerve fibers and their surrounding cells) and subsequent sensitization of nociceptors in the infected skin[1]. Concurrently, it causes deafferentation secondary to the destruction of sensory neurons in VZV-infected dorsal root ganglia (DRG)[4].

In addition to peripheral neuronal sensitization, acute HZ pain is also associated with central sensitization. When sensory axons are damaged during HZ, a transient period of extremely high-frequency discharge occurs, leading to prolonged depolarization of spinal cord neurons. During this period, the responsiveness of dorsal horn cells to all inputs is augmented (termed “wind-up”). Following impulse-induced glutamate-mediated activation of N-methyl-D-aspartate (NMDA) receptors, calcium influx may result in long-term neurological dysfunction (or even death) of dorsal horn neurons[5]. Any subsequent reduction in the disinhibition of dorsal horn cells may convert transient central sensitization into a persistent state, independent of further nociceptor input.

Furthermore, findings from several animal studies have demonstrated that following VZV infection of neurons, transcription of viral genes within neurons may also serve as an inducer of neuralgia—either through the induction of inflammatory mechanisms or the modulation of protein expression (e.g., VZV transcripts function as transcriptional regulators that alter the gene expression profile of host cells)[6].

Mechanisms of PHN

Since the clinical manifestations of pain in PHN and HZ are usually similar, including pain location and characteristics, and there is usually no pain-free interval between HZ and PHN, there is no clear temporal boundary between PHN and acute HZ pain in clinical practice. Based on this, in contrast to the conventional definition of PHN as pain persisting for more than 3 months after rash healing[7], the Chinese Guidelines for the Whole-Course Management of Herpes Zoster-Associated Pain (2025 Edition) defines PHN as pain that persists for more than 1 month after lesion healing. This definition can remind clinicians to regard ZAP as an integrated entity and manage acute pain early and comprehensively to avoid progression to intractable pain.

Studies have shown that the pathogenesis of PHN is not identical to that of acute herpes zoster neuralgia, but is closely related to neural plasticity, involving peripheral neuronal sensitization, central neuronal sensitization, inflammatory response, neural deafferentation, and sympathetic nerve dysfunction[8,9]. To facilitate understanding of the pathogenesis cascade from VZV reactivation to central sensitization in ZAP and PHN, a schematic diagram is presented in Figure 1 (created with BioGDP.com.)[10].

Neuronal sensitization mechanisms

Peripheral neuronal sensitization

As mentioned earlier, during the acute phase of HZ, continuous and repeated stimulation by a large number of inflammatory mediators reduces the action potential threshold of locally sensitized nociceptors, impairs the ability of damaged peripheral nerve fibers to inhibit nociceptive stimulus signals, enhances the response to specific stimuli, increases the receptive field, and raises the firing rate. Damaged nociceptors discharge abnormally, and primary sensory neurons undergo neurochemical, physiological, and anatomical changes, which amplify afferent nerve signals and simultaneously affect adjacent undamaged neurons, leading to increased pain sensitivity. After peripheral nerve injury, spontaneous electrical activity is significantly increased in both injured and adjacent undamaged nociceptive afferent nerves, resulting in spontaneous ectopic neuronal discharge and allodynia, namely the peripheral sensitization phase, which is one of the important mechanisms underlying hyperalgesia and ectopic pain in patients with PHN. Abnormal function of ion channels (sodium channels, potassium channels, calcium channels, and transient receptor potential vanilloid [TRPV]) is a core link of peripheral sensitization (e.g., abnormally increased expression of sodium channels Nav1.7 and Nav1.8), providing clear targets for clinical drug therapy (e.g., calcium channel blockers)[11].

Central neuronal sensitization

Central neuronal sensitization is the main mechanism by which acute HZ pain evolves into chronic pain (i.e., PHN), referring to the abnormal increase in excitability and enhanced synaptic transmission of pain-related neurons in the spinal cord and above the spinal cord, which is manifested by increased spontaneous neuronal discharge, expanded receptive field, and decreased stimulation threshold. Central neuronal sensitization is the result of the combined effects of multiple factors, including disinhibition of the descending pain regulation pathway, neural deafferentation, peripheral neuronal sensitization, abnormal ion channels, and immune inflammation. The spinal dorsal horn is the first site for the transmission and regulation of nociceptive information, and depending on the duration and intensity of pain, it may affect the pain-related areas of the central nervous system and reduce the pain threshold[12]. Compensatory formation of nociceptive neural pathways further amplifies pain signals, leading to the occurrence of central sensitization, which results in long-term and significant responses to sensory input and the chronicization of pain[13].

In addition, the process of central neuronal sensitization also involves excitatory amino acids and neuropeptides. Pathologically sensitized C-fibers release glutamate, leading to the phosphorylation and activation of NMDA and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Excessive nociceptive stimulus signals can lead to continuous discharge of peripheral afferent fibers, postsynaptic changes and increased excitability of nociceptive neurons in the spinal cord and above, enhanced responses to many sensory signals, enabling low-threshold mechanically sensitive Aβ and Aδ afferent fibers to activate pain-related neurons in the spinal cord and above, and transmit sensory information to the brain. Therefore, specific sensory stimuli can activate more pain-related neurons in the spinal cord and above, and mild harmless mechanical stimulation of the skin can cause pain (i.e., dynamic mechanical allodynia), resulting in the so-called central neuronal sensitization[3].

It is worth noting that central neuronal sensitization in the brain caused by chronic pain is usually accompanied by changes in central neural plasticity, which may also alter brain structure and function[14]. Studies based on structural and functional magnetic resonance imaging have shown that PHN patients have different structural and functional changes in brain regions within the attention, default, and pain network systems. PHN patients have functional changes in the cerebellum, occipital lobe, temporal lobe, parietal lobe, and limbic lobe, and these changes in brain activity may be related to the evolution of HZ into PHN[15–19]. Multiple studies have shown that compared with healthy brains, the gray matter volume (GMV) of PHN patients changes in regions such as the insula, middle frontal gyrus, posterior cerebellar lobe, and parahippocampal gyrus[17–21]. Studies have shown that PHN patients have microstructural changes in white matter regions such as the frontoparietal lobe, insula, occipital lobe, cerebellum, amygdala, posterior limb of the internal capsule, and corpus callosum, and these changes increase with the duration of pain, and the integrity of white matter structure deteriorates with the extension of pain duration[22].

Role of ion channels

Abnormalities in ion channel expression and function are the core molecular mechanism of central neuronal sensitization, which directly determine the increased excitability, enhanced synaptic plasticity, and amplification of pain signals of central pain-related neurons such as those in the spinal dorsal horn, thalamus, and cortex, and are key driving factors for the persistence of chronic neuropathic pain such as PHN. A large number of studies have shown that the ion channels involved in the occurrence of chronic neuropathic pain mainly include voltage-gated sodium channels, calcium channels, potassium channels, ligand-gated ion channels (NMDA receptors, AMPA receptors, and GABA receptors), transient receptor potential (TRP) channels, and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels[23]. Under pathological conditions, the upregulation, increased density, and enhanced function of pro-excitatory ion channels, including voltage-gated sodium channels (Nav), voltage-gated calcium channels (Cav), and HCN channels enhance neurotransmitter release, excitability, and ectopic discharge of peripheral sensory neurons. This is further enhanced by the downregulation of the KCNA gene encoding the voltage-gated potassium channel (Kv); for example, the inhibition of KCNA by long non-coding RNAs (lncRNAs) and the reduced inhibition of the cold sensor TRP melastatin 8 (TRPM8) by Kv. Thrombospondins 1–4 (Tsp1–4) act through the α2δ1 subunit of Cav to mediate enhanced activity-dependent synaptogenesis[24].

Ectopic pacemaker hypothesis

This hypothesis holds that nerve injury can also increase spinal afferent electricity by generating ectopic discharges, which is the main cause of neuropathic pain. The central nervous system is the main generator of ectopic discharges that induce persistent nociceptive pain. The damaged DRG of the spinal cord can cause afferent nerve block, which may influence the central nervous system and increase neuropathic pain[25].

Neuroelectrophysiological studies have revealed that ectopic impulses in damaged nerve fibers can induce spontaneous pain and tactile allodynia, and the disappearance of sensory endings of epidermal C-fibers leads to hypoalgesia to thermal stimulation; as a peripheral nervous system generator of spontaneous pain and tactile allodynia, ectopic pacemakers initiate the generation of ectopic impulses in damaged nerve fibers[26]. The DRG, as a driving factor of spontaneous pain in herpes zoster and PHN[27], are considered to be caused by central sensitization enhancing the sensory effect of normal cutaneous Aβ tactile afferents. In turn, central sensitization is maintained by spontaneous ectopic discharges. Spontaneous discharges of Aβ afferents and nociceptors may also be “amplified” by central sensitization (i.e., becoming painful and more intense). This factor can exacerbate spontaneous pain[28].

Neuro-immune-inflammatory interaction

As mentioned earlier, after primary infection, the VZV persists latently in the sensory ganglia. When the virus migrates along the sensory nerves, reactivation occurs, thereby inducing inflammation and viral replication in the affected dermatomes[29]. Virus-induced inflammation may lead to nerve injury and sensitization, thereby altering nervous system signal transmission and ultimately resulting in PHN. During this process, pro-inflammatory cytokines such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and IL-1β are released, which play a role in maintaining the inflammatory environment and peripheral neuronal sensitization[30]. Even after the initial rash subsides, this persistent inflammatory condition may lead to brain sensitization and subsequent chronic pain[31]. In addition, the inflammatory response can worsen, and the chronic pain of PHN is maintained by the migration of immune cells such as T cells and macrophages to the site of VZV reactivation[29].

Furthermore, a growing body of evidence indicates that glial cell activation plays a crucial role in central nervous system inflammatory responses and peripheral neuropathic pain. This is because the subsequent release of cytokines and inflammatory mediators leads to nerve edema, axonal degeneration, and glial cell proliferation, thereby promoting the formation and development of PHN[32]. Ma et al. found that intravenous injection of lidocaine inhibited neuroinflammation induced by the activation of microglia and astrocytes in the spinal dorsal horn, prefrontal cortex, anterior cingulate cortex, and hippocampus. It also downregulated the expression of TNF-α and IL-1 in the spinal dorsal horn, ultimately alleviating neuroinflammation and PHN symptoms[33].

Microglia act on neurons repeatedly, promoting glial cell-mediated neuroinflammatory responses and peripheral sensitization[34]. A specific marker of astrocytes is glial fibrillary acidic protein (GFAP); the upregulation of GFAP activates astrocytes, while a specific marker of microglia is cluster of differentiation 11b (OX-42). Lei et al. found that peripheral nerve injury increased the expression of OX-42 and GFAP, indicating that the activation of microglia and astrocytes induces and maintains PHN pain[35]. A large body of evidence suggests that neuroinflammation, characterized by glial cell activation-mediated release of inflammatory mediators, plays a decisive role in central sensitization of neuropathic pain[36]. Glial cell activation releases pro-inflammatory factors and chemokines, which prolong pain and induce and maintain PHN[37].

In vivo experiments have also corroborated this point. In animal models of herpetic neuralgia induced by HSV-1 (used as a surrogate for VZV), leukocytes composed of macrophages and neutrophils infiltrate the virus-infected DRG. The infiltrating leukocytes are responsible for driving the production of inflammatory mediators such as TNF-α and S100A9, and lead to the development of herpetic neuralgia[38,39]. Inhibiting the immune-inflammatory response through molecular (targeting S100A9) or pharmacological (anti-inflammatory drugs) approaches can effectively alleviate virus-induced mechanical pain[40].

Changes in gene expression

Genetic studies have shown that human genetic variations and single nucleotide polymorphisms (SNPs) are associated with various pain-related phenotypes. These genetic variations involve genes encoding structural proteins that are involved in the nociceptive pathways and pain regulation of PHN. They can be used to determine the risk, susceptibility, severity, and protective measures of PHN[41,42].

However, the impact of genetic variations on PHN susceptibility remains poorly understood. Some studies have only focused on key genes encoding ion channels related to neuropathic pain in a scattered manner, such as SCN9A, the key gene encoding Nav1.7[43]. Another focus is on a variant genotype in the gene of purinergic P2X receptor 7 (P2X7R), a core driver molecule in pain processing and neuronal sensitization, which is considered to have a protective effect[41].

Some studies have identified genes associated with PHN and its pathogenesis: genotypes and molecular targets of human leukocyte antigen (HLA). It has been reported that the HLAs associated with the development of PHN include HLA-A33, HLA-B44, and HLA-A33-B44; as well as HLA-A3303, HLA-B4403, and HLA-DRB1*1302[44]. In contrast, another study found an association between the PRKCQ gene, which encodes protein kinase Cθ (PKCθ), and PHN[42]. Zhang et al. showed that miR-16-5p may alleviate RTX-induced PHN-like pain by inhibiting the expression of Akt3 in the skin[45]. Guedon et al.[46] used gene microarray chips to study the VZV-induced PHN rat model; the gene microarray data showed significant changes in the gene expression pattern of DRG, including the upregulated expression of nociception-related genes NTRK2, TRPV1, and Calca (CGRP). Bioinformatics analysis identified 11 and 31 miRNAs associated with neuropathic pain and inflammation in rats, respectively, and identified 10 hub genes associated with PHN (S1PR1, OPRM1, PDYN, CXCL3, S1PR5, TBX5, TNNI3, MYL7, PTGDR2, and FBXW2), which may play important roles in the occurrence and development of PHN and serve as therapeutic targets[18].

In addition, with the discovery of transcripts encoded by VZV genes and a new VZV transcript (VLT), greater attention has been paid to the key issue of the nature and extent of viral gene transcription during VZV latency, which antisense maps to the viral transactivator gene[47,48]. In recent years, significant epigenetic regulation of VZV gene transcription has also been found, and the underlying mechanisms are complex and being unraveled[49]. Currently, genome-wide association studies on the efficacy of pain treatment drugs are underway, which may have important significance and benefits for the treatment of PHN. Furthermore, methods to determine the individual uniqueness of these channels and receptors before initiating treatment remain elusive. The genetic basis of drug therapy provides insights into the protective effects of genes, susceptible genotypes, and high-risk HLAs[50].

Sympathetic nerve system dysfunction

Hypotheses suggested that sympathetic nervous system (SNS) lesions play a role in the development of PHN pain. However, the contribution of the SNS to the development and maintenance of PHN remains unclear. This hypothesis holds that acute inflammatory responses produce strong sympathetic nerve stimulation, leading to reduced neuronal blood flow and neuronal ischemia. This may be related to its functions in regulating the vascular system, glandular secretion, and pain transmission; blocking the sympathetic nerves can dilate blood vessels and increase blood flow, thereby relieving pain[51].

Indeed, clinical practices have suggested that sympathetic nerve therapy can improve PHN, and numerous studies have shown that the sympathetic nerves are closely related to the pathology of PHN, while sympathetic nerve block therapy can improve PHN-related clinical symptoms[52,53]. The VZV (HZ virus) reactivates in the ganglia and spreads to the corresponding dermatomes through the affected nerves, leading to severe ganglionitis and neuritis, inducing strong sympathetic nerve stimulation, resulting in arteriolar vasospasm within the nerves, reducing blood flow in the intra-neural capillary bed, and causing neuronal ischemia and edema[54,55]. In the early stage of HZ, intervening in the sympathetic nerves can alleviate vasospasm and prevent irreversible nerve damage.

Having detailed the cellular and molecular mechanisms underlying ZAP and PHN, we summarize the key molecular targets and their corresponding therapeutic strategies in Table 1, providing a concise overview for translational research.

Conclusion

In summary, the occurrence and development of ZAP involve multiple complex pathophysiological processes, including inflammation-induced peripheral and central sensitization, abnormalities in brain structure and function, abnormal gene expression, neuro-immune-inflammatory interactions, and sympathetic nerve abnormalities. However, more specific and reliable studies are needed to thoroughly analyze the details of its complex pathogenesis. Given the high prevalence of ZAP and its extensive harmful effects on individuals and society, in-depth research is necessary. A more comprehensive understanding of the potential pathogenesis of ZAP is required to enable effective management and treatment.

References

[1] Liu Q, Han J, Zhang X. Peripheral and central pathogenesis of postherpetic neuralgia. Skin Res Technol. 2024;30(8):e13867.

[2] Chinese Society of Pain Medicine, Chinese Society of Dermatology and Venereology, Chinese Medical Doctor Association Pain Medicine Branch, et al. Guidelines for the whole-course management of herpes zoster-associated pain in china (2025 edition). Chinese Journal of Pain Medicine. 2025;31(8):561-571.

[3] Devor M. Rethinking the causes of pain in herpes zoster and postherpetic neuralgia: the ectopic pacemaker hypothesis. Pain Rep. 2018;3(6):e702.

[4] Adriaansen EJM, Jacobs JG, Vernooij LM, et al. 8. Herpes zoster and post herpetic neuralgia. Pain Pract. 2024;25:e13423.

[5] Zepeda-Morales K, Bravo D, Aránguiz-Barrera J, et al. N-methyl-d-aspartate receptor activation is downstream coupled to pannexin 1 opening by src kinase in dorsal horn neurons: an essential link for mechanical hyperalgesia in nerve-injured rats. Pain. 2025;166(6):1369-1381.

[6] Kong E, Hua T, Li J, et al. Hsv-1 reactivation results in post-herpetic neuralgia by upregulating prmt6 and inhibiting cgas-sting. Brain. 2024;147(7):2552-2565.

[7] Werner RN, Nikkels AF, Marinović B, et al. European consensus-based (s2k) guideline on the management of herpes zoster-guided by the european dermatology forum (edf) in cooperation with the european academy of dermatology and venereology (eadv), part 1: diagnosis. J Eur Acad Dermatol Venereol. 2017;31(1):9-19.

[8] Alles SRA, Smith PA. Etiology and pharmacology of neuropathic pain. Pharmacol Rev. 2018;70(2):315-347.

[9] Tang J, Zhang Y, Liu C, Zeng A, Song L. Therapeutic strategies for postherpetic neuralgia: mechanisms, treatments, and perspectives. Curr Pain Headache Rep. 2023;27(9):307-319.

[10] Jiang S, Li H, Zhang L, et al. Generic diagramming platform (gdp): a comprehensive database of high-quality biomedical graphics. Nucleic Acids Res. 2025;53(D1):D1670-D1676.

[11] Aronoff GM. What do we know about the pathophysiology of chronic pain? implications for treatment considerations. Med Clin North Am. 2016;100(1):31-42.

[12] Yarmolinsky DA, Zeng X, MacKinnon-Booth N, et al. Differential modification of ascending spinal outputs in acute and chronic pain states. Neuron. 2025;113(8):1223-1239.e5.

[13] Zhang KL, Li SJ, Pu XY, et al. Targeted up-regulation of drp1 in dorsal horn attenuates neuropathic pain hypersensitivity by increasing mitochondrial fission. Redox Biol. 2022;49:102216.

[14] Lei X, Liao T, He R, et al. Central effects of short-term spinal cord stimulation in postherpetic neuralgia: a longitudinal fmri and dti study. Front Neurosci. 2025;19:1744783.

[15] Cao S, Li Y, Deng W, et al. Local brain activity differences between herpes zoster and postherpetic neuralgia patients: a resting-state functional mri study. Pain Physician. 2017;20(5):E687-E699.

[16] Hong S, Gu L, Zhou F, et al. Altered functional connectivity density in patients with herpes zoster and postherpetic neuralgia. J Pain Res. 2018;11:881-888.

[17] Huang J, Li Y, Xie H, et al. Abnormal intrinsic brain activity and neuroimaging-based fmri classification in patients with herpes zoster and postherpetic neuralgia. Front Neurol. 2020;11:532110.

[18] Tang Y, Wang M, Zheng T, et al. Structural and functional brain abnormalities in postherpetic neuralgia: a systematic review of neuroimaging studies. Brain Res. 2021;1752:147219.

[19] May A. Chronic pain may change the structure of the brain. Pain. 2008;137(1):7-15.

[20] Liu J, Gu L, Huang Q, et al. Altered gray matter volume in patients with herpes zoster and postherpetic neuralgia. J Pain Res. 2019;12:605-616.

[21] Zhang Y, Yu T, Qin B, Li Y, Song G, Yu B. Microstructural abnormalities in gray matter of patients with postherpetic neuralgia: a diffusional kurtosis imaging study. Pain Physician. 2016;19(4):E601-E611.

[22] Chen F, Chen F, Shang Z, et al. White matter microstructure degenerates in patients with postherpetic neuralgia. Neurosci Lett. 2017;656:152-157.

[23] Bouali-Benazzouz R, Landry M, Benazzouz A, Fossat P. Neuropathic pain modeling: focus on synaptic and ion channel mechanisms. Prog Neurobiol. 2021;201:102030.

[24] Finnerup NB, Kuner R, Jensen TS. Neuropathic pain: from mechanisms to treatment. Physiol Rev. 2021;101(1):259-301.

[25] Midha R, Grochmal J. Surgery for nerve injury: current and future perspectives. J Neurosurg. 2019;130(3):675-685.

[26] Buonocore M, Gatti AM, Amato G, Aloisi AM, Bonezzi C. Allodynic skin in post-herpetic neuralgia: histological correlates. J Cell Physiol. 2012;227(3):934-938.

[27] Koplovitch P, Devor M. Dilute lidocaine suppresses ectopic neuropathic discharge in dorsal root ganglia without blocking axonal propagation: a new approach to selective pain control. Pain. 2018;159(7):1244-1256.

[28] Devor M. Neural basis of pain in herpes zoster and postherpetic neuralgia: the ectopic pacemaker hypothesis. In: Watson CPN, Gershon AA, Oxman MN, eds. Herpes Zoster: Postherpetic Neuralgia and Other Complications. Cham, Switzerland: Springer International Publishing; 2017:157-187.

[29] Hakami MA, Khan FR, Abdulaziz O, et al. Varicella-zoster virus-related neurological complications: from infection to immunomodulatory therapies. Rev Med Virol. 2024;34(4):e2554.

[30] Shen Y, Lin P. The role of cytokines in postherpetic neuralgia. J Integr Neurosci. 2025;24(4):25829.

[31] Baskett J, Culos KA, Satyanarayana G, et al. Risk factors associated with early viral reactivation following haploidentical hematopoietic cell transplantation with post-transplant cyclophosphamide: a pilot study. Ann Hematol. 2020;99(5):1137-1139.

[32] Chen K, Wei X, Zhang W, Wang R, Wang Y, Yang L. Bone morphogenetic protein 4 derived from the cerebrospinal fluid in patients with postherpetic neuralgia induces allodynia via the crosstalk between microglia and astrocyte. Brain Behav Immun. 2024;119:836-850.

[33] Ma L, Li J, Zhou J, et al. Intravenous lidocaine alleviates postherpetic neuralgia in rats via regulation of neuroinflammation of microglia and astrocytes. iScience. 2021;24(2):102108.

[34] Huang L, Huang Q, Zhang Z. Glial contributions to neuropathic pain: central and peripheral strategies in postherpetic neuralgia pathogenesis and therapeutics. Eur J Neurosci. 2026;63(2):e70398.

[35] Lei Y, Sun Y, Lu C, Ma Z, Gu X. Activated glia increased the level of proinflammatory cytokines in a resiniferatoxin-induced neuropathic pain rat model. Reg Anesth Pain Med. 2016;41(6):744-749.

[36] Yadav S, Surolia A. Lysozyme elicits pain during nerve injury by neuronal toll-like receptor 4 activation and has therapeutic potential in neuropathic pain. Sci Transl Med. 2019;11(504):eaav4176.

[37] Jung Y, Lee JH, Kim W, Yoon SH, Kim SK. Anti-allodynic effect of buja in a rat model of oxaliplatin-induced peripheral neuropathy via spinal astrocytes and pro-inflammatory cytokines suppression. BMC Complement Altern Med. 2017;17(1):48.

[38] Silva JR, Lopes AH, Talbot J, et al. Neuroimmune-glia interactions in the sensory ganglia account for the development of acute herpetic neuralgia. J Neurosci. 2017;37(27):6408-6422.

[39] Silva CR, Melo BMS, Silva JR, et al. S100a9 plays a pivotal role in a mouse model of herpetic neuralgia via tlr4/tnf pathway. Brain Behav Immun. 2020;88:353-362.

[40] Ueda Y, Uta D, Tanbo S, et al. Inhibitory effect of amenamevir on acute herpetic pain and postherpetic neuralgia in mice infected with herpes simplex virus-1. J Dermatol Sci. 2020;98(1):50-57.

[41] Xing X, Bai Y, Sun K, et al. Identification of candidate genes associated with postherpetic neuralgia susceptibility. Pain Physician. 2020;23(3):E281-E288.

[42] Nishizawa D, Iseki M, Arita H, et al. Genome-wide association study identifies candidate loci associated with chronic pain and postherpetic neuralgia. Mol Pain. 2021;17:1744806921999924.

[43] Price N, Namdari R, Neville J, et al. Safety and efficacy of a topical sodium channel inhibitor (tv-45070) in patients with postherpetic neuralgia (phn): a randomized, controlled, proof-of-concept, crossover study, with a subgroup analysis of the nav1.7 r1150w genotype. Clin J Pain. 2017;33(4):310-318.

[44] Kambur O, Kaunisto MA, Winsvold BS, et al. Genetic variation in p2rx7 and pain tolerance. Pain. 2018;159(6):1064-1073.

[45] Zhang D, Ma L, Tan X, et al. Intradermal mir-16-5p targets akt3 and reduces rtx-induced postherpetic neuralgia-mimic pain in mice. Eur J Pharmacol. 2023;946:175665.

[46] Guedon JM, Yee MB, Zhang M, Harvey SA, Goins WF, Kinchington PR. Neuronal changes induced by varicella zoster virus in a rat model of postherpetic neuralgia. Virology. 2015;482:167-180.

[47] Kennedy PGE, Mogensen TH, Cohrs RJ. Recent issues in varicella-zoster virus latency. Viruses. 2021;13(10):2018.

[48] Bisht P, Das B, Kinchington PR, Goldstein RS. Varicella-zoster virus (vzv) small noncoding rnas antisense to the vzv latency-encoded transcript vlt enhance viral replication. J Virol. 2020;94(13):e00123-20.

[49] Zerboni L, Sen N, Oliver SL, Arvin AM. Molecular mechanisms of varicella zoster virus pathogenesis. Nat Rev Microbiol. 2014;12(3):197-210.

[50] Anosike UG, Ouko I, Mwaura AW, Ongidi I, Mbonu CC. Phenotypes and genotypes in postherpetic neuralgia drug therapy: a narrative mini-review. Clin J Pain. 2022;38(8):536-540.

[51] Kim MK, Yi MS, Park PG, Kang H, Lee JS, Shin HY. Effect of stellate ganglion block on the regional hemodynamics of the upper extremity: a randomized controlled trial. Anesth Analg. 2018;126(5):1705-1711.

[52] Makharita MY. Prevention of post-herpetic neuralgia from dream to reality: a ten-step model. Pain Physician. 2017;20(2):E209-E220.

[53] Jeon Y. Therapeutic potential of stellate ganglion block in orofacial pain: a mini review. J Dent Anesth Pain Med. 2016;16(3):159-163.

[54] Gopal D, Singh NG, Jagadeesh AM, Ture A, Thimmarayappa A. Comparison of left internal mammary artery diameter before and after left stellate ganglion block. Ann Card Anaesth. 2013;16(4):238-242.

[55] Kim EM, Yoon KB, Lee JH, Yoon DM, Kim DH. The effect of oxygen administration on regional cerebral oxygen saturation after stellate ganglion block on the non-blocked side. Pain Physician. 2013;16(2):117-124.

RIGHTS & PERMISSIONS

The Author(s) 2026. This article is published by Higher Education Press on behalf of People’s Medical Publishing House.