Trigeminal Ganglion Research Articles

MicroRNA-6954-3p Downregulation Contributes to Orofacial Neuropathic Pain in Mice Via Targeting Voltage-Gated Sodium Channel β2 Subunit Protein

The voltage-gated sodium channel β2 subunit protein (SCN2B) plays a crucial role in neuropathic pain. However, the role and mechanisms of SCN2B in orofacial neuropathic pain are still unclear. This study aimed to investigate the upstream regulatory mechanisms of SCN2B in the trigeminal ganglion (TG) underlying orofacial neuropathic pain. Chronic constriction injury of the infraorbital nerve (CCI-ION) of mice was performed to establish the model of orofacial neuropathic pain. Von Frey filament test was performed to detect the head withdrawal threshold (HWT) of mice. Quantitative reverse transcription-polymerase chain, western blotting (WB), fluorescence in situ hybridization, and immunofluorescence (IF) staining were used to detect the expression and distribution of SCN2B and miR-6954-3p in the TG of mice. A luciferase activity assay was carried out to prove the binding between SCN2B messenger ribonucleic acid (mRNA) and miR-6954-3p. After the CCI-ION surgery, the levels of Scn2b mRNA and protein significantly increased and miR-6954-3p decreased in the TG of mice with decreasing HWT. IF staining revealed that SCN2B was expressed specifically in the TG neurons. Silencing SCN2B in the TG of CCI-ION mice significantly increased the HWT. Importantly, the 3′-untranslated region of Scn2b mRNA was proved to bind with miR-6954-3p. Fluorescence in situ hybridization and IF staining demonstrated that miR-6954-3p was expressed in TG neurons and co-expressed with SCN2B. Furthermore, intraganglionic injection of miR-6954-3p agomir into the TG of CCI-ION mice resulted in the downregulation of SCN2B and increased the HWT. These findings suggest that the downregulation of miR-6954-3p in the TG promotes orofacial neuropathic pain by promoting SCN2B expression following trigeminal nerve injury. PerspectiveThis study points to the important role of SCN2B in orofacial neuropathic pain. Furthermore, miR-6954-3p is proven to regulate the expression of SCN2B by binding to the 3′-untranslated region of Scn2b mRNA. These findings indicate that SCN2B and miR-6954-3p are potential therapeutic targets for the treatment of orofacial neuropathic pain.

A comprehensive exploration of astrocytes in migraine: a bibliometric and visual analysis

BackgroundMigraine, as a prevalent neurologic disorder, involves intricate and yet incompletely elucidated pathophysiological mechanisms. A plethora of research findings underscores the pivotal role played by astrocytes in the progression of migraines. In order to elucidate the current advances and directions in research pertaining to astrocytes in migraines, we conducted bibliometric analysis of relevant literature and visualized the results. Subsequently, we expound upon these findings to contribute to the evolving understanding of the role of astrocytes in migraine pathophysiology.MethodsOn November 21, 2023, we conducted a search on Web of Science (WOS), restricting the document type to articles or reviews and language to English. Following a meticulous selection process involving three researchers, we identified the literature to be included in our analysis. Subsequently, we employed Microsoft Office Excel programs, R, VOSviewer, Scimago Graphica, and CiteSpace software to conduct visualization analysis of basic information and trends regarding journals, countries/regions, and influential authors, institutions, keywords, and papers.ResultsAs of November 21, 2023, relevant literature has been published in 71 journals across 27 countries/regions. This corpus comprises contributions from 576 authors affiliated with 220 institutions, encompassing 865 keywords and referencing 6065 scholarly articles. CEPHALALGIA stands out as the most influential journal in this field, while authors PIETROBON D and DALKARA T have significant impact. The United States is highly influential, with CNR and UNIV PADUA emerging as highly influential institutions. The predominant category is Neurosciences.ConclusionsFuture investigators may continue to focus on migraines with aura, familial hemiplegic migraine (FHM), and the crucial calcitonin gene-related peptide (CGRP) system. Employing advanced observational techniques, such as imaging, researchers should pay attention to cellular and tissue structures, such as microglia and the trigeminal ganglion, as well as mechanisms involving inflammation and central sensitization. Moreover, animal models are paramount in obtaining high-quality evidence.

Oxytocin Receptors on Calvarial Periosteal Innervation: Therapeutic Target for Post-Traumatic Headache?

Following a mild traumatic brain injury (mTBI), the most prevalent and profoundly debilitating occurrence is the emergence of an acute and persistent post-traumatic headache (PTH), for which there are presently no approved treatments. A crucial gap in knowledge exists regarding the consequences of an mTBI, which could serve as a foundation for the development of therapeutic approaches. The activation of trigeminal sensory nerve terminals that innervate the calvarial periosteum (CP)-a densely innervated tissue layer covering the calvarial skull-has been implicated in both migraines and PTHs. We have previously shown that trigeminal oxytocin receptors (OTRs) may provide a therapeutic target for PTHs. This study examined the expression of oxytocin receptors on trigeminal nerves innervating the periosteum and whether these receptors might serve as a therapeutic target for PTHs using a direct application of oxytocin to the periosteum in a rodent model of PTH. We used retrograde tracing and immunohistochemistry to determine if trigeminal ganglion (TG) neurons innervating the periosteum expressed OTRs and/or CGRPs. To model the impact of local inflammation that occurs following an mTBI, we applied chemical inflammatory mediators directly to the CP and assessed for changes in immediate-early gene expression as an indication of neuronal activation. We also determined whether mTBI would lead to expression changes to OTR levels. To determine whether these OTRs could be a viable therapeutic target, we assessed the impact of oxytocin injections into the CP in a mouse model of PTH-induced periorbital allodynia. The results of these experiments demonstrate the following: (1) the cell bodies of CP afferents reside in the TG and express both OTRs and CGRPs; (2) inflammatory chemical stimulation of the periosteum leads to rapid activation of TG neurons (phospho-ERK (p-ERK) expression), (3) mTBI-induced inflammation increased OTR expression compared to the sham group; and (4) administration of oxytocin into the periosteum on day 2 and day 40 blocked cutaneous allodynia for up to one hour post-administration for both acute and persistence phases in the PTH model-an effect that was preventable by the administration of an OTR antagonist. Taken together, our observations suggest that periosteal trigeminal afferents contribute to post-TBI craniofacial pain, and that periosteum tissue can be used as a potential local target for therapeutics such as oxytocin.

Interleukin-22 receptor 1-mediated stimulation of T-type Ca2+ channels enhances sensory neuronal excitability through the tyrosine-protein kinase Lyn-dependent PKA pathway

BackgroundInterleukin 24 (IL-24) has been implicated in the nociceptive signaling. However, direct evidence and the precise molecular mechanism underlying IL-24’s role in peripheral nociception remain unclear.MethodsUsing patch clamp recording, molecular biological analysis, immunofluorescence labeling, siRNA-mediated knockdown approach and behavior tests, we elucidated the effects of IL-24 on sensory neuronal excitability and peripheral pain sensitivity mediated by T-type Ca2+ channels (T-type channels).ResultsIL-24 enhances T-type channel currents (T-currents) in trigeminal ganglion (TG) neurons in a reversible and dose-dependent manner, primarily by activating the interleukin-22 receptor 1 (IL-22R1). Furthermore, we found that the IL-24-induced T-type channel response is mediated through tyrosine-protein kinase Lyn, but not its common downstream target JAK1. IL-24 application significantly activated protein kinase A; this effect was independent of cAMP and prevented by Lyn antagonism. Inhibition of PKA prevented the IL-24-induced T-current response, whereas inhibition of protein kinase C or MAPK kinases had no effect. Functionally, IL-24 increased TG neuronal excitability and enhanced pain sensitivity to mechanical stimuli in mice, both of which were suppressed by blocking T-type channels. In a trigeminal neuropathic pain model induced by chronic constriction injury of the infraorbital nerve, inhibiting IL-22R1 signaling alleviated mechanical allodynia, which was reversed by blocking T-type channels or knocking down Cav3.2.ConclusionOur findings reveal that IL-24 enhances T-currents by stimulating IL-22R1 coupled to Lyn-dependent PKA signaling, leading to TG neuronal hyperexcitability and pain hypersensitivity. Understanding the mechanism of IL-24/IL-22R1 signaling in sensory neurons may pave the way for innovative therapeutic strategies in pain management.

A Comparison Between the Efficacy of Trigeminal Ganglion Radiofrequency Thermocoagulation and Ultrasound-Guided Maxillary-Mandibular Nerve Pulsed Radiofrequency in the Treatment of Trigeminal Neuralgia: A Randomized Clinical Trial.

Background and objective Trigeminal neuralgia (TN) is a debilitating disorder characterized by acute episodic attacks of pain that significantly impair patients' quality of life and overall functioning. Initial therapeutic strategies to treat this condition include pharmacological options, particularly carbamazepine. In cases with resistance to dose escalation and polypharmacy, interventional procedures may be warranted. Theprimary aimof this study was tocompare the efficacyoftrigeminal ganglion(TG) radiofrequency thermocoagulation (RFT) and ultrasound (US)-guided maxillary/mandibular (max/mand) nervepulsed radiofrequency(PRF) for treating TN, based on the findings at six months post-treatment. Thesecondary aimswere toassess the impactof these interventions on drug consumption and interventional safetybased on adverse events. Methods This prospective, randomized, single-blind study was conducted at a single pain clinic. Forty-four patients were randomized into two groups. Group RFT received TG RFT at 60 °C, 65 °C, and 70 °C for 60 seconds each, whereas Group PRF received max/mand PRF for 240 seconds. Pain relief was assessed by using the numeric rating scale (NRS) and intervention effectiveness on medication consumption was evaluated by using the Medication Quantification Scale III (MQS III). The rates of intervention-related adverse events were also compared. Results Both RFT and PRF significantly alleviated pain at one and six months post-treatment compared to baseline (p<0.05). No statistical differences were found in the NRS and MQS III scores between the groups. At six months, 77.3% of RFT patients and 63.9% of PRF patients experienced at least 50% pain relief, with no statistically significant difference. Hypoesthesia occurred in two RFT patients, and masseter weakness was observed in one patient, while no adverse events were reported in the PRF group. Conclusions TG RFT and max/mand PRF are effective treatments for TN. US-guided max/mand PRF, which avoids RFT-associated complications and radiation exposure, may be the superior and preferable option. In this study, the potential space between the coronoid process and maxilla was used to access the maxillary nerve during the maxillary block and PRF procedures, in contrast to the classical approach through the mandibular notch. Further large-scale randomized controlled trials are required to gain deeper insights into the topic.

약물 치료에 반응하지 않는 대상포진후 가려움 환자에서의 삼차신경절주사와 싸이모신알파1 치료 효과 증례

Postherpetic itch (PHI), a common condition in neuropathic itch is not as well studied as postherpetic neuralgia. Intractable PHI is thought to be hyperexcitability of itch-transmission nervous system caused by neural injury from herpes zoster. In some cases, PHI is very severe to compromise patient’s quality of life and refractory to conventional treatments. Here, it is reported that a case of severe chronic PHI was reduced with trigeminal ganglion blocks and thymosin alpha 1 injections. A 74-year-old man complained of severe itching with hypoesthesia in his left eyebrow and scalp for 5 years after the initial onset of herpes zoster at the same site, despite treatment with two types of antihistamines, gabapentin, and amitriptyline. He developed ulcers on his forehead and scalp because of his scratching. Trigeminal ganglion blocks and thymosin alpha 1 injections reduced itching, with the ulcers disappearing within 1 month. In this case, it is suggested that trigeminal ganglion blocks and thymosin alpha 1 injection may be a useful treatment option for PHI.

Dietary supplementation with grape seed extract from Vitus vinifera prevents suppression of GABAergic protein expression in female Sprague Dawley trigeminal ganglion in a model of chronic temporomandibular joint disorder

ObjectiveTo investigate cellular changes in protein expression in the trigeminal ganglion in an established preclinical chronic model of temporomandibular joint disorder (TMD) in response to grape seed extract (GSE) supplementation based on its beneficial use in preclinical chronic orofacial pain models. DesignThree experimental conditions included female Sprague-Dawley rats as naïve controls, and animals subjected to neck muscle inflammation and prolonged jaw opening with and without daily supplementation of GSE in the drinking water prior to inflammation. Changes were evaluated in mechanical sensitivity to von Frey filaments and protein expression in the trigeminal ganglion of animals 14 days post jaw opening. ResultsCalcitonin-gene related peptide and protein kinase A, proteins positively associated with peripheral sensitization and enhanced nociception, did not show elevated expression at day 14 in the model compared to naïve or GSE supplemented animals. However, neuronal levels of glutamate decarboxylase (GAD) 65/67, which are enzymes responsible for the synthesis of the inhibitory neurotransmitter GABA that functions to suppress neuronal excitability, were significantly decreased on day 14 post jaw opening. Similarly, a significant decrease in neuronal expression of the GABA receptor subunits GABAB1 and GABAB2, but not GABAA, was observed in the TMD model. Importantly, GSE prevented suppression of GAD 65/67 and GABAB subunits, maintaining levels similar to naïve animals. ConclusionResults from our study provide evidence of the downregulation of inhibitory GABAergic proteins in trigeminal ganglion neurons in a preclinical chronic TMD model and the benefits of GSE supplementation in preventing their suppression and maintaining normal levels.

PACAP38/mast-cell-specific receptor axis mediates repetitive stress-induced headache in mice.

Pain, an evolutionarily conserved warning system, lets us recognize threats and motivates us to adapt to those threats. Headache pain from migraine affects approximately 15% of the global population. However, the identity of any putative threat that migraine or headache warns us to avoid is unknown because migraine pathogenesis is poorly understood. Here, we show that a stress-induced increase in pituitary adenylate cyclase-activating polypeptide-38 (PACAP38), known as an initiator of allosteric load inducing unbalanced homeostasis, causes headache-like behaviour in male mice via mas-related G protein-coupled receptor B2 (MrgprB2) in mast cells. The repetitive stress model and dural injection of PACAP38 were performed to induce headache behaviours. We assessed headache behaviours using the facial von Frey test and the grimace scale in wild-type and MrgprB2-deficient mice. We further examined the activities of trigeminal ganglion neurons using in vivo Pirt-GCaMP Ca2+ imaging of intact trigeminal ganglion (TG). Repetitive stress and dural injection of PACAP38 induced MrgprB2-dependent headache behaviours. Blood levels of PACAP38 were increased after repetitive stress. PACAP38/MrgprB2-induced mast cell degranulation sensitizes the trigeminovascular system in dura mater. Moreover, using in vivo intact TG Pirt-GCaMP Ca2+ imaging, we show that stress or/and elevation of PACAP38 sensitized the TG neurons via MrgprB2. MrgprB2-deficient mice showed no sensitization of TG neurons or mast cell activation. We found that repetitive stress and dural injection of PACAP38 induced headache behaviour through TNF-a and TRPV1 pathways. Our findings highlight the PACAP38-MrgprB2 pathway as a new target for the treatment of stress-related migraine headache. Furthermore, our results pertaining to stress interoception via the MrgprB2/PACAP38 axis suggests that migraine headache warns us of stress-induced homeostatic imbalance.

MERTK in the rat trigeminal system: a potential novel target for cluster headache?

The trigeminal system is key to the pathophysiology of migraine and cluster headache, two primary headache disorders that share many features. Recently, MER proto-oncogene tyrosine kinase (MERTK), a cell surface receptor, was strongly associated with cluster headache through genetic studies. Further, the MERTK ligand galectin-3 has been found to be elevated in serum of migraine patients. In this study, MERTK and MERTK ligands were investigated in key tissue to better understand their potential implication in the pathophysiology of primary headache disorders. Immunohistochemistry was used to map MERTK and galectin-3 expression in rat trigeminal ganglia. RT-qPCR was used to assess MERTK gene expression in blood, and ELISA immunoassays were used for MERTK ligand quantification in serum from study participants with and without cluster headache. MERTK gene expression was elevated in blood samples from study participants with cluster headache compared to controls. In addition, MERTK ligand galectin-3 was found at increased concentration in the serum of study participants with cluster headache, whereas the levels of MERTK ligands growth arrest specific 6 and protein S unaffected. MERTK and galectin-3 were both expressed in rat trigeminal ganglia. Galectin-3 was primarily localized in smaller neurons and to a lesser extent in C-fibres, while MERTK was found in satellite glia cells and in the outer membrane of Schwann cells. Interestingly, a strong MERTK signal was found specifically in the region proximal to the nodes of Ranvier. The overexpression of MERTK and galectin-3 in tissue from study participants with cluster headache, as well as the presence of MERTK in rat peripheral satellite glia cells and Schwann cells in the trigeminal ganglia, further highlights MERTK signalling as an interesting potential future therapeutic target in primary headache.Graphical

A cell cycle regulator, E2F2, and glucocorticoid receptor cooperatively transactivate the bovine alphaherpesvirus 1 immediate early transcription unit 1 promoter.

Bovine alpha-herpesvirus 1 (BoHV-1) acute infection in cattle leads to establishment of latency in sensory neurons in the trigeminal ganglia (TG). A synthetic corticosteroid dexamethasone consistently initiates BoHV-1 reactivation in latently infected calves. The BoHV-1 immediate early transcription unit 1 (IEtu1) promoter regulates expression of infected cell protein 0 (bICP0) and bICP4, two viral transcriptional regulators. Hence, the IEtu1 promoter must be activated for the reactivation to occur. The number of TG neurons expressing E2F2, a transcription factor and cell cycle regulator, increased during early stages of reactivation from latency. The glucocorticoid receptor (GR) and E2F2, but not E2F1, E2F3a, or E2F3b, cooperatively transactivated a 436-bp cis-regulatory module (CRM) in the IEtu1 promoter that contains two GR responsive elements. Chromatin immunoprecipitation studies revealed that E2F2 occupies IEtu1 promoter sequences in cultured cells. GR and E2F2 mediate cooperative transactivation of IEtu1 promoter activity, which is predicted to stimulate viral replication following stressful stimuli.

Quercetin, Main Active Ingredient of Moutan Cortex, Alleviates Chronic Orofacial Pain via Block of Voltage-Gated Sodium Channel.

Chronic orofacial pain (COP) therapy is challenging, as current medical treatments are extremely lacking. Moutan Cortex (MC) is a traditional Chinese medicine herb widely used for chronic inflammatory diseases. However, the mechanism behind MC in COP therapy has not been well-established. The purpose of this study was to identify the active ingredients of MC and their specific underlying mechanisms in COP treatment. In this study, the main active ingredients and compound-target network of MC in COP therapy were identified through network pharmacology and bioinformatics analysis. Adult male Sprague-Dawley rats received oral mucosa lipopolysaccharide (LPS) injection to induce COP. Pain behaviors were evaluated by orofacial mechanical nociceptive assessment after intraganglionar injection. In vitro inflammatory cytokines in LPS-pretreated human periodontal ligament stem cells (hPDLSCs) and rat primary cultural trigeminal ganglion (TG) neurons were quantified by real-time quantitative polymerase chain reaction (RT-qPCR). Schrödinger software was used to verify the molecular docking of quercetin and critical targets. Whole-cell recording electrophysiology was used to evaluate the effect of quercetin on voltage-gated sodium (Na v ) channel in rat TG neurons. The assembled compound-target network consisted of 4 compounds and 46 targets. As 1 of the active components of MC correlated with most related targets, quercetin alleviated mechanical allodynia in LPS-induced rat model of COP (mechanical allodynia threshold median [interquartile range (IQR) 0.5 hours after drug administration: vehicle 1.3 [0.6-2.0] g vs quercetin 7.0 [6.0-8.5] g, P = .002). Gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that immune response and membrane functions play essential roles in MC-COP therapy. Five of the related targets were identified as core targets by protein-protein interaction analysis. Quercetin exerted an analgesic effect, possibly through blocking Na v channel in TG sensory neurons (peak current density median [IQR]: LPS -850.2 [-983.6 to -660.7] mV vs LPS + quercetin -589.6 [-711.0 to -147.8] mV, P = .006) while downregulating the expression level of proinflammatory cytokines-FOS (normalized messenger RNA [mRNA] level mean ± standard error of mean [SEM]: LPS [2. 22 ± 0.33] vs LPS + quercetin [1. 33 ± 0.14], P = .034) and TNF-α (normalized mRNA level mean ± SEM: LPS [8. 93 ± 0.78] vs LPS + quercetin [3. 77 ± 0.49], P < .0001). Identifying Na v as the molecular target of quercetin clarifies the analgesic mechanism of MC, and provides ideas for the development of novel selective and efficient chronic pain relievers.

Satellite Glial Cells: No Longer the Most Overlooked Glia.

Many glial biologists consider glia the neglected cells of the nervous system. Among all the glia of the central and peripheral nervous system, satellite glia may be the most often overlooked. Satellite glial cells (SGCs) are located in ganglia of the cranial nerves and the peripheral nervous system. These small cells surround the cell bodies of neurons in the trigeminal ganglia (TG), spiral ganglia, nodose and petrosal ganglia, sympathetic ganglia, and dorsal root ganglia (DRG). Essential SGC features include their intimate connections with the associated neurons, their small size, and their derivation from neural crest cells. Yet SGCs also exhibit tissue-specific properties and can change rapidly, particularly in response to injury. To illustrate the range of SGC functions, we will focus on three types: those of the spiral, sympathetic, and DRG, and consider both their shared features and those that differ based on location.

Effects of the Dual FAAH/MAGL Inhibitor AKU-005 on Trigeminal Hyperalgesia in Male Rats.

The inhibition of endocannabinoid hydrolysis by enzymatic inhibitors may interfere with mechanisms underlying migraine-related pain. The dual FAAH/MAGL inhibitor AKU-005 shows potent inhibitory activity in vitro. Here, we assessed the effect of AKU-005 in a migraine animal model based on nitroglycerin (NTG) administration. Male rats were treated with AKU-005 (0.5 mg/kg, i.p.) or vehicle 3 h after receiving NTG (10 mg/kg, i.p.) or NTG vehicle. One hour later, rats were subjected to the open field test followed by the orofacial formalin test. At the end of the test, we collected serum samples for assessing calcitonin gene-related peptide (CGRP) levels as well as meninges, trigeminal ganglia, and brain areas to assess mRNA levels of CGRP and pro-inflammatory cytokines, and endocannabinoid and related lipid levels. AKU-005 reduced NTG-induced hyperalgesia during the orofacial formalin test but did not influence NTG-induced changes in the open field test. It significantly reduced serum levels of CGRP, CGRP, and pro-inflammatory cytokine mRNA levels in the meninges, trigeminal ganglia, and central areas. Surprisingly, AKU-005 caused no change in endocannabinoids and related lipids in the regions evaluated. The present findings suggest that AKU-005 may have anti-migraine effects by reducing CGRP synthesis and release and the associated inflammatory events. This effect, however, does not seem mediated via an interference with the endocannabinoid pathway.

The role of voltage-gated calcium channel α2δ-1 in the occurrence and development in myofascial orofacial pain

Patients who suffer from myofascial orofacial pain could affect their quality of life deeply. The pathogenesis of pain is still unclear. Our objective was to assess Whether Voltage-gated calcium channel α2δ-1(Cavα2δ-1) is related to myofascial orofacial pain. Rats were divided into the masseter tendon ligation group and the sham group. Compared with the sham group, the mechanical pain threshold of the masseter tendon ligation group was reduced on the 4th, 7th, 10th and 14th day after operation(P < 0.05). On the 14th day after operation, Cavα2δ-1 mRNA expression levels in trigeminal ganglion (TG) and the trigeminal spinal subnucleus caudalis and C1-C2 spinal cervical dorsal horn (Vc/C2) of the masseter tendon ligation group were increased (PTG=0.021, PVc/C2=0.012). Rats were divided into three groups. On the 4th day after ligating the superficial tendon of the left masseter muscle of the rats, 10 ul Cavα2δ-1 antisense oligonucleotide, 10 ul Cavα2δ-1 mismatched oligonucleotides and 10 ul normal saline was separately injected into the left masseter muscle of rats in Cavα2δ-1 antisense oligonucleotide group, Cavα2δ-1 mismatched oligonucleotides group and normal saline control group twice a day for 4 days. The mechanical pain threshold of the Cavα2δ-1 antisense oligonucleotides group was higher than Cavα2δ-1 mismatched oligonucleotides group on the 7th and 10th day after operation (P < 0.01). After PC12 cells were treated with lipopolysaccharide, Cavα2δ-1 mRNA expression level increased (P < 0.001). Cavα2δ-1 may be involved in the occurrence and development in myofascial orofacial pain.

Influence of Human Leukocyte Antigen in Susceptibility to Migraine in Patients

Migraine affects more than one billion individuals each year across the world, and is one of the most common neurologic disorders, with a high prevalence and morbidity, especially among young adults and females. Migraine is associated with a wide range of comorbidities, which range from stress and sleep disturbances to suicide. The complex and largely unclear mechanisms of migraine development have resulted in the proposal of various social and biological risk factors, such as hormonal imbalances, genetic and epigenetic influences, as well as cardiovascular, neurological, and autoimmune diseases. Experimental findings suggest an involvement of neuroinflammatory mechanisms in the pathophysiology of migraine. Specifically, preclinical models of migraine have emphasized the role of neuroinflammation following the activation of the trigeminal pathway at several peripheral and central sites including dural vessels, the trigeminal ganglion, and the trigeminal nucleus caudalis. The evidence of an induction of inflammatory events in migraine pathophysiological mechanisms has prompted researchers to investigate the human leukocyte antigen (HLA) phenotypes as well as cytokine genetic polymorphisms in order to verify their potential relationship with migraine risk and severity. Furthermore, the role of neuroinflammation in migraine seems to be supported by evidence of an increase in pro-inflammatory cytokines, both ictally and interictally, together with the prevalence of Th1 lymphocytes and a reduction in regulatory lymphocyte subsets in peripheral blood of migraineurs. Cytokine profiles of cluster headache (CH) patients and those of tension-type headache patients further suggest an immunological dysregulation in the pathophysiology of these primary headaches, although evidence is weaker than for migraine.

Do bubbles matter amid PBC for trigeminal neuralgia?

ABSTRACT Background As a simple and safe alternative intervention, percutaneous balloon compression (PBC) has been gradually adopted by a growing number of neurosurgeons to treat trigeminal neuralgia. A pear-shaped opacity observed fluoroscopically, which indicates full suffusion of Meckel’s cave conducting sufficient pressure against Gasserian ganglion, is believed to be the key to its success. Sometimes, a bitten pear may appear due to bubbles in the balloon but is usually ignored. Objective This study aims to investigate the effects of the bubbles on postoperative outcomes. Methods Patient data were obtained from the consecutive cases undergoing PBCs in our department between 2019 and 2021. Among them, pain and numbness were used to assess the efficacy of PBC based on Barrow Neurology Institute (BNI) scoring system. It was defined as an effective outcome if the postoperative pain intensity grade was lower than II. And those with numbness grade > II were regarded as numb incidence. Results We eventually recruited 59 cases, including 42 in full pear and 17 in bitten pear groups with follow-up time up to 44 months. The early effective rates were 95.2% and 82.4%, respectively (p > 0.05), which turned to 88.1% and 52.9% during the last follow-up period (p < 0.01). This result indicated that the bitten pear gave rise to a significantly higher recurrence. In terms of numbness, there was no significant difference. Conclusion Gas does not yield enough pressure as liquid, and cannot exert enough pressure to the semilunar ganglion. Therefore, air evacuation should not be ignored before injection.

Inhibiting Nav1.7 channels in pulpitis: An in vivo study on neuronal hyperexcitability

Pulpitis constitutes a significant challenge in clinical management due to its impact on peripheral nerve tissue and the persistence of chronic pain. Despite its clinical importance, the correlation between neuronal activity and the expression of voltage-gated sodium channel 1.7 (Nav1.7) in the trigeminal ganglion (TG) during pulpitis is less investigated. The aim of this study was to examine the relationship between experimentally induced pulpitis and Nav1.7 expression in the TG and to investigate the potential of selective Nav1.7 modulation to attenuate TG abnormal activity associated with pulpitis. Acute pulpitis was induced at the maxillary molar (M1) using allyl isothiocyanate (AITC). The mice were divided into three groups: control, pulpitis model, and pulpitis model treated with ProTx-II, a selective Nav1.7 channel inhibitor. After three days following the surgery, we conducted a recording and comparative analysis of the neural activity of the TG utilizing in vivo optical imaging. Then immunohistochemistry and Western blot were performed to assess changes in the expression levels of extracellular signal-regulated kinase (ERK), c-Fos, collapsin response mediator protein-2 (CRMP2), and Nav1.7 channels. The optical imaging result showed significant neurological excitation in pulpitis TGs. Nav1.7 expressions exhibited upregulation, accompanied by signaling molecular changes suggestive of inflammation and neuroplasticity. In addition, inhibition of Nav1.7 led to reduced neural activity and subsequent decreases in ERK, c-Fos, and CRMP2 levels. These findings suggest the potential for targeting overexpressed Nav1.7 channels to alleviate pain associated with pulpitis, providing practical pain management strategies.

The impact of the migraine treatment onabotulinumtoxinA on inflammatory and pain responses: Insights from an animal model.

Migraine, a prevalent and debilitating disease, involves complex pathophysiology possibly including inflammation and heightened pain sensitivity. The current study utilized the complete Freund's adjuvant (CFA) model of inflammation, with onabotulinumtoxinA (BoNT/A) as a treatment of interest due to its use in clinical migraine management. Using an animal model, the study sought to investigate the role of BoNT/A in modulating CFA-induced inflammation, alterations in pain sensitivity, and the regulation of calcitonin gene-related peptide (CGRP) release. Further, we aimed to assess the changes in SNAP-25 through western blot analysis to gain insights into the mechanistic action of BoNT/A. BoNT/A or control was administered subcutaneously at the periorbital region of rats 3 days before the induction of inflammation using CFA. Periorbital mechanical sensitivity was assessed post-inflammation, and alterations in CGRP release were evaluated. Changes in SNAP-25 levels were determined using western blot analysis. Upon CFA-induced inflammation, there was a marked increase in periorbital mechanical sensitivity, with the inflammation side showing increased sensitivity compared to other periorbital areas. BoNT/A did decrease the withdrawal thresholds in the electronic von Frey test. Despite not being able to observe differences in pain thresholds or CGRP release, BoNT/A reduced baseline release under CFA inflamed conditions. Analysis of SNAP-25 levels in the trigeminal ganglion revealed both intact and cleaved forms that were notably elevated in BoNT/A-treated animals. These findings, derived from western blot analysis, suggest an effect on neurotransmitter release. Our investigation highlights the role of BoNT/A in reducing baseline CGRP in the context of inflammation and its involvement in SNAP-25 cleavage. In contrast, BoNT/A did not appear to alter facial pain sensitivity induced by inflammation, suggesting that mechanisms other than baseline CGRP could be implicated in the elevated thresholds in the CFA model.

Understanding the Mechanisms of the Gβ5/R7-RGS Complex in Pain Transmission through Single Cell mRNA Profiling

The dorsal root ganglion (DRG) and trigeminal ganglion (TG) contain cell bodies of the peripheral sensory neurons that transmit pain signals from different parts of body to the central nervous system. Peripheral neuropathy and trigeminal neuralgia are common painful conditions that can be caused by pathologies affecting these nerves. Current clinical treatment of these conditions often relies on anticonvulsant drugs with significant neurological side effects. Lack of effective treatments of these conditions highlights the need for better therapeutic approaches. GNB5 encodes the protein Gβ5, a divergent member of the G protein β family, that binds with members (RGS6, 7, 9 and 11) of the R7 subfamily of the regulators of G signaling (R7-RGS) to form obligate Gβ5/R7-RGS complexes. The Gβ5/R7-RGS complex proteins are expressed primarily in neurons including those in the DRG and TG. They function as GTPase-Activating Proteins (GAP) to dampen signaling downstream of Gi/o-coupled receptors. Studies in our lab demonstrated that Adv-Cre+/−; Gnb5fl/fl mice lacking Gnb5 in sensory neurons have significantly reduced mechanical, thermal and chemical nociception. However, RGS7-Cre+/−; Gnb5fl/fl mice lacking Gnb5 in Rgs7 expressing neurons exhibited only diminished mechanical nociception. Additionally, treatment with GABA-B receptor antagonist 2- hydroxysaclofen abolished the inhibition of mechanical nociception in both Advillin- Cre+/-; Gnb5fl/fl and Rgs7-Cre+/-; Gnb5fl/fl mice, implicating the involvement of GABA-B receptor signaling in Gβ5/Rgs7-associated mechanical nociception. To further understand the cellular and molecular mechanisms of Gβ5/R7-RGS complex-mediated nociception, we analyzed and compared the expression profiles of the Gβ5/R7-RGS genes in DRG and TG through bioinformatic analysis of publicly available scRNAseq datasets and in situ hybridization of selected genes using RNAscope technology. We found high levels of Gnb5 expression across all sensory neuron cell types while the expressions of members of R7-RGS subfamily showed distinctive patterns among these neuron cell types. Single cell clustering analysis using known neuronal markers revealed that Rgs7 and Rgs11 were highly expressed in majority of neuron types, while Rgs6 and Rgs9 were represented in smaller, more distinct clusters. These results suggest that particular members of R7-RGS gene family might play distinct roles in different types of nociception, a finding that warrants further investigation into the individual mechanisms of each member of this gene family in pain transmission. NIDDK Intramural Research Program ZIA DK043304-29. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Exploring the mechanism of Nav1.3 in the ION-CCI rat model based on the TLR4/TRAF6/NF-κB pathway

BackgroundTrigeminal neuralgia (TN) is a common and difficult-to-treat neuropathic pain disorder in clinical practice. Previous studies have shown that Toll-like receptor 4 (TLR4) modulates the activation of the NF-κB pathway to affect neuropathic pain in rats. Voltage-gated sodium channels (VGSCs) are known to play an important role in neuropathic pain electrical activity. ObjectiveTo investigate whether TLR4 can regulate Nav1.3 through the TRAF6/NF-κB p65 pathway after infraorbital nerve chronic constriction injury (ION-CCI).Study design: ION-CCI modeling was performed on SD (Sprague Dawley) rats. To verify the success of the modeling, we need to detect the mechanical pain threshold and ATF3. Then, detecting the expression of TLR4, TRAF6, NF-κB p65, p-p65, and Nav1.3 in rat TG. Subsequently, investigate the role of TLR4/TRAF6/NF-κB pathway in ION-CCI model by intrathecal injections of LPS-rs (TLR4 antagonist), C25-140 (TRAF6 inhibitor), and PDTC (NF-κB p65 inhibitor). ResultsION-CCI surgery decreased the mechanical pain threshold of rats and increased the expression of ATF3, TLR4, TRAF6, NF-κB p-p65 and Nav1.3, but there was no difference in NF-κB p65 expression. After inject antagonist or inhibitor of the TLR4/TRAF6/NF-κB pathway, the expression of Nav1.3 was decreased and mechanical pain threshold was increased. ConclusionIn the rat model of ION-CCI, TLR4 in the rat trigeminal ganglion regulates Nav1.3 through the TRAF6/NF-κB p65 pathway, and TLR4 antagonist alleviates neuropathic pain in ION-CCI rats.