Search Results (172)

Bovine alphaherpesvirus 1 (BoHV-1) acute infection induces respiratory tract disorders and conjunctivitis and suppresses immune responses that may cause bacterial pneumonia. BoHV-1 infection establishes lifelong latency in sensory neurons in trigeminal ganglia (TG), the central nervous system, and certain cells in the pharyngeal tonsil. BoHV-1 is a chronic problem in the cattle industry because stress, including the synthetic corticosteroid dexamethasone, triggers reactivation from latency after an intravenous injection. The BoHV-1 immediate early transcription unit 1 (IEtu1) promoter drives expression of infected cell protein 0 (bICP0) and bICP4, two viral transcriptional regulators. Stress activates the glucocorticoid receptor (GR), and Krüppel-like factor 15 (KLF15) cooperatively transactivates the BoHV-1 IEtu1 promoter if both GR response elements (GREs) are intact. Since the bICP0 gene contains a separate early (E) promoter, we tested the hypothesis that GR+KLF family members transactivate the bICP0 E-promoter. GR+KLF4, both pioneer transcription factors, cooperatively stimulate bICP0 E-promoter activity in mouse neuroblastoma cells (Neuro-2A), and stimulate productive infection. Notably, the bICP0 E-promoter lacks GREs, suggesting that a novel mechanism triggers transactivation. CA motifs and C-rich Sp1 binding sites in bICP0 E-promoter sequences are crucial for transactivation and binding to GR and KLF4. Full article

Neurovascular compression syndromes (NVCS), including trigeminal neuralgia (TN) and hemifacial spasm (HFS), are characterized by disabling symptoms caused by vascular compression of cranial nerves. Although microvascular decompression is an established treatment, mechanisms linking neurovascular compression to abnormal neural activity remain incompletely understood. In this review, we integrate evidence from microanatomical, electrophysiological, and computational studies to provide a mechanistic framework for NVCS. Chronic vascular compression induces focal demyelination, redistribution of voltage-gated ion channels, ectopic impulse generation, and ephaptic transmission, leading to abnormal neuronal excitation. We further summarize emerging evidence that persistent peripheral hyperactivity may contribute to electrophysiological alterations in central neural circuits. Particular attention is given to computational approaches, including cable theory and axonal interaction models, which offer quantitative insights into abnormal synchronization and cross-excitation among nerve fibers. Recent findings regarding ion channel dysfunction, including familial TN associated with gain-of-function calcium channel variants, are also discussed. Collectively, these findings support an integrated model linking neurovascular compression to clinical manifestations, and highlight the value of combining electrophysiology and computational neuroscience to improve mechanistic understanding and to guide future therapeutic strategies for NVCS. Full article

Pathogen–host interaction plays key roles in the pathogenesis of infectious diseases. The miR-183/96/182 cluster (miR-183C) is highly expressed in trigeminal ganglion (TG) sensory neurons (SNs) and modulates corneal response to Pseudomonas aeruginosa (PA) infection. To uncover the molecular mechanisms of miR-183C modulating the interactions of PA and TG SN, we employed the miR-183C conventional knockout (KO) or sensory neuron-specific (SNS) conditional (C)KO mouse models. Trigeminal ganglion (TG) SNs were isolated for neurite growth and branching analyses. Neuropeptide and chemokine production by TG SNs in response to PA infection was studied by ELISA assays. Key target genes of miR-183C were validated by target luciferase reporter assays. Our data showed that the total neurite length and number of branches per TG SN were decreased in the CKO vs. WT mice, and in the male vs. female WT mice. PA infection of TG SN induced the production and secretion of CX3CL1 and substance P (sP); this response was significantly enhanced in miR-183C KO vs. WT mice. Antagonists to Toll-like receptor (TLR)4 and/or formyl peptide receptor (FPR)1 inhibited PA-induced responses. Target luciferase reporter assays confirmed that genes encoding TLR4 and FPR1, as well as NRP1—a repulsive axon guidance receptor, TAC1—the precursor gene of sP, CX3CL1 and ADAM10, a metalloproteinase involved in the production of soluble CX3CL1, were direct targets of miR-183C. These data suggest that PA directly activates TG SNs and induces chemokine and neuropeptide production/secretion through interactions with TLR4 and FPR1. miR-183C modulates this process by targeting a collection of key genes involved in axon guidance/projection, chemokine and neuropeptide biogenesis and receptors mediating PA-induced activation. Full article

Satellite glial cells (SGCs) play a critical role in the development and maintenance of chronic pain through complex interactions with inflammatory mediators and the opioid pathway. This systematic review synthesizes recent advances in the molecular mechanisms underlying SGC activation and implications for chronic pain management, particularly in conditions associated with the dorsal root ganglia (DRG) and trigeminal ganglia (TG). A systematic search was conducted in four databases (PubMed, Embase, Scopus, and Web of Science) covering studies published between January 2004 and May 2026. After screening 111 records, 19 studies were included. This review highlights how pro-inflammatory cytokines such as IL-1β, IL-1α, and TNF-α, as well as neurotransmitters like ATP and glutamate, contribute to SGC activation, neuroinflammation, and pain modulation. It also explores the role of receptors like CXCR4, TLR4, and P2X7 in SGCs in enhancing analgesic effects and their contributions to opioid tolerance and hyperalgesia. The findings underscore the potential of targeting SGCs to improve pain management outcomes across various pain models, including neuropathic, cancer-related, and visceral pain. Despite promising insights, variability in study methodologies and the complexity of glial–neuronal interactions present challenges. Future research should focus on standardizing experimental protocols and developing targeted therapies to modulate SGC activity to offer hope for patients suffering from chronic pain, particularly in managing opioid tolerance. Full article

Background/Objectives: Chronic orofacial pain represents a heterogeneous group of disorders affecting the trigeminal system and remains difficult to treat due to its complex pathophysiology, which involves glial cells in the development and maintenance of persistent pain states. This systematic review aimed to synthesize evidence from animal studies investigating the pathophysiological role of glial cells in chronic orofacial pain. Methods: After registering on PROSPERO, a systematic search of the literature, based on PRISMA guidelines, was conducted to identify experimental animal studies evaluating glial involvement in orofacial pain models. After screening and eligibility assessment, 10 studies met the inclusion criteria. Data regarding experimental models, glial populations investigated, and pain-related behavioral outcomes were extracted and qualitatively synthesized. Results: Activation of satellite glial cells, microglia, and astrocytes was consistently associated with increased neuroinflammatory signaling and enhanced neuronal excitability within trigeminal pathways, demonstrating that both peripheral and central nervous tissues were involved. Several studies reported that pharmacological modulation of glial activity may reduce pain-related behaviors. Conclusions: Glial cells are key modulators of chronic orofacial pain through neuroimmune interactions that contribute to peripheral and central sensitization. Although these findings highlight promising therapeutic targets, further translational research is required to clarify their relevance for human pain conditions. Full article

This review aims to provide a translational link between clinical evidence in the application of photobiomodulation for treatment of painful conditions in medicine and dentistry and neurophysiological effects of photobiomodulation therapy (PBMt). PBMt is gaining increasing acceptance as a therapeutic modality for pain management, particularly within dental practice. However, a clearer understanding of its mechanisms of action remains essential for broader clinical adoption and integration into mainstream healthcare. Central to the therapeutic effects of PBMt for pain is its interaction with neurons, which possess unique structural and functional characteristics. Advances in our understanding of the cellular architecture of dorsal root and trigeminal ganglion neurons highlight the importance of the stem axon and axon initial segment (AIS), a specialized region adjacent to the axon hillock that is now recognized as the principal site of action potential initiation. These developments have important implications for understanding the biological effects of PBMt and its clinical application. This review synthesizes evidence demonstrating that PBM influences cytoskeletal organization, mitochondrial structure and function, and intracellular signaling pathways, with downstream effects on neuronal excitability and nerve conduction. By integrating findings from cellular, neurophysiological, and clinical studies, the review examines how these mechanistic effects may contribute to pain modulation and analgesia. Full article

Orthodontic pain, a fundamental biological response to mechanically induced tooth movement, is primarily associated with sterile inflammation and neurogenic processes within the periodontal ligament (PDL). Although photobiomodulation therapy (PBMT) has been widely investigated as a nonpharmacological approach for pain attenuation, its mechanisms of action remain incompletely understood, and current interpretations are often limited to peripheral anti-inflammatory effects. This review re-examines the biological basis of orthodontic pain by integrating evidence derived predominantly from in vitro and in vivo experimental studies. Particular emphasis is placed on neurogenic inflammation, neuropeptide regulation, and neuron–glia interactions along the trigeminal nociceptive pathway. PBMT can reduce periodontal inflammatory/neuropeptide-related markers and pain-related behaviors in selected models; however, evidence for direct central neuron–glia modulation remains largely marker-based and parameter-dependent. Direct functional validation of trigeminal circuit modulation (e.g., electrophysiological recordings or calcium imaging) remains limited in orthodontic pain models; thus, the proposed neuroimmune mechanisms should be interpreted as testable hypotheses for future work. By synthesizing mechanistic insights across multiple biological levels, this review proposes a broader framework for understanding PBMT-mediated pain modulation extending beyond conventional peripheral models. These perspectives may help clarify inconsistencies in the reported outcomes and provide a rationale for future hypothesis-driven experimental and translational research. Full article

As the primary peripheral relay station for vibrissal tactile information, the trigeminal ganglion (TG) features heterogeneous three-dimensional (3D) cytoarchitecture that eludes full characterization using conventional two-dimensional methodologies. A high-resolution 3D imaging and reconstruction pipeline is thus required to unveil TG structural organization and define the spatial framework of target-related sensory neurons. Herein, we established a fluorescence micro-optical sectioning tomography (fMOST)-based workflow for 3D cytoarchitectural mapping of TG anatomy and validated its utility for profiling the distributions of TG neurons innervating vibrissae via single-axon tracing. fMOST imaging coupled with propidium iodide (PI) staining was applied to acquire whole-head anatomical data encompassing the vibrissae and the TG at cellular resolution. Based on clearly resolved cellular morphology and the spatial distribution of neuronal somata, we delineated the soma distribution of TG neurons and revealed a spatially heterogeneous 3D organization pattern, from which we operationally defined two anatomically distinct subdomains: the neuronal soma-rich region (NSRR) and the fiber-rich region (FRR). Furthermore, with retrograde viral/genetic labeling combined with neuronal tracing, TG neurons innervating the C2, D3, and δ vibrissae were observed in both NSRR and FRR, showing partially overlapping yet spatially biased distributions consistent with previous population-level observations of vibrissa-row-dependent topography. Notably, TG neurons innervating the δ vibrissa occupied a comparatively broader spatial extent along the anteroposterior plane in our dataset. Overall, this study facilitates an in-depth mechanistic and anatomical understanding of TG cytoarchitectural organization and underlying functional mechanisms. Full article

We previously demonstrated that botulinum neurotoxin A (BoNT-A) exerts bilateral antinociceptive effects, involving trans-synaptic transport at the level of the lumbar spinal cord. However, the potential distribution of the toxin to supraspinal sites has not yet been investigated. In the present study, we examined the distribution of cleaved SNAP-25 (cl-SNAP-25), a marker of BoNT-A activity, in the rat brain following peripheral unilateral BoNT-A administration. Brain tissues from rats treated with BoNT-A (7 U/kg, into the hind paw) were analyzed using immunofluorescent tyramide signal amplification to detect cl-SNAP-25. To assess the contribution of trans-synaptic transport, a BoNT-A-neutralizing antitoxin (2 IU) was administered intrathecally 24 h after BoNT-A injection. Signal intensity was evaluated using a semi-quantitative immunohistochemical scoring method based on cl-SNAP-25-positive nerve fibers. Bilateral cl-SNAP-25 immunoreactivity was observed in multiple supraspinal regions, most prominently within the trigeminal complex and the facial and gracile nuclei. Signal intensity was significantly reduced by intrathecal antitoxin, indicating that trans-synaptic transport contributes to central BoNT-A distribution. Peripherally administered BoNT-A reaches distant supraspinal regions, possibly via neuronal retrograde and trans-synaptic transport. Further studies are warranted to clarify exact pathways and alternative distribution routes, determine the functional relevance of central BoNT-A presence, and assess its clinical implications. Full article

Background: Neurovascular compression syndromes (NVCS) represent a spectrum of disabling neurologic disorders caused by vascular or structural compression of cranial nerves, most commonly at the root entry zone. Conditions such as trigeminal neuralgia (TN), hemifacial spasm (HFS), and glossopharyngeal neuralgia (GN) are associated with significant pain, functional impairment, and reduced quality of life. This review provides a multidisciplinary, anatomically grounded overview of the pathophysiology, diagnosis, imaging, and contemporary management strategies for NVCS. Methods: A narrative review of the literature was conducted, synthesizing historical perspectives, neuroanatomy of the cerebellopontine angle, mechanisms of neurovascular conflict, advances in imaging and neuromonitoring, and current treatment modalities. Medical, percutaneous, surgical, radiosurgical, and neuromodulatory approaches were evaluated, with emphasis on patient selection and outcome considerations. Results: Neurovascular compression, most frequently arterial compression at the root entry zone, leads to focal demyelination, ephaptic transmission, and neuronal hyperexcitability. High-resolution Magnetic resonance imagin (MRI) remains the diagnostic gold standard. First-line management for TN and related syndromes typically includes pharmacotherapy, particularly sodium channel blockers. Refractory cases may benefit from percutaneous rhizotomy, balloon compression, stereotactic radiosurgery, or microvascular decompression (MVD), which offers the most durable relief in appropriately selected patients. Emerging technologies, including endoscopic visualization, advanced neuromodulation, and virtual reality-assisted surgical planning, continue to refine treatment precision and safety. Conclusions: Effective management of NVCS requires a comprehensive understanding of neuroanatomy, pathogenesis, and individualized risk–benefit profiles. A multidisciplinary, stepwise approach optimizes outcomes and improves quality of life in patients with these complex disorders. Full article

Dental pain due to dentine hypersensitivity or pulpitis is characterized by short or lasting episodes of pain triggered by normally innocuous stimuli originating from exposed dentine. Both represent the most frequent pain of the orofacial region. Transient receptor potential (TRP) superfamily of ion channels participates in the detection of different modalities of sensibility in the mammalian sensory teeth system, i.e., trigeminal neurons and odontoblasts. In particular, some members of the melastatin family (TRPM) serve as molecular thermal sensors, and temperature is one of the most potent stimuli in triggering dentine hypersensitivity. Here we review and update the information about the distribution of TRPM channels in the trigeminal ganglion and dental pulp cells, especially odontoblasts, in humans and animal models. In addition to the well-known sensory roles of TRPM, other functions such as the development and mineralization of teeth are considered. Full article

Following acute infection, herpes simplex virus type 1 (HSV-1) establishes life-long latency in neurons. Although sensory neurons in trigeminal ganglia (TG) are primary sites for latency, the brainstem is also an important site for latency. The rationale for examining the principal sensory nucleus of the spinal trigeminal tract (Pr5) receives afferent inputs from TG. Notably, the (LC) is indirectly linked to Pr5. Our previous studies revealed that senescent cells and inflammation were detected in the Pr5 and LC of aged mice and young mice that are latently infected with HSV-1. To expand our understanding of how HSV-1 influences senescence and inflammation in Pr5 and LC, NanoString studies in mice latently infected with wild-type HSV-1 or a latency-associated transcript (LAT) null mutant (dLAT2903) was compared to age-matched uninfected C57Bl/6 male and female mice. LAT is the only viral gene abundantly expressed during latency, suggesting it influences cellular gene expression during latency. Cellular genes that regulate neuron differentiation, axonal projection, and pro-inflammatory mediators were more prevalent in mice latently infected with wild-type (wt) HSV-1 and dLAT2903 versus uninfected mice. Finally, these studies revealed that latency in Pr5 and LC is a dynamic process. Full article

Listeria monocytogenes (Lm) is an important zoonotic foodborne pathogen that causes severe rhombencephalitis in ruminants. The trigeminal ganglion is a critical node for Lm invasion of the central nervous system via neural pathways. However, the roles of key virulence factors InlA, InlB, and LLO from ovine-derived Lm in trigeminal ganglion neuron infection remain unclear. In this study, LM90SB2, an ovine-derived Lm strain isolated from a sheep with encephalitis in Xinjiang, China, was used as the wild type, and its ΔInlAB double-gene deletion and ΔInlABO triple-gene deletion mutants were constructed. Primary mouse trigeminal ganglion cells (TGCs) were infected with these strains, and cell-association and invasion assays, bacterial colonization analysis, cell scratch tests, Western blotting, and qRT-PCR were performed to explore the effects of InlA, InlB, and LLO on Lm infection of TGCs and their regulatory roles in host adhesion molecules N-cadherin and NCAM1. The results showed that the wild-type LM90SB2 had significantly stronger cell-association, invasion, and colonization abilities in TGCs than the ΔInlAB and ΔInlABO mutants (p < 0.01 or p < 0.0001). LM90SB2 infection significantly upregulated the mRNA and protein expression levels of N-cadherin and NCAM1 in TGCs and enhanced TGC migration, while these effects were gradually attenuated with the sequential deletion of InlA, InlB and LLO. This study clarifies the synergistic roles of InlA, InlB, and LLO in mediating the infection of trigeminal ganglion neurons by ovine-derived Lm and reveals the molecular mechanism by which Lm promotes neural invasion by regulating the expression of host cell adhesion molecules. Our findings provide important experimental data for elucidating the neural invasion pathway of Lm in ruminants and lay a theoretical foundation for the development of targeted prevention and control strategies for ruminant listeriosis in veterinary clinical practices. Full article

Migraine is a highly prevalent and disabling neurovascular disorder that represents a major global health burden due to its significant impact on quality of life and socioeconomic costs. Increasing evidence suggests that migraine pathophysiology involves complex interactions between neuronal hyperexcitability, vascular dysregulation, oxidative stress, and neuroinflammatory processes. Oxidative and nitrosative stress are increasingly recognized as key contributors to migraine mechanisms, influencing mitochondrial dysfunction, cortical spreading depression, and trigeminovascular activation. Nitric oxide plays a central role in these processes by regulating vascular tone, nociceptive signaling, and neurogenic inflammation through downstream pathways such as the soluble guanylate cyclase–cyclic guanosine monophosphate (NO–sGC–cGMP) signaling cascade. Dysregulation of nitric oxide signaling and increased oxidative stress may contribute to endothelial dysfunction and impaired cerebrovascular regulation observed in migraine patients. In addition, accumulating evidence highlights the role of neuroinflammatory mechanisms, including microglial activation and cytokine-mediated signaling, which may amplify nociceptive transmission within trigeminal pathways. Migraine is increasingly recognized as a systemic disorder associated with several comorbid conditions, including Parkinson’s disease, fibromyalgia, and autoimmune diseases such as Sjögren’s syndrome. This review summarizes recent advances regarding the interactions between oxidative stress, nitric oxide signaling, endothelial dysfunction, and neuroinflammation in migraine and discusses their potential therapeutic implications. Full article

The maxillary sinus is frequently implicated in facial pain syndromes arising from infection, neoplasia, dental procedures, and, importantly, migraine, which can mimic “sinus headache” and contribute to misdiagnosis and inappropriate antibiotic use. Despite the clinical burden of chronic maxillary sinus pain, the sensory neuron subtypes that convey nociceptive and mechanosensory signals from the sinus mucosa remain incompletely defined. In this study, trigeminal ganglion (TG) neurons innervating the maxillary sinus (maxillary sinus TG neurons) were retrogradely labeled with the fluorescent dye DiD in mice and characterized using ex vivo patch-clamp electrophysiology and single-cell RT-PCR. Maxillary sinus TG neurons were found to be predominantly small-diameter, C-afferent nociceptors with electrophysiologic features including high thresholds, repetitive firing, and broad action potentials. Notably, maxillary sinus TG neurons formed a distinct molecular and functional subgroup: they expressed Nav1.9, while showing minimal Nav1.8 expression and limited overlap with Nav1.8-positive nociceptor populations. A majority of maxillary sinus TG neurons were mechanically responsive, generating mechanically activated currents with heterogeneous adaptation profiles, and a subset expressed the mechanoreceptor Piezo2. Collectively, these findings identify maxillary sinus TG neurons as a specialized population of Nav1.9-enriched C-afferent nociceptors with mechanosensitive properties, providing a mechanistic framework for pressure-evoked sinus pain. This work advances the neurobiological basis of sinus-related pain and suggests that Nav1.9 and mechanoreceptor pathways may be potential therapeutic targets for conditions in which sinus symptoms overlap with migraine and other craniofacial pain disorders. Full article