BACKGROUND:Previous studies have confirmed that the microglial activation and subsequent inflammatory responses in the trigeminal nucleus caudalis (TNC) are involved in the central sensitization of chronic migraine (CM). MicroRNA-155-5p has been shown to modulate the polarization of microglia and participate in inflammatory processes in a variety of neurological diseases. However, its role in CM remains unclear. The purpose of this study was to determine the precise role of miR-155-5p in CM. METHODS:A model of CM in C57BL/6 mice was established by recurrent intraperitoneal injection of nitroglycerin (NTG). Mechanical and thermal hyperalgesia were evaluated by Von Frey filaments and radiant heat. The expression of miR-155-5p was examined by qRT-PCR, and the mRNA and protein levels of silent information regulator 1(SIRT1) were measured by qRT-PCR, Western blotting (WB) and immunofluorescence (IF) analysis. The miR-155-5p antagomir, miR-155-5p agomir, SRT1720 (a SIRT1 activator) and EX527 (a SIRT1 inhibitor) were administered to confirm the effects of miR-155-5p and SIRT1 on neuroinflammation and the central sensitization of CM. ELISA, WB and IF assays were applied to evaluate the expression of TNF-α, myeloperoxidase (MPO), IL-10, p-ERK, p-CREB, calcitonin gene-related peptide (CGRP), c-Fos and microglial activation. The cellular localization of SIRT1 was illustrated by IF. RESULTS:After the NTG-induced mouse model of CM was established, the expression of miR-155-5p was increased. The level of SIRT1 was decreased, and partly colocalized with Iba1 in the TNC. The miR-155-5p antagomir and SRT1720 downregulated the expression of p-ERK, p-CREB, CGRP, and c-Fos, alleviating microglial activation and decreasing inflammatory substances (TNF-α, MPO). The administration of miR-155-5p agomir or EX527 exacerbated neuroinflammation and central sensitization. Importantly, the miR-155-5p agomir elevated CGRP and c-Fos expression and microglial activation, which could subsequently be alleviated by SRT1720. CONCLUSIONS:These data demonstrate that upregulated miR-155-5p in the TNC participates in the central sensitization of CM. Inhibiting miR-155-5p alleviates neuroinflammation by activating SIRT1 in the TNC of CM mice.

Trigeminal neuralgia (TN)-related cognitive impairment is a common cause of decreased quality of life in patients and is closely associated with neuroinflammation. Although minocycline has demonstrated anti-inflammatory, analgesic, and neuroprotective functions, its role in treating TN-related cognitive impairment remains unreported. In this study, we used an in vivo TN model and an in vitro model of primary microglial neuroinflammation to investigate the potential effects of minocycline on cognitive function and microglial polarization in TN rats. Our results suggested that minocycline treatment attenuated cognitive deficits by alleviating hippocampal neuronal damage and enhancing synaptic plasticity in TN rats. Furthermore, both in vitro and in vivo assays demonstrated that minocycline polarized activated microglia to the M2 phenotype, leading to the reduction of pro-inflammatory factors, including tumor necrosis factor-α and interleukin-1, and an increase in the anti-inflammatory factors, such as interleukin-4 and interleukin-10, thereby attenuating neuroinflammation. Moreover, it was found that the TLR4/MyD88/NF-κB pathway was involved in the shift of microglia from a pro-inflammatory (M1) to an anti-inflammatory (M2). In summary, minocycline likely mediated the process of microglia polarization partly via the TLR4/MyD88/NF-κB pathway, promoting neuronal survival and restoring synaptic plasticity, thereby improving TN-related cognitive impairment.

The N6-methyladenosine (mA) modification of RNA is an emerging epigenetic regulatory mechanism that has been shown to participate in various pathophysiological processes. However, its involvement in modulating neuropathic pain is still poorly understood. In this study, we elucidate a functional role of the mA demethylase alkylation repair homolog 5 (ALKBH5) in modulating trigeminal-mediated neuropathic pain. Peripheral nerve injury selectively upregulated the expression level of ALKBH5 in the injured trigeminal ganglion (TG) of rats. Blocking this upregulation in injured TGs alleviated trigeminal neuropathic pain, while mimicking the upregulation of ALKBH5 in intact TG neurons sufficiently induced pain-related behaviors. Mechanistically, histone deacetylase 11 downregulation induced by nerve injury increases histone H3 lysine 27 acetylation (H3K27ac), facilitating the binding of the transcription factor forkhead box protein D3 (FOXD3) to the promoter and promoting transcription. The increased ALKBH5 erases mA sites in messenger RNA (mRNA), resulting in an inability of YT521-B homology domain 2 (YTHDF2) to bind to mRNA, thus causing an increase in 5-HT3A protein expression and 5-HT3 channel currents. Conversely, blocking the increased expression of ALKBH5 in the injured TG destabilizes nerve injury-induced 5-HT3A upregulation and reverses mechanical allodynia, and the effect can be blocked by 5-HT3A knockdown. Together, FOXD3-mediated transactivation of ALKBH5 promotes neuropathic pain through mA-dependent stabilization of mRNA in TG neurons. This mechanistic understanding may advance the discovery of new therapeutic targets for neuropathic pain management.

The pathogenesis of neuropathic pain (NP) is complex, and there are various pathological processes. Previous studies have suggested that lncRNA PCAT19 is abnormally expressed in NP conduction and affects the occurrence and development of pain. The aim of this study is to analyze the role and mechanism of PCAT19 in NP induced by chronic compressive nerve injury (CCI) in mice. In this study, C57BL/6 mice were applied to establish the CCI model. sh-PCAT19 was intrathecally injected once a day for 5 consecutive days from the second day after surgery. We discovered that PCat19 level was gradually up-regulated with the passage of modeling time. Downregulation of Iba-1-positive expression, M1/M2 ratio of microglia, and pro-inflammatory factors in the spinal cords of CCI-mice after PCat19 knock-downed was observed. Mechanically, the expression of miR-378a-3p was negatively correlated with KDM3A and PCat19. Deletion of KDM3A prevented H3K9me2 demethylation of BDNF promoter and suppressed BDNF expression. Further, KDM3A promotes CCI-induced neuroinflammation and microglia activation by mediating Brain-derived neurotrophic factor (BDNF) demethylation. Together, the results suggest that PCat19 may be involved in the development of NP and that PCat19 shRNA injection can attenuate microglia-induced neuroinflammation by blocking KDM3A-mediated demethylation of BDNF and BDNF release.

Trigeminal neuralgia is a manifestation of orofacial neuropathic pain disorder, always deemed to be an insurmountable peak in the field of pain research and treatment. The pain is recurrent, abrupt in onset and termination similar to an electric shock or described as shooting. A poor quality of life has been attributed to trigeminal neuralgia, as the paroxysms of pain may be triggered by innocuous stimuli on the face or inside the oral cavity, such as talking, washing face, chewing and brushing teeth in daily life. The pathogenesis of trigeminal neuralgia has not been fully elucidated, although the microvascular compression in the trigeminal root entry zone is generally considered to be involved in the emergence and progression of the pain disorder. In addition, orofacial neuropathic pain restricted to one or more divisions of the trigeminal nerve might be secondary to peripheral nerve injury. Based on current hypotheses regarding the potential causes, a variety of animal models have been designed to simulate the pathogenesis of trigeminal neuralgia, including models of compression applied to the trigeminal nerve root or trigeminal ganglion, chronic peripheral nerve injury, peripheral inflammatory pain and center-induced pain. However, it has not yet been possible to determine which model can be perfectly employed to explain the mechanisms. The selection of appropriate animal models is of great significance for the study of trigeminal neuralgia. Therefore, it is necessary to discuss the characteristics of the animal models in terms of animal strains, materials, operation methods and behavior observation, in order to gain insight into the research progress in animal models of trigeminal neuralgia. In the future, animal models that closely resemble the features of human trigeminal neuralgia pathogenesis need to be developed, with the aim of making valuable contributions to the relevant basic and translational medical research.

Neuropathic pain is a chronic pain condition that is primarily caused by underlying neurological damage and dysfunction. Recent studies have identified microRNAs (miRNAs) as a key factor in the treatment of neuropathic pain. To explore the effects of miR-133a-3p on neuroinflammation and neuropathic pain via GTP cyclohydrolase (GCH1), and its underlying mechanisms. In vitro models were constructed using BV-2 cells that had been treated with lipopolysaccharide, followed by treatment with either miR-133a-3p mimic or GCH1 viral knockdown/overexpression. The expression of miR-133a-3p and GCH1 in BV-2 cells was quantified by RT-qPCR. The degree of neuroinflammation was quantified using an enzyme-linked immunosorbent assay (ELISA). The targeting relationship between miR-133a-3p and GCH1 was confirmed by western blot and dual luciferase reporter assay. A chronic constriction injury model was employed to induce neuropathic pain in rats, and the mechanical withdrawal threshold (MWT) was quantified. Immunofluorescence was used to demonstrate alterations in microglial cells. The expression of miR-133a-3p was found to be decreased in lipopolysaccharide-induced BV-2 cells. The overexpression of miR-133a-3p was observed to inhibit the expression of IL-1β, IL-6, TNF-α and iNOS, which was attributed to a reduction in GCH1.Nevertheless, OE-GCH1 could partially reverse the downregulation by miR-133a-3p of the expression of inflammatory factors. In animal experiments, intrathecal injection of AVV-miR-133a-3p was observed to alleviate mechanical nociceptive abnormalities induced by activated microglia. Furthermore, miR-133a-3p ameliorated neuroinflammation in the spinal cord of chronic constriction injury rats. In summary, miR-133a-3p improves neuroinflammation and neuropathic pain by binding to GCH1. The binding of miR-133a-3p to GCH1 has been demonstrated to improve neuroinflammation and neuropathic pain.This insight will facilitate the development of new methods to effectively treat neuropathic pain.

Multiple sclerosis (MS) is an inflammatory disease characterized by myelin loss. While therapies exist to slow MS progression, no treatment currently exists for remyelination. Remyelination, linked to reduced disability in MS, relies on microglia and monocyte-derived macrophages (MDMs). This study aims to understand the role of microglia during remyelination by lineage tracing and depleting them. Microglial lineage tracing reveals that both microglia and MDMs initially accumulate, but microglia later dominate the lesion. Microglia and MDMs engulf equal amounts of inhibitory myelin debris, but after microglial depletion, MDMs compensate by engulfing more myelin debris. Microglial depletion does, however, reduce the recruitment and proliferation of oligodendrocyte progenitor cells (OPCs) and impairs their subsequent differentiation and remyelination. These findings underscore the essential role of microglia during remyelination and offer insights for enhancing this process by understanding microglial regulation of remyelination.

Microglia induced chronic inflammation is the critical pathology of Neuropathic pain (NP). Metabolic reprogramming of macrophage has been intensively reported in various chronic inflammation diseases. However, the metabolic reprogramming of microglia in chronic pain remains to be elusive. Here, we reported that immuno-metabolic markers (HIF-1α, PKM2, GLUT1 and lactate) were related with increased expression of PRMT6 in the ipsilateral spinal cord dorsal horn of the chronic construction injury (CCI) mice. PRMT6 deficiency or prophylactic and therapeutic intrathecal administration of PRMT6 inhibitor (EPZ020411) ameliorated CCI-induced NP, inflammation and glycolysis in the ipsilateral spinal cord dorsal horn. PRMT6 knockout or knockdown inhibited LPS-induced inflammation, proliferation and glycolysis in microglia cells. While PRMT6 overexpression exacerbated LPS-induced inflammation, proliferation and glycolysis in BV2 cells. Recent research revealed that PRMT6 could interact with and methylate HIF-1α, which increased HIF-1α protein stability. In sum, increased expression of PRMT6 exacerbates NP progress by increasing glycolysis and neuroinflammation through interacting with and stabilizing HIF-1α in a methyltransferase manner, which outlines novel pathological mechanism and drug target for NP.

BACKGROUND:This study aimed to investigate the potential mechanism of paeonol in the treatment of neuropathic pain. METHODS:Relevant mechanisms were explored through microglial pseudotime analysis and the use of specific inhibitors in cell experiments. In animal experiments, 32 SD rats were randomly divided into the sham operation group, the chronic constrictive injury (CCI) group, the ibuprofen group, and the paeonol group. We performed behavioral testing, ELISA, PCR, Western blotting, immunohistochemistry, and immunofluorescence analysis. RESULTS:The pseudotime analysis of microglia found that RhoA, Rock1, and p38MAPK were highly expressed in activated microglia, and the expression patterns of these genes were consistent with the expression trends of the M1 markers CD32 and CD86. Paeonol decreased the levels of M1 markers (IL1β, iNOS, CD32, IL6) and increased the levels of M2 markers (IL10, CD206, ARG-1) in LPS-induced microglia. The expression of iNOS, IL1β, RhoA, and Rock1 was significantly increased in LPS-treated microglia, while paeonol decreased the expression of these proteins. Thermal hyperalgesia occurred after CCI surgery, and paeonol provided relief. In addition, paeonol decreased the levels of IL1β and IL8 and increased the levels of IL4 and TGF-β in the serum of CCI rats. Paeonol decreased expression levels of M1 markers and increased expression levels of M2 markers in the spinal cord. Paeonol decreased IBA-1, IL1β, RhoA, RhoA-GTP, COX2, Rock1, and p-p38MAPK levels in the spinal dorsal horn. CONCLUSION:Paeonol relieves neuropathic pain by modulating microglial M1 and M2 phenotypes through the RhoA/p38 MAPK pathway.

Microglia are so versatile that they not only provide immune surveillance for central nervous system, but participate in neural circuitry development, brain blood vessels formation, blood-brain barrier architecture, and intriguingly, the regulation of emotions and behaviors. Microglia have a profound impact on neuronal survival, brain wiring and synaptic plasticity. As professional phagocytic cells in the brain, they remove dead cell debris and neurotoxic agents via an elaborate mechanism. The functional profile of microglia varies considerately depending on age, gender, disease context and other internal or external environmental factors. Numerous studies have demonstrated a pivotal involvement of microglia in neuropsychiatric disorders, including negative affection, social deficit, compulsive behavior, fear memory, pain and other symptoms associated with major depression disorder, anxiety disorder, autism spectrum disorder and schizophrenia. In this review, we summarized the latest discoveries regarding microglial ontogeny, cell subtypes or state spectrum, biological functions and mechanistic underpinnings of emotional and behavioral disorders. Furthermore, we highlight the potential of microglia-targeted therapies of neuropsychiatric disorders, and propose outstanding questions to be addressed in future research of human microglia.

Microglia, resident macrophages of the CNS, are essential to brain development, homeostasis, and disease. Microglial activation and proliferation are hallmarks of many CNS diseases, including neuropathic pain. However, molecular mechanisms that govern the spinal neuroimmune axis in the setting of neuropathic pain remain incompletely understood. Here, we show that genetic ablation or pharmacological blockade of transient receptor potential vanilloid type 4 (TRPV4) markedly attenuated neuropathic pain-like behaviors in a mouse model of spared nerve injury. Mechanistically, microglia-expressed TRPV4 mediated microglial activation and proliferation and promoted functional and structural plasticity of excitatory spinal neurons through release of lipocalin-2. Our results suggest that microglial TRPV4 channels reside at the center of the neuroimmune axis in the spinal cord, which transforms peripheral nerve injury into central sensitization and neuropathic pain, thereby identifying TRPV4 as a potential new target for the treatment of chronic pain.

Neuropathic pain is a complex pain condition accompanied by prominent neuroinflammation involving activation of both central and peripheral immune cells. Metabolic switch to glycolysis is an important feature of activated immune cells. Hexokinase 2 (HK2), a key glycolytic enzyme enriched in microglia, has recently been shown important in regulating microglial functions. Whether and how HK2 is involved in neuropathic pain-related neuroinflammation remains unknown. Using a HK2-tdTomato reporter line, we found that HK2 was prominently elevated in spinal microglia. Pharmacological inhibition of HK2 effectively alleviated nerve injury-induced acute mechanical pain. However, selective ablation of Hk2 in microglia reduced microgliosis in the spinal dorsal horn (SDH) with little analgesic effects. Further analyses showed that nerve injury also significantly induced HK2 expression in dorsal root ganglion (DRG) macrophages. Deletion of Hk2 in myeloid cells, including both DRG macrophages and spinal microglia, led to the alleviation of mechanical pain during the first week after injury, along with attenuated microgliosis in the ipsilateral SDH, macrophage proliferation in DRGs, and suppressed inflammatory responses in DRGs. These data suggest that HK2 plays an important role in regulating neuropathic pain-related immune cell responses at acute phase and that HK2 contributes to neuropathic pain onset primarily through peripheral monocytes and DRG macrophages rather than spinal microglia.

After spinal cord injury (SCI), the control of activated glial cells such as microglia and astrocytes has emerged as a promising strategy for neuropathic pain management. However, signaling mechanism involved in glial activation in the process of neuropathic pain development and maintenance after SCI is not well elucidated. In this study, we investigated the potential role and mechanism of the JAK2/STAT3 pathway associated with glial cell activation in chronic neuropathic pain development and maintenance after SCI. One month after contusive SCI, the activation of JAK2/STAT3 pathway was markedly upregulated in both microglia and astrocyte in nociceptive processing regions of the lumbar spinal cord. In addition, both mechanical allodynia and thermal hyperalgesia was significantly inhibited by a JAK2 inhibitor, AG490. In particular, AG490 treatment inhibited both microglial and astrocyte activation in the lumbar (L) 4-5 dorsal horn and significantly decreased levels of p-p38MAPK, p-ERK and p-JNK, which are known to be activated in microglia (p-p38MAPK and p-ERK) and astrocyte (p-JNK). Experiments using primary cell cultures also revealed that the JAK2/STAT3 pathway promoted microglia and astrocyte activation after lipopolysaccharide stimulation. Furthermore, JAK2/STAT3 signaling and pain behaviors were significantly attenuated when the rats were treated with anti-IL-6 antibody. Finally, minocycline, a tetracycline antibiotic, inhibited IL-6/JAK2/STAT3 signaling pathway in activated glial cells and restored nociceptive thresholds and the hyperresponsiveness of dorsal neurons. These results suggest an important role of the IL-6/JAK2/STAT3 pathway in the activation of microglia and astrocytes and in the maintenance of chronic below-level pain after SCI.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease worldwide, but therapeutic strategies to slow down AD pathology and symptoms have not yet been successful. While attention has been focused on neurodegeneration in AD pathogenesis, recent decades have provided evidence of the importance of microglia, and resident immune cells in the central nervous system. In addition, new technologies, including single-cell RNA sequencing, have revealed heterogeneous cell states of microglia in AD. In this review, we systematically summarize the microglial response to amyloid-β and tau tangles, and the risk factor genes expressed in microglia. Furthermore, we discuss the characteristics of protective microglia that appear during AD pathology and the relationship between AD and microglia-induced inflammation during chronic pain. Understanding the diverse roles of microglia will help identify new therapeutic strategies for AD.

Microglia play pivotal roles in controlling CNS functions in diverse physiological and pathological contexts, including neuropathic pain, a chronic pain condition caused by lesions or diseases of the somatosensory nervous system. In this review article, we summarize evidence primarily from basic research on the role of microglia in the development and remission of neuropathic pain. The identification of a subset of microglia that emerged after pain development and that was necessary for remission of neuropathic pain highlights the highly divergent and dynamic nature of microglia in the course of neuropathic pain. Understanding microglial diversity in terms of gene expression, physiological states, and functional roles could lead to new strategies that aid in the diagnosis and management of neuropathic pain, and that may not have been anticipated from the viewpoint of targeting all microglia uniformly.

BACKGROUND:Chronic inflammatory pain significantly reduces the quality of life and lacks effective interventions. In recent years, human umbilical cord mesenchymal stem cells (huc-MSCs)-derived exosomes have been used to relieve neuropathic pain and other inflammatory diseases as a promising cell-free therapeutic strategy. However, the therapeutic value of huc-MSCs-derived exosomes in complete Freund's adjuvant (CFA)-induced inflammatory pain remains to be confirmed. In this study, we investigated the therapeutic effect and related mechanisms of huc-MSCs-derived exosomes in a chronic inflammatory pain model. METHODS:C57BL/6J male mice were used to establish a CFA-induced inflammatory pain model, and huc-MSCs-derived exosomes were intrathecally injected for 4 consecutive days. BV2 microglia cells were stimulated with lipopolysaccharide (LPS) plus adenosine triphosphate (ATP) to investigate the effect of huc-MSCs-derived exosomes on pyroptosis and autophagy. Bioinformatic analysis and rescue experiments were used to demonstrate the role of miR-146a-5p/ TRAF6 in regulating pyroptosis and autophagy. Western blotting, RT-qPCR, small interfering RNA and Yo-Pro-1 dye staining were performed to investigate the related mechanisms. RESULTS:Huc-MSCs-derived exosomes alleviated mechanical allodynia and thermal hyperalgesia in CFA-induced inflammatory pain. Furthermore, huc-MSCs-derived exosomes attenuated neuroinflammation by increasing the expression of autophagy-related proteins (LC3-II and beclin1) and inhibiting the activation of NLRP3 inflammasomes in the spinal cord dorsal horn. In vitro, NLRP3 inflammasome components (NLRP3, caspase1-p20, ASC) and gasdermin D (GSDMD-F, GSDMD-N) were inhibited in BV2 cells pretreated with huc-MSCs-derived exosomes. Western blot and Yo-Pro-1 dye staining demonstrated that 3-MA, an autophagy inhibitor, weakened the protective effect of huc-MSCs-derived exosomes on BV2 cell pyroptosis. Importantly, huc-MSCs-derived exosomes transfected with miR-146a-5p mimic promoted autophagy and inhibited BV2 cell pyroptosis. TRAF6, as a target gene of miR-146a-5p, was knocked down via small-interfering RNA, which increased pyroptosis and inhibited autophagy. CONCLUSION:Huc-MSCs-derived exosomes attenuated inflammatory pain via miR-146a-5p/TRAF6, which increased the level of autophagy and inhibited pyroptosis.

Objective Previous studies of neuropathic pain have suggested that the P2X4 purinoceptor (P2X4R) in spinal microglia is essential for maintaining allodynia following nerve injury. However, little is known about its role in inflammatory soup-induced trigeminal allodynia, which closely mimics chronic migraine status. Here, we determined the contributions of P2X4R and related signaling pathways in an inflammatory soup-induced trigeminal allodynia model. Methods P2X4R gene and protein levels in the trigeminal nucleus caudalis were analyzed following repeated dural inflammatory soup infusions. p38, brain-derived neurotrophic factor, excitatory amino acid transporter 3, c-Fos, and calcitonin gene-related peptide protein levels in the trigeminal nucleus caudalis, as well as trigeminal sensitivity, were assessed among the different groups. Immunofluorescence staining was used to detect protein localization and expression in the trigeminal nucleus caudalis. Results Repeated inflammatory dural stimulation induced trigeminal hyperalgesia and the upregulation of P2X4R. Immunofluorescence revealed that P2X4R was expressed in trigeminal nucleus caudalis microglial cells. Blockage of P2X4R produced an anti-nociceptive effect, which was associated with an inhibition of inflammatory soup-induced increases in p38, brain-derived neurotrophic factor, excitatory amino acid transporter 3, c-Fos, and calcitonin gene-related peptide protein levels. The tyrosine receptor kinase B antagonist ANA-12 reversed trigeminal allodynia and the upregulation of excitatory amino acid transporter 3, c-Fos, and calcitonin gene-related peptide, whereas the agonist 7,8-dihydroxyflavone exacerbated these effects. Double immunostaining indicated that p38 and brain-derived neurotrophic factor were mainly expressed in microglial cells, whereas excitatory amino acid transporter 3 was primarily expressed in trigeminal nucleus caudalis neurons. Conclusions These data indicate that microglial P2X4R is involved in the regulation of excitatory amino acid transporter 3 via brain-derived neurotrophic factor-tyrosine receptor kinase B signaling following repeated inflammatory dural stimulation. Microglial P2X4R activation and microglia-neuron interactions in the trigeminal nucleus caudalis may play a role in the pathogenesis of migraine chronicity, and the modulation of P2X4R activation might be a potential therapeutic strategy.

Neuroinflammation induced by engulfment of synapses by phagocytic microglia plays a crucial role in neuropathic pain. Stauntonia chinensis is extracted from DC, which has been used as a traditional Chinese medicine to control trigeminal neuralgia or sciatica. However, the specific anti-neuralgia mechanism of Stauntonia chinensis is unknown. In this study, the analgesic effect of Stauntonia chinensis injection (SCI) in mice with neuropathic pain and the possible mechanisms are explored. We find that a local injection of 0.1 mL Stauntonia chinensis for 14 days can considerably relieve mechanical hyperalgesia and thermal hyperalgesia in mice with sciatic chronic constriction injury (CCI). Immunofluorescence staining shows that SCI reduces neuroinflammation in the spinal cord of CCI mice. RNA sequencing reveals that the expression of postsynaptic density protein 95 (PSD-95), a postsynaptic scaffold protein, is downregulated in the spinal cord of CCI mice, but upregulated after SCI administration. Immunofluorescence experiments also demonstrate that SCI administration reverses microglia proliferation and PSD-95 downregulation in CCI mice. These data suggest that SCI relieves neuropathic pain by increasing the expression of PSD-95 and reducing the proliferation of phagocytic microglia.

Activation of microglia is known to be involved in neuropathic pain. However, the pathway that regulates the microglial activation is not completely understood. Transient receptor potential (TRP) melastatin 2 (TRPM2), which is part of the TRP superfamily, is reportedly expressed on microglia and is suggested to be involved in neuropathic pain. To explore the effect of a TRPM2 antagonist on orofacial neuropathic pain and the relationship between TRPM2 and the activation of microglia, experiments were conducted using male rats that underwent infraorbital nerve (ION) ligation as orofacial neuropathic pain models. TRPM2 expression was detected on microglia in the trigeminal spinal subnucleus caudalis (Vc). The immunoreactivity of TRPM2 in the Vc increased after ION ligation. Mechanical threshold for head-withdrawal response was measured using von Frey filament, and it decreased after ION ligation. When the TRPM2 antagonist was administered to the ION-ligated rats, the low mechanical threshold for head-withdrawal response increased, and the number of phosphorylated extracellular signal-regulated kinase (pERK)-immunoreactive cells in the Vc decreased. The number of CD68-immunoreactive cells in the Vc also decreased after the administration of the TRPM2 antagonist in the ION-ligated rats. These findings suggest that TRPM2 antagonist administration suppresses hypersensitivity to mechanical stimulation induced by ION ligation and microglial activation, and TRPM2 is also involved in microglial activation in orofacial neuropathic pain.

PURPOSE:Hepatocellular carcinoma (HCC) lacks effective curative therapy. Hypoxia is commonly found in HCC. Hypoxia elicits a series of protumorigenic responses through hypoxia-inducible factor-1 (HIF1). Better understanding of the metabolic adaptations of HCC cells during hypoxia is essential to the design of new therapeutic regimen. EXPERIMENTAL DESIGN:Expressions of genes involved in the electron transport chain (ETC) in HCC cell lines (20% and 1% O2) and human HCC samples were analyzed by transcriptome sequencing. Expression of NDUFA4L2, a less active subunit in complex I of the ETC, in 100 pairs of HCC and nontumorous liver tissues were analyzed by qRT-PCR. Student t test and Kaplan-Meier analyses were used for clinicopathologic correlation and survival studies. Orthotopic HCC implantation model was used to evaluate the efficiency of HIF inhibitor. RESULTS:NDUFA4L2 was drastically overexpressed in human HCC and induced by hypoxia. NDUFA4L2 overexpression was closely associated with tumor microsatellite formation, absence of tumor encapsulation, and poor overall survival in HCC patients. We confirmed that NDUFA4L2 was HIF1-regulated in HCC cells. Inactivation of HIF1/NDUFA4L2 increased mitochondrial activity and oxygen consumption, resulting in ROS accumulation and apoptosis. Knockdown of NDUFA4L2 markedly suppressed HCC growth and metastasis in vivo HIF inhibitor, digoxin, significantly suppressed growth of tumors that expressed high level of NDUFA4L2. CONCLUSIONS:Our study has provided the first clinical relevance of NDUFA4L2 in human cancer and suggested that HCC patients with NDUFA4L2 overexpression may be suitable candidates for HIF inhibitor treatment. Clin Cancer Res; 22(12); 3105-17. ©2016 AACR.

BRAF V600E is the most common mutation identified in thyroid cancers. However, the relationship between BRAF V600E and metabolic reprogramming in thyroid cancer is unclear. Here, we investigate the mechanism of metabolic reprogramming in BRAF V600E thyroid cancer by constructing BRAF V600E-overexpressing and BRAF-knockdown thyroid cell lines for use in mitochondrial respiration and glycolysis experiments. Western blot and RT-qPCR were performed to measure the level of metabolism-related proteins, and various approaches were used to investigate transcriptional regulation. In thyroid cancer cells, the overexpression of BRAF V600E inhibited OXPHOS gene expression and mitochondrial respiration but enhanced aerobic glycolysis. Clinical thyroid cancer samples carrying the BRAF V600E mutation had suppressed levels of PGC-1β but increased expression of HIF1α. Our results show that BRAF V600E reduced mitochondrial respiration by decreasing the expression of PGC-1β. In addition, HIF1α, which is a target of BRAF V600E, was found to regulate the expression of PGC-1β via MYC. Furthermore, glycolysis-related enzymes, such as LDHA and PKM2, were upregulated in BRAF V600E mutant thyroid cancer specimens, thereby promoting glycolysis. MEK1/2 inhibitor treatment enhanced the specific dependence of BRAF V600E mutant thyroid cancer on mitochondrial respiration. These results indicate that in thyroid cancer, the BRAF V600E mutation alters the HIF1α-MYC-PGC-1β axis, causing mitochondrial respiration to be inhibited and aerobic glycolysis to be enhanced.

Trigeminal neuralgia (TN) is a facial pain disorder characterized by intense and paroxysmal pain that profoundly affects quality of life and presents complex challenges in diagnosis and treatment. TN can be categorized as classical, secondary and idiopathic. Epidemiological studies show variable incidence rates and an increased prevalence in women and in the elderly, with familial cases suggesting genetic factors. The pathophysiology of TN is multifactorial and involves genetic predisposition, anatomical changes, and neurophysiological factors, leading to hyperexcitable neuronal states, central sensitization and widespread neural plasticity changes. Neurovascular compression of the trigeminal root, which undergoes major morphological changes, and focal demyelination of primary trigeminal afferents are key aetiological factors in TN. Structural and functional brain imaging studies in patients with TN demonstrated abnormalities in brain regions responsible for pain modulation and emotional processing of pain. Treatment of TN involves a multifaceted approach that considers patient-specific factors, including the type of TN, with initial pharmacotherapy followed by surgical options if necessary. First-line pharmacological treatments include carbamazepine and oxcarbazepine. Surgical interventions, including microvascular decompression and percutaneous neuroablative procedures, can be considered at an early stage if pharmacotherapy is not sufficient for pain control or has intolerable adverse effects or contraindications.

Introduction Trigeminal neuralgia (TN) is characterized by touch-evoked unilateral brief shock-like paroxysmal pain in one or more divisions of the trigeminal nerve. In addition to the paroxysmal pain, some patients also have continuous pain. TN is divided into classical TN (CTN) and secondary TN (STN). Etiology and pathophysiology Demyelination of primary sensory trigeminal afferents in the root entry zone is the predominant pathophysiological mechanism. Most likely, demyelination paves the way for generation of ectopic impulses and ephaptic crosstalk. In a significant proportion of the patients, the demyelination is caused by a neurovascular conflict with morphological changes such as compression of the trigeminal root. However, there are also other unknown etiological factors, as only half of the CTN patients have morphological changes. STN is caused by multiple sclerosis or a space-occupying lesion affecting the trigeminal nerve. Differential diagnosis and treatment Important differential diagnoses include trigeminal autonomic cephalalgias, posttraumatic or postherpetic pain and other facial pains. First line treatment is prophylactic medication with sodium channel blockers, and second line treatment is neurosurgical intervention. Future perspectives Future studies should focus on genetics, unexplored etiological factors, sensory function, the neurosurgical outcome and complications, combination and neuromodulation treatment as well as development of new drugs with better tolerability.

BACKGROUND:Trigeminal neuralgia (TN) is the most common neuropathic disorder in the maxillofacial region. The etiology and pathogenesis of TN have not been clearly determined to date, although there are many hypotheses. OBJECTIVE:The goal of this study was to investigate the interactions between different types of cells in TN, particularly the impact and intrinsic mechanism of demyelination on the trigeminal ganglion, and to identify new important target genes and regulatory pathways in TN. METHODS:TN rat models were prepared by trigeminal root compression, and trigeminal nerve tissues were isolated for spatial transcriptome sequencing. The gene expression matrix was reduced dimensionally by PCA and presented by UMAP. Gene function annotation was analyzed by Metascape. The progression of certain clusters and the developmental pseudotime were analyzed using the Monocle package. Modules of the gene coexpression network between different groups were analyzed based on weighted gene coexpression network analysis and assigned AddModuleScore values. The intercellular communication of genes in these networks via ligand-receptor interactions was analyzed using CellPhoneDB analysis. RESULTS:The results suggested that the trigeminal ganglion could affect Schwann cell demyelination and remyelination responses through many ligand-receptor interactions, while the effect of Schwann cells on the trigeminal ganglion was much weaker. Additionally, ferroptosis may be involved in the demyelination of Schwann cells. CONCLUSIONS:This study provides spatial transcriptomics sequencing data on TN, reveals new markers, and redefines the relationship between the ganglion and myelin sheath, providing a theoretical basis and supporting data for future mechanistic research and drug development.

Neuropathic pain(NP) is difficult to be treated since it has similar phenotypes but different pathogenesis in different pathological stages. Targeted intervention of the core regulatory elements at different pathological stages of NP has become a new direction of drug research and development in recent years and provides the possibility for the treatment of NP. The Mongolian medicine Naru-3(NR-3) is effective in the treatment of sciatica and trigeminal neuralgia, the mechanisms of which remain unknown. On the basis of the previous study of the priming stage, this study established the mouse model of spinal nerve ligation(SNL) and measured the changes of pain thresholds by behavioral tests. The network analysis, Western blot, immunofluorescence assay, ELISA, and agonist/antagonist were employed to decipher the mechanism of NR-3 in the treatment of NP in the maintenance stage. The results showed that NR-3 increased the mechanical and thermal pain thresholds of SNL mice, while it had no significant effect on the basal pain threshold of normal mice. NR-3 may relieve the pain in the maintenance stage of NP by blocking the matrix metalloproteinase 2(MMP2)/interleukin-1β(IL-1β) pathway in the astrocytes of the dorsal root ganglion(DRG) and spinal cord. The findings have enriched the biological connotation of NR-3 in the treatment of the maintenance stage of NP and provide reference for the rational use of this medicine in clinical practice.

ETHNOPHARMACOLOGICAL RELEVANCE:Chuanxiong, a plant of the Umbelliferae family, is a genuine medicinal herb from Sichuan Province. Phthalides are one of its main active components and exhibit good protective effect against cerebrovascular diseases. However, the mechanism by which phthalides exert neuroprotective effects is still largely unclear. AIM OF THE STUDY:In this study, we extracted a phthalein component (named as QBT) from Ligusticum Chuanxiong, and investigated its neuroprotective effects against vascular dementia (VaD) rats and the underlying mechanism, focusing on the chemokine 12 (CXCL12)/chemokine (C-X-C motif) receptor 4 (CXCR4) axis. METHODS:A rat model of VaD was established, and treated with QBT. Cognitive dysfunction in VaD rats was assessed using the Y-maze, new object recognition, and Morris water maze tests. Neuronal damage and inflammatory response in VaD rats were examined through Nissl staining, immunofluorescence, enzyme-linked immunospecific assay, and western blotting analysis. Furthermore, the effects of QBT on CXCL12/CXCR4 axis and its downstream signaling pathways, Janus kinase 2 (JAK2)/signal transducers and activators of transcription 3 (STAT3) and phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT)/nuclear factor-κB (NF-κB), were investigated in VaD rats and BV2 microglial cells exposed to oxygen glucose deprivation. RESULTS:QBT significantly alleviated cognitive dysfunction and neuronal damage in VaD rats, along with inhibition of VaD-induced over-activation of microglia and astrocytes and inflammatory response. Moreover, QBT exhibited anti-inflammatory effects by inhibiting the CXCL12/CXCR4 axis and its downstream JAK2/STAT3 and PI3K/AKT/NF-κB pathways, thereby attenuating the neuroinflammatory response both in vivo and in vitro. CONCLUSION:QBT effectively mitigated neuronal damage and cognitive dysfunction in VaD rats, exerting neuroprotective effects by suppressing neuroinflammatory response through inhibition of the CXCL12/CXCR4 axis.

Periradicular tissues have a rich supply of peripheral afferent neurons, also known as nociceptive neurons, originating from the trigeminal nerve. While their primary function is to relay pain signals to the brain, these are known to be involved in modulating innate and adaptive immunity by initiating neurogenic inflammation (NI). Studies have investigated neuroanatomy and measured the levels of biomolecules such as cytokines and neuropeptides in human saliva, gingival crevicular fluid, or blood/serum samples in apical periodontitis (AP) to validate the possible role of trigeminal nociceptors in inflammation and tissue regeneration. However, the contributions of nociceptors and the mechanisms involved in the neuro-immune interactions in AP are not fully understood. This narrative review addresses the complex biomolecular interactions of trigeminal nociceptors with macrophages, the effector cells of the innate immune system, in the clinical manifestations of AP.

To investigate the protective effect of inhibiting miR-181a on diabetic corneal nerve in mice, we chose male C57BL/6 mice with streptozotocin (STZ) -induced diabetes as animal models. The expression of miR-181a in trigeminal ganglion tissue (TG) of diabetic mice was detected by real-time PCR. In vitro, we cultured mouse trigeminal ganglion neurons and measured the neuronal axon growth when treated under miR-181a antagomir and negative conditions (NTC). Immunofluorescence showed a significant increase in neuronal axon length in trigeminal ganglion cells treated with miR-181a antagomir. In animal models, we performed epithelial scraping and subconjunctival injection of the miR-181a antagomir and miRNA antagomir NTC to observe the corneal nerve repair by corneal nerve staining. miR-181a antagomir subconjunctival injection significantly increased the corneal epithelium healing of diabetic mice compared with that of the NTC group. Meanwhile, corneal nerve staining showed that the repair of corneal nerve endings was significantly promoted. As the targets of the 181a, ATG5 and BCL-2 were previously identified. The results of Western blot showed that the expression of autophagy associated protein ATG5 and LC3B-II and the expression of anti-apoptotic protein Bcl-2 were decreased in the high-glucose cell culture environment and the diabetic TG tissue. The expression of ATG5, LC3B-II and Bcl-2 were significantly increased after miR-181a antagomir treatment compared with negative control group. This study showed that inhibition of miR-181a expression in diabetic mice could increase ATG5-mediated autophagic activation, BCL-2-mediated inhibition of apoptosis, and promote the growth of trigeminal sensory neurons and the regeneration of corneal nerve fibers. It has a protective effect on diabetic corneal neuropathy.

Trigeminal nerve injury is a common complication of various dental and oral procedures, which could induce trigeminal neuropathic pain but lack effective treatments. P2 purinergic receptors have emerged as novel therapeutic targets for such pain. Recent reports implied that the P2Y receptor (P2YR) was activated and promoted orofacial inflammatory pain and migraine. However, the role and mechanism of P2YR in trigeminal neuropathic pain remain unknown. We induced an orofacial neuropathic pain model by chronic constriction injury of the infraorbital nerve (CCI-ION). Von-Frey tests showed that CCI-ION induced orofacial mechanical hypersensitivity. The increased activating transcription factor 3 (ATF3) expression in the trigeminal ganglion (TG) measured by immunofluorescence confirmed trigeminal nerve injury. Immunofluorescence showed that P2YR was expressed in trigeminal ganglion neurons (TGNs) and satellite glial cells (SGCs). RT-qPCR and Western blot identified increased expression of P2YR in TG after CCI-ION. CCI-ION also upregulated interleukin-1β (IL-1β), interleukin-6 (IL-6), C-C motif chemokine ligand 2 (CCL2), and tumor necrosis factor-α (TNF-α) in TG. Notably, CCI-ION-induced mechanical hypersensitivity and pro-inflammatory cytokines production were decreased by a P2YR antagonist (PPTN). Trigeminal administration of P2YR agonist (UDP-glucose) evoked orofacial mechanical hypersensitivity and increased pro-inflammatory cytokines above in TG. Furthermore, CCI-ION induced activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 in TG, which also were reduced by PPTN. The inhibitors of ERK1/2 (U0126) and p38 (SB203580) decreased these upregulated pro-inflammatory cytokines after CCI-ION. Collectively, this study revealed that P2YR in TG contributed to trigeminal neuropathic pain via ERK- and p38-dependent neuroinflammation. Thus, P2YR may be a potential drug target against trigeminal neuropathic pain.

The primary studies have shown that scorpion analgesic peptide N58A has a significant effect on voltage-gated sodium channels (VGSCs) and plays an important role in neuropathic pain. The purpose of this study was to investigate the analgesic effect of N58A on trigeminal neuralgia (TN) and its possible mechanism. The results showed that N58A could significantly increase the threshold of mechanical pain and thermal pain and inhibit the spontaneous asymmetric scratching behavior of rats. Western blotting results showed that N58A could significantly reduce the protein phosphorylation level of ERK1/2, P38, JNK, and ERK5/CREB pathways and the expression of Nav1.8 and Nav1.9 proteins in a dose-dependent manner. The changes in current and kinetic characteristics of Nav1.8 and Nav1.9 channels in TG neurons were detected by the whole-cell patch clamp technique. The results showed that N58A significantly decreased the current density of Nav1.8 and Nav1.9 in model rats, and shifted the activation curve to hyperpolarization and the inactivation curve to depolarization. In conclusion, the analgesic effect of N58A on the chronic constriction injury of the infraorbital (IoN-CCI) model rats may be closely related to the regulation of the MAPK pathway and Nav1.8 and Nav1.9 sodium channels.

BACKGROUND:Microglial activation in the spinal trigeminal nucleus (STN) plays a crucial role in the development of trigeminal neuralgia (TN). The involvement of adenosine monophosphate-activated protein kinase (AMPK) and N-methyl-D-aspartate receptor 1 (NMDAR1, NR1) in TN has been established. Initial evidence suggests that stem cells from human exfoliated deciduous teeth (SHED) have a potential therapeutic effect in attenuating TN. In this study, we propose that SHED-derived exosomes (SHED-Exos) may alleviate TN by inhibiting microglial activation. This study sought to assess the curative effect of SHED-Exos administrated through the tail vein on a unilateral infraorbital nerve chronic constriction injury (CCI-ION) model in mice to reveal the role of SHED-Exos in TN and further clarify the potential mechanism. RESULTS:Animals subjected to CCI-ION were administered SHED-Exos extracted by differential ultracentrifugation. SHED-Exos significantly alleviated TN in CCI mice (increasing the mechanical threshold and reducing p-NR1) and suppressed microglial activation (indicated by the levels of TNF-α, IL-1β and IBA-1, as well as p-AMPK) in vivo and in vitro. Notably, SHED-Exos worked in a concentration dependent manner. Mechanistically, miR-24-3p-upregulated SHED-Exos exerted a more significant effect, while miR-24-3p-inhibited SHED-Exos had a weakened effect. Bioinformatics analysis and luciferase reporter assays were utilized for target gene prediction and verification between miR-24-3p and IL1R1. Moreover, miR-24-3p targeted the IL1R1/p-p38 MAPK pathway in microglia was increased in CCI mice, and participated in microglial activation in the STN. CONCLUSIONS:miR-24-3p-encapsulated SHED-Exos attenuated TN by suppressing microglial activation in the STN of CCI mice. Mechanistically, miR-24-3p blocked p-p38 MAPK signaling by targeting IL1R1. Theoretically, targeted delivery of miR-24-3p may offer a potential strategy for TN.

Histone lysine crotonylation (KCR), a novel epigenetic modification, is important in regulating a broad spectrum of biological processes and various diseases. However, whether KCR is involved in neuropathic pain remains to be elucidated. We found KCR occurs in macrophages, sensory neurons, and satellite glial cells of trigeminal ganglia (TG), neurons, astrocytes, and microglia of the medulla oblongata. KCR in TG was detected mainly in small and medium sensory neurons, to a lesser extent in large neurons. Peripheral nerve injury elevated KCR levels in macrophages in the trigeminal and dorsal root ganglia and microglia in the medulla oblongata but reduced KCR levels in sensory neurons. Inhibition of histone crotonyltransferases (p300) by intra-TG or intrathecal administration of C646 significantly alleviated partial infraorbital nerve transection (pIONT)- or spinal nerve ligation (SNL)-induced mechanical allodynia and thermal hyperalgesia. Intra-TG or intrathecal administration of Crotonyl coenzyme A trilithium salt to upregulate KCR dose-dependently induced mechanical allodynia and thermal hyperalgesia in mice. Mechanismly, inhibition of p300 alleviated pIONT-induced macrophage activation and reduced the expression of pain-related inflammatory cytokines , and chemokines and . Correspondingly, exogenous crotonyl-CoA induced macrophage activation and the expression of , , , and in TG, which C646 can repress. These findings suggest that might be functionally involved in neuropathic pain and neuroinflammation regulation.

OBJECTIVES:This study aimed to investigate whether the microglia in the spinal trigeminal nucleus caudal part (Sp5C) were activated in a rat model of trigeminal neuralgia and to explore whether the activation level of microglia is consistent with maxillofacial pain level. METHODS:Chronic constriction injury of trigeminal nerve (CCI) was induced by partial ligation of infraorbital nerve (IoN) in rats. The behavioral change of rats observed at D1, D5, D10, D15, and D30 days post-surgery and the change of pain threshold were detected with electronic Von Frey filaments served as an evaluation index of maxillofacial pain. Weight change was measured by weighing. Ionized calcium binding adaptor molecule-1 (Iba-1) expression level of Sp5C at each time point was detected, and three microglia morphological categories were analyzed by immunohistochemical staining. RESULTS:The changes of behavioral and pain threshold suggested the maxillofacial pain level first increased and then decreased post-surgery in the IoN-CCI group. Both the expressions of Iba-1 and proportion of ameboid morphology in ipsilateral Sp5C increased from D1 and reached their peaks in D10 and D5, respectively. Then, they recovered nearly to the same level with contralateral Sp5C on D30. This trend was consistent with the maxillofacial change. CONCLUSIONS:The model of trigeminal neuralgia in rats constructed by partial ligation of infraorbital nerve can induce the activation of microglia in Sp5C, and the activation level is consistent with maxillofacial pain, which reached its peak at around D10 post-surgery.

BACKGROUND AND PURPOSE:Patients suffering from trigeminal neuralgia are often accompanied by anxiety and depression. Microglia-mediated neuroinflammation is involved in the development of neuropathic pain and anxiodepression pathogenesis. Whether and how microglia are involved in trigeminal neuralgia-induced anxiodepression remains unclear. EXPERIMENTAL APPROACH:Unilateral constriction of the infraorbital nerve (CION) was performed to establish trigeminal neuralgia in rat and mouse models. Mechanical allodynia and anxiodepressive-like behaviours were measured. Optogenetic and pharmacological manipulations were employed to investigate the role of hippocampal microglia in anxiety and depression caused by trigeminal neuralgia. KEY RESULTS:Trigeminal neuralgia activated ipsilateral but not contralateral hippocampal microglia, up-regulated ipsilateral hippocampal ATP and interleukin-1β (IL-1β) levels, impaired ipsilateral hippocampal long-term potentiation (LTP) and induced anxiodepressive-like behaviours in a time-dependent manner in rodents. Pharmacological or optogenetic inhibition of ipsilateral hippocampal microglia completely blocked trigeminal neuralgia-induced anxiodepressive-like behaviours. Activation of unilateral hippocampal microglia directly elicited an anxiodepressive state and impaired hippocampal LTP. Knockdown of ipsilateral hippocampal P2X7 receptors prevented trigeminal neuralgia-induced microglial activation and anxiodepressive-like behaviours. Furthermore, we demonstrated that microglia-derived IL-1β mediated microglial activation-induced anxiodepressive-like behaviours and LTP impairment. CONCLUSION AND IMPLICATIONS:These findings suggest that priming of microglia with ATP/P2X7 receptors in the ipsilateral hippocampus drives pain-related anxiodepressive-like behaviours via IL-1β. An asymmetric role of the bilateral hippocampus in trigeminal neuralgia-induced anxiety and depression was uncovered. The approaches targeting microglia and P2X7 signalling might offer novel therapies for trigeminal neuralgia-related anxiety and depressive disorder.

Trigeminal neuralgia (TN) is a complex orofacial pain syndrome characterized by the paroxysmal onset of pain attacks in the trigeminal distribution. The underlying mechanism for this debilitating condition is still not clearly understood. Decades of basic and clinical evidence support the demyelination hypothesis, where demyelination along the trigeminal afferent pathway is a major driver for TN pathogenesis and pathophysiology. Such pathological demyelination can be triggered by physical compression of the trigeminal ganglion or another primary demyelinating disease, such as multiple sclerosis. Further examination of TN patients and animal models has revealed significant molecular changes, channelopathies, and electrophysiological abnormalities in the affected trigeminal nerve. Interestingly, recent electrophysiological recordings and advanced functional neuroimaging data have shed new light on the global structural changes and the altered connectivity in the central pain-related circuits in TN patients. The current article aims to review the latest findings on the pathophysiology of TN and cross-examining them with the current surgical and pharmacologic management for TN patients. Understanding the underlying biology of TN could help scientists and clinicians to identify novel targets and improve treatments for this complex, debilitating disease.