Search Results (98)

Fibromyalgia (FM) is a complex syndrome associated with chronic widespread pain and with various other symptoms, including sleep and mood disturbances. Its underlying causes are not fully understood, and the lack of diagnostic blood tests and imaging, along with the absence of definitive treatments, makes management challenging. Recent studies showed that passive transfer of immunoglobulins from FM patients into mice activated satellite glial cells (SGCs) in mouse dorsal root ganglia (DRG), leading to pain behaviors. Here, we aimed to determine whether whole serum from FM patients activates mouse SGCs in DRGs and other ganglia that may be involved in FM’s diverse symptoms. Serum from FM patients (N = 15) and healthy controls (HCs, N = 8) was collected. Sera were incubated with different types of mouse sensory ganglia: DRG, trigeminal ganglion (TG), the nodose ganglion (NG), and the superior cervical sympathetic ganglion (Sup-CG). SGC activation was assessed by immunostaining of SGCs for the glial activation marker glial fibrillary acidic protein (GFAP). All the ganglia tested, DRG, TG, NG, and Sup-CG, displayed induced upregulation of GFAP labeling in SGCs after incubation with FM serum compared with HCs, indicating SGC activation by the serum. Similar responses were observed in both male and female mice. We conclude that serum from FM patients contains factors that can activate SGCs across various types of mouse ganglia, which may reflect the diverse symptom profile of FM. These findings provide evidence for pathogenic factors that could serve as a foundation for a diagnostic method for FM and require further purification and identification, hopefully paving the way for future targeted FM therapy. 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

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

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

Satellite glial cells (SGCs) in sensory ganglia are increasingly recognized as active regulators of neuronal excitability and inflammatory signaling involved in pain conditions. In craniofacial and orofacial pain, trigeminal SGCs exhibit stimulus-dependent responses that develop over time and contribute to disease-related plasticity. Additionally, advances in experimental modeling, computational analysis, and data integration have fueled interest in “digital twins” as tools for hypothesis generation and decision support in biomedicine. However, most current biomedical applications are loosely defined and rarely explicitly address glial biology. Here, we propose a digital twin-inspired framework focused on trigeminal satellite glial cells to combine stimulus-response experiments with computational state modeling. Instead of claiming a fully developed digital twin, we describe a hybrid experimental–computational approach where glial activation states are inferred from measurable outputs, iteratively refined, and used to explore what-if scenarios related to pain mechanisms and treatments. These scenarios are intended to guide experimental design and hypothesis prioritization rather than to generate clinical predictions. We detail how this framework could enhance understanding of underlying mechanisms, prioritize potential interventions, and align with New Approach Methodologies (NAMs) and the 3Rs by reducing exploratory animal use. We also discuss key limitations, including biological simplification, uncertainty, and translational challenges. By viewing glial systems as dynamic, updateable entities rather than static readouts, this approach offers a practical and ethically grounded pathway toward more integrated research on craniofacial pain. Full article

Background: Our growing understanding of the brain basis of mind has seen an interest in evolutionarily ancient structures, most notably the brainstem. This paper offers an interesting example of this underexplored territory, by considering the mesencephalic component of the trigeminal nucleus. This largely uncelebrated brainstem structure is central to control of the jaw, and for the foundational acts of eating, oral exploration, and biting. Objectives: This paper explores the interesting anatomy of the mesencephalic trigeminal: unique in the nervous system as a centrally located sensory ganglion, which combines sensory and motor function for the jaw. An unexplored aspect of its anatomy is that the mesencephalic component of the nucleus lies directly adjacent to the brain’s core system for the experience of emotion, the peri-acqueductal gray (PAG). Results: The data suggest a role for the jaw, and more broadly the oral cavity, in relation to a range of feeling states, from pleasure to aggression. This is supported by behavioural and classic neuropsychological findings, such as the Klüver-Bucy syndrome. However, the proposal is not well-supported by findings of direct connections between the trigeminal nucleus and the PAG. Conclusions: While these contrasting findings present a conundrum, there may be a role for non-synaptic signalling, of the sort increasingly understood to be important for interoception and homeostasis. Full article

Dental pain often arises from the compromised integrity of the tooth pulp due to dental injury or caries. The dentin–pulp complex has long been considered to be central to the unique biology of dental pain. Most trigeminal ganglion afferents projecting into tooth pulp are myelinated neurons, which lose their myelination at the site of peripheral dentin innervation. The pulpal afferents likely combine multiple internal and external stimuli to mediate nociception and maintain pulp homeostasis. Transient receptor potential (TRP) ion channels in neurons and odontoblasts, along with mechanosensitive ion channels such as Piezo, form a key molecular hub for pulpal nociception by sensing thermal, chemical, and hydrodynamic stimuli. Among these, TRP vanilloid 1 (TRPV1) mediates nociception and the release of calcitonin-gene-related peptides (CGRPs), while TRP canonical 5 (TRPC5) mediates cold pain. TRP melastatin 8 (TRPM8) mediates the transduction of hyperosmotic stimuli. Pulpitis elevates endogenous TRPV1 and TRPA1 agonists, while inflammatory mediators sensitize TRP channels, amplifying pain. CGRP recruits immune cells and promotes bacterial clearance and reparative dentinogenesis, yet the roles of TRP channels in these processes remain unclear. Future studies should use advanced multi-omics and in vivo or organotypic models in animal and human teeth to define TRP channel contributions to pain, immune responses, and regeneration. Understanding neuronal and non-neuronal TRP channel interactions and their integration with other ion channels may enable novel analgesic and regenerative strategies in dentistry. Full article

Background: Dry eye disease is a multifactorial ocular surface disorder characterized by tear film instability, inflammation, and neurosensory abnormalities that can lead to corneal pain and discomfort. In this study, we evaluated the effects of specific eye drops for dry eyes on neuronal pain receptors to gain insight into the mechanisms underlying corneal nerve pain in patients with dry eyes using a primary cell culture model of murine trigeminal ganglion cells. Methods: Trigeminal ganglia were obtained from wild-type postnatal day 7–10 mice. Primary cultures were prepared using the cell suspension method. After culturing for one week, the cells were stained with neuron-specific anti-neuronal nuclei, polymodal nociceptor, and transient receptor potential vanilloid 1 (TRPV1) antibodies. The calcium ion probe Fura2-AM^® was added to cultured cells after 2 weeks of incubation. The effects of capsaicin alone, in combination with the TRPV1 antagonist AMG9810, and in the presence of components of commercially available eye drops (cyclosporine, diquafosol tetrasodium, or rebamipide) were evaluated by monitoring calcium signals. Results: Neural excitation and capsaicin-induced increase in fluorescence intensity ratio were suppressed by AMG9810, cyclosporine, and diquafosol tetrasodium, but not by rebamipide. Conclusions: Inhibition of cellular excitation by cyclosporine and diquafosol tetrasodium may underlie their clinical pain suppressive effects. The primary culture model described here may serve as a useful tool for future studies on corneal perception. Full article

Background: Herpes simplex virus (HSV) is a neurotropic virus that can be categorized into two serotypes: HSV-1 and HSV-2. HSV-1 causes symptoms such as herpes labialis, herpetic keratitis, genital ulcers, and encephalitis, and primarily establishes latent infection in the trigeminal ganglion. The complexity of membrane fusion mechanisms and potential infection in nerves allow HSV to easily evade recognition and clearance by host immune cells. Therefore, developing a vaccine that can prevent both primary and reactivated HSV-1 infection is critical. Currently, no preventive or therapeutic HSV-1 vaccines have been approved for marketing. Methods: In this study, we utilized the gC, gD, and gE proteins of HSV-1, which are associated with viral fusion and immune escape, to design a trivalent antigen vaccine that is capable of inducing a cellular immune response. Two formulations of the vaccine are available: a subunit vaccine incorporating oligodeoxynucleotides with CpG motifs (CpG ODNs) and QS-21 as adjuvants, as well as an mRNA vaccine. Mice were immunized via intramuscular injection to evaluate and compare the immunological responses and protective efficacy of the two vaccines. Results: After the challenge, the viral load in the tissues of both vaccine groups was significantly lower than that in the positive control group, indicating that both vaccines were able to control viral proliferation in the tissues. Conclusions: The findings indicated that both mRNA and subunit vaccines were capable of eliciting comparable humoral and cellular immune responses. Full article

Objective: Given the side effects and reduced efficacy of conventional local anesthetics in inflammatory conditions, there is a compelling need for complementary alternative medicine (CAM), particularly those based on phytochemicals. While a previous study showed that in vivo local injection of (-)-epigallocatechin-3-gallate (EGCG) into the peripheral receptive field suppresses the excitability of rat trigeminal ganglion (TG) neurons in the absence of inflammation, the acute effects of EGCG in vivo, especially on TG neurons under inflammatory conditions, are still unknown. We aimed to determine if acute local EGCG administration into inflamed tissue effectively attenuates the excitability of nociceptive TG neurons evoked by mechanical stimulation. Methods: The escape reflex threshold was measured to assess hyperalgesia caused by complete Freund’s adjuvant (CFA)-induced inflammation. To assess neuronal activity, extracellular single-unit recordings were performed on TG neurons in anesthetized CFA-inflamed rats in response to orofacial mechanical stimulation. Results: The mechanical escape threshold was significantly lower in CFA-inflamed rats compared to before CFA injection. EGCG (1–10 mM) reversibly and dose-dependently inhibited the mean firing frequency of TG neurons evoked by both non-noxious and noxious mechanical stimuli (p < 0.05). For comparison, 1% lidocaine (37 mM), a local anesthetic, also caused reversible inhibition of the mean firing frequency in inflamed TG neurons responding to mechanical stimuli. Importantly, 10 mM EGCG produced a significantly greater magnitude of inhibition on TG neuronal discharge frequency than 1% lidocaine (noxious, lidocaine vs. EGCG, 19.7 ± 3.3% vs. 42.3 ± 3.4%, p < 0.05). Conclusions: Local injection of EGCG into inflamed tissue effectively suppresses the excitability of nociceptive primary sensory TG neurons, as indicated by these findings. Significantly, locally administered EGCG exerted a more potent local analgesic action compared to conventional voltage-gated sodium channel blockers. This heightened efficacy originates from EGCG’s ability to inhibit both generator potentials and action potentials directly at nociceptive primary nerve terminals. As a result, EGCG stands out as a compelling candidate for novel analgesic development, holding particular relevance for CAM strategies. Full article

Headache disorders are among the most prevalent and disabling neurological conditions worldwide, affecting more than three billion individuals and contributing to a substantial socioeconomic burden. Despite the availability of pharmacologic treatments such as triptans, NSAIDs, and CGRP monoclonal antibodies, a significant proportion of patients remain refractory or intolerant to these therapies. The sphenopalatine ganglion (SPG), a parasympathetic neural structure in the pterygopalatine fossa, is increasingly recognized as a critical node in the pathophysiology of primary headache disorders. SPG blocks—using local anesthetics, neurolytic agents, or electrical neuromodulation—offer a minimally invasive therapeutic approach by disrupting nociceptive transmission and autonomic activation. This narrative review synthesizes the anatomical and physiological rationale for SPG intervention, details various procedural techniques, evaluates clinical evidence across headache subtypes, and explores future research directions. Conditions covered include migraine, cluster headache, tension-type headache, trigeminal neuralgia, and persistent idiopathic facial pain. With expanding evidence and evolving technologies, SPG-targeted interventions have the potential to reshape the management of refractory headaches and facial pain syndromes. Full article

While gut microbiota-derived short-chain fatty acids (SCFAs) are recognized to modulate pathological pain by decreasing inflammation, the neurophysiological basis for SCFAs, butyrate’s ability to reduce hyperexcitability in nociceptive primary neurons during inflammatory conditions is still unknown. The objective of this study was to determine, using in vivo conditions, whether systemic butyrate administration attenuates inflammation-induced hyperexcitability of trigeminal ganglion (TG) primary neurons and the concomitant mechanical inflammatory hyperalgesia. Rats received complete Freund’s adjuvant (CFA) injections in their whisker pads to induce inflammation. CFA-inflamed rats showed a significantly lower mechanical stimulation-induced escape threshold compared to naïve rats. Systemic butyrate administration restored the mechanical threshold to levels comparable to naïve rats within four days. Four days of butyrate administration significantly decreased the mean increased discharge frequency of TG neurons to both non-noxious and noxious mechanical stimuli in inflamed rats. The increased mean spontaneous discharge of TG neurons in inflamed rats significantly decreased four days after butyrate administration. Collectively, our findings indicate that butyrate reduces inflammatory hyperexcitability in nociceptive primary TG neurons, thereby alleviating inflammatory hyperalgesia. These results suggest that butyrate may serve as a promising therapeutic approach for the prevention of trigeminal inflammatory mechanical hyperalgesia and its clinical manifestations. Full article

Background: Histamine intolerance, a disorder due to impaired degradation of dietary histamine, is frequently associated with headaches, but the underlying pathophysiology is largely unknown; the sensitization of meningeal afferents appears likely. We approached this issue by examining histamine concentrations in different tissues and meningeal histamine release in a new mouse model of high-histamine diets. Methods: C57BL/6 mice of both sexes were fed with diets containing 3 or 9 g/kg histamine and compared to control groups. After 10–30 days, the histamine concentration was determined in plasma, samples of homogenized ileum, trigeminal ganglia, spinal medulla, and cerebellum using an ELISA. The histamine release from mast cells in the dura mater stimulated with compound 48/80 was also examined. Results: Animals supplied with high dietary histamine showed normal behavior and no signs of suffering. Compared with the controls, the histamine concentration was significantly higher in plasma and ileum of mice fed with 3 g/kg, highest in animals fed with 9 g/kg histamine. In addition, this group of animals showed also higher histamine concentrations in the trigeminal ganglion. The histamine release from the dura mater in mice supplied with 3 g/kg histamine was not significantly different to control animals, but the relative increase in stimulated release was lower in male animals of the high histamine group. Conclusions: High dietary histamine increases histamine levels in blood plasma and the gut, whereas the histamine content of neural tissues is not significantly influenced. The lowered stimulated release in animals subjected to high dietary histamine may indicate compensatory mechanisms. Full article

Antagonism of transient receptor potential ankyrin type-1 (TRPA1) channels counteracts the experimentally induced trigeminal neuralgia (TN) pain. TRPA1 channels activated/sensitized by inflammatory stimuli can modulate glial cell activity, a driving force for pathological pain. Additionally, the evidence of a link between TRPA1 and the inflammatory-related Toll-like receptors 4 (TLR4) and 7 (TLR7) highlights the potential of the TRPA1-blocking strategy to reduce pain and inflammation in TN. In this study, we aimed to further investigate the putative involvement of TRPA1 channels in the inflammatory pathways following the development of TN. We focused on the possible modulation of glial activity after TRPA1 blockade and the crosstalk of TRPA1 with TLR7 and TLR4. In a rat model of TN, based on chronic constriction injury of the infraorbital nerve, the impact of TRPA1 antagonism through ADM_12 treatment was assessed following the onset of mechanical allodynia (26 days post-surgery). The evaluation of central and peripheral inflammatory mediators (by rt-PCR and ELISA) and immunofluorescence staining of glial expression in the trigeminal nucleus caudalis was investigated using plasma samples and areas related to the trigeminal system (trigeminal ganglion and areas containing the trigeminal nucleus caudalis). Compared to sham-operated rats, the TN-like animals showed significant increases in the number of microglial and astroglial cells in the trigeminal nucleus caudalis, with higher and lower protein plasma levels of pro-inflammatory and anti-inflammatory cytokines, respectively. Additionally, in the trigeminal-related areas, TN-like animals showed significantly higher gene expression levels of TLR4, TLR7, miR-let-7b, and high-mobility group box-1. TRPA1 antagonism reverted all the observed alterations in TN-like rats in the trigeminal-related areas and plasma except microglial cell number in the trigeminal nucleus caudalis. The findings suggest that, in addition to their known involvement in the nociceptive pathway, TRPA1 channels may also play a direct or indirect role in pain-related inflammation, through the activation of TLR4- and TLR7-mediated pathways at the neuronal and glial levels. Full article

The trigeminal nerve is the primary gateway through which the rabies virus enters the brain. Viral infection-related trigeminal neuritis is associated with certain clinical signs. This study investigated trigeminal ganglion histopathology in 92 rabid dogs. Trigeminal ganglionitis was classified into three pathological grades: mild, moderate, and severe. Immunostaining of selected sections was performed using antibodies against lymphocytes (CD3, CD20), stellate cells (glial fibrillary acidic protein, GFAP), macrophages (Iba-1, HLA-DR), ganglion cells (neurofilament, NF), and Schwann cells (S-100) to identify lesion cell types. In moderate and severe cases, double-immunofluorescence staining was performed to determine neuronophagia and Nageotte nodule cell types. Mild (13.0%) cases had minimal morphological changes in ganglion cells; moderate (56.5%) and severe (30.4%) cases showed infected ganglion cells and axons with degenerative necrosis, which were replaced by inflammatory cells. Immunohistochemically, viral antigens were detected in most ganglion cells in mild cases and were significantly reduced in severe cases. The number of CD3-, CD20-, GFAP-, and Iba-1-positive cells increased as the severity progressed, and neuronophagia and Nageotte nodules primarily comprised HLA-DR-positive cells. These findings suggest that the rabies virus reaches the trigeminal ganglion via ascending or descending routes and induces trigeminal neuropathological changes, contributing to neurological symptoms in rabid dogs. Full article