Separation of Oral Cooling and Warming Requires TRPM8.

Cooling sensations arise inside the mouth during ingestive and homeostasis behaviors. Oral presence of cooling temperature engages the cold and menthol receptor TRPM8 (transient receptor potential melastatin 8) on trigeminal afferents. Yet, how TRPM8 influences brain and behavioral responses to oral temperature is undefined. Here we used in vivo neurophysiology to record action potentials stimulated by cooling and warming of oral tissues from trigeminal nucleus caudalis neurons in female and male wild-type and TRPM8 gene deficient mice. Using these lines, we also measured orobehavioral licking responses to cool and warm water in a novel, temperature-controlled fluid choice test. Capture of antidromic electrophysiological responses to thalamic stimulation identified that wild-type central trigeminal neurons showed diverse responses to oral cooling. Some neurons displayed relatively strong excitation to cold <10°C (COLD neurons) while others responded to only a segment of mild cool temperatures below 30°C (COOL neurons). Notably, TRPM8 deficient mice retained COLD-type but lacked COOL cells. This deficit impaired population responses to mild cooling temperatures below 30°C and allowed warmth-like (≥35°C) neural activity to pervade the normally innocuous cool temperature range, predicting TRPM8 deficient mice would show anomalously similar orobehavioral responses to warm and cool temperatures. Accordingly, TRPM8 deficient mice avoided both warm (35°C) and mild cool (≤30°C) water and sought colder temperatures in fluid licking tests, whereas control mice avoided warm but were indifferent to mild cool and colder water. Results imply TRPM8 input separates cool from warm temperature sensing and suggest other thermoreceptors also participate in oral cooling sensation.

Premature gray hair development in the interbrow region owing to the loss of maxillary first molars in young mice.

The exact sites of premature hair graying and whether tooth loss causes this condition remain unknown. In this study, we aimed to explore the effect of reduced mastication on premature hair graying. Maxillary first molars were extracted from young mice, and the mice were observed for 3 months, along with non-extraction control group mice. After 3 months, gray hair emerged in the interbrow region of mice in the tooth extraction group but not in the control group. The expression of tyrosinase-related protein-2 (TRP-2) mRNA was lower in the interbrow tissues of young mice without maxillary molars than in those with maxillary molars. Tooth loss leads to interbrow gray hair growth, possibly because of weakened trigeminal nerve input, suggesting that reduced mastication causes premature graying. Thus, prompt prosthetic treatment after molar loss is highly recommended.

Acute pulpitis promotes purinergic signaling to induce pain in rats via P38MAPK/NF-κB signaling pathway.

Toothache is one of the most common types of pain, but the mechanisms underlying pulpitis-induced pain remain unknown. The ionotropic purinergic receptor family (P2X) is reported to mediate nociception in the nervous system. This study aims to investigate the involvement of P2X3 in the sensitisation of the trigeminal ganglion (TG) and the inflammation caused by acute pulpitis. An acute tooth inflammation model was established by applying LPS to the pulp of SD rats. We found that the increased expression of P2X3 was induced by acute pulpitis. A selective P2X3 inhibitor (A-317491) reduced pain-like behavior in the maxillofacial region of rats and depressed the activation of neurons in the trigeminal ganglion induced by pulpitis. The upregulated MAPK signaling (p-p38, p-ERK1/2) expression in the ipsilateral TG induced by pulpitis could also be depressed by the application of the P2X3 inhibitor. Furthermore, the expression of markers of inflammatory processes, such as NF-κB, TNF-α and IL-1ß, could be induced by acute pulpitis and deduced by the intraperitoneal injection of P2X3 antagonists. Our findings demonstrate that purinergic P2X3 receptor signaling in TG neurons contributes to pulpitis-induced pain in rats and that P2X3 signaling may be a potential therapeutic target for tooth pain.

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.

Hyperexcitability of muscle spindle afferents in jaw-closing muscles in experimental myalgia: Evidence for large primary afferents involvement in chronic pain.

The goals of this review are to improve understanding of the aetiology of chronic muscle pain and identify new targets for treatments. Muscle pain is usually associated with trigger points in syndromes such as fibromyalgia and myofascial syndrome, and with small spots associated with spontaneous electrical activity that seems to emanate from fibers inside muscle spindles in EMG studies. These observations, added to the reports that large-diameter primary afferents, such as those innervating muscle spindles, become hyperexcitable and develop spontaneous ectopic firing in conditions leading to neuropathic pain, suggest that changes in excitability of these afferents might make an important contribution to the development of pathological pain. Here, we review evidence that the muscle spindle afferents (MSAs) of the jaw-closing muscles become hyperexcitable in a model of chronic orofacial myalgia. In these afferents, as in other large-diameter primary afferents in dorsal root ganglia, firing emerges from fast membrane potential oscillations that are supported by a persistent sodium current (INaP ) mediated by Na+ channels containing the α-subunit NaV 1.6. The current flowing through NaV 1.6 channels increases when the extracellular Ca2+ concentration decreases, and studies have shown that INaP -driven firing is increased by S100ß, an astrocytic protein that chelates Ca2+ when released in the extracellular space. We review evidence of how astrocytes, which are known to be activated in pain conditions, might, through their regulation of extracellular Ca2+ , contribute to the generation of ectopic firing in MSAs. To explain how ectopic firing in MSAs might cause pain, we review evidence supporting the hypothesis that cross-talk between proprioceptive and nociceptive pathways might occur in the periphery, within the spindle capsule.

Combined open maxillectomy and endoscopic endonasal resection of a giant V2 trigeminal schwannoma.

BACKGROUND: Trigeminal schwannoma is a rare type of tumor that arises from the Schwann cells of the trigeminal nerve. METHOD: We present a case of a patient with a giant V2 trigeminal schwannoma with painful swelling in the left maxilla. A complete resection using a combined open maxillectomy and endoscopic endonasal approach was performed. CONCLUSION: This case highlights the importance of a multidisciplinary approach to perform a combined open and endoscopic approach for safe resection while preserving adequate speech and swallowing.

Pharmacologic management of trigeminal nerve injury after endodontic treatment: A retrospective analysis.

BACKGROUND: Trigeminal nerve injury following endodontic treatment, leading to unpleasant sensations or partial sensory loss in the face or oral mucosa, is uncommon but significant when it occurs. OBJECTIVE: This study analysed the pharmacological management of trigeminal nerve injuries (TNI) in a university-based hospital. METHODS: We conducted a retrospective analysis of 47 patients who visited the Department of Orofacial Pain and Oral Medicine at Yonsei University Dental Hospital, Seoul, Korea, after TNI following endodontic procedures in primary clinics. Both objective tests and subjective evaluations, assessed the extent and duration of sensory injury during the initial visit. The patient's initial symptoms, presumed cause of TNI, referral delay (time interval between TNI and the first visit to our clinic), and medications were analysed to determine whether these factors affected the outcomes. RESULTS: Most patients with TNI experienced dysesthesia with hypoesthesia (70.2%). The mandibular molars were predominantly affected (72.3%), with the inferior alveolar nerve (IAN), lingual nerve (LN), both IAN and LN, and maxillary nerve compromised in 83.0, 12.8, 2.1, and 2.1% of cases, respectively. Causes of TNI included local anaesthesia (29.8%), overfilling/over-instrumentation (25.5%), endodontic surgery (17.0%), and unknown factors (27.7%). A shorter referral delay was associated with better outcomes, with an average delay of 8.6 weeks for symptom improvement compared with 44.1 weeks for no change. The medication regimens included steroids, NSAIDs, topical lidocaine, vitamin B complex, Adenosine Triphosphate (ATP), antiepileptics, antidepressants, and opioids administered alone or in combination, with a mean duration of 20.7 weeks. 53.2% of the patients reported improvement in their symptoms, 27.7% experienced no significant change, and 19.1% had unknown outcomes. CONCLUSIONS: Swift referral to an orofacial pain specialist is recommended for effective recovery in cases of TNI arising from endodontic treatment.

Pleasantness and unpleasantness in somatosensory investigation.

BACKGROUND: Qualitative sensory testing (QualST) is a simple, standardised, chairside method for evaluating somatosensory function; however, testing focuses on detection of cold, touch and pain with no recognition of perceptions of pleasantness and unpleasantness. OBJECTIVES: The study aimed to utilise the stimuli in QualST, with the addition of a soft brush, to investigate stimulus-evoked perceptions of pleasantness and unpleasantness on the facial skin and if any side-to-side differences. Additional aims were to determine the inter- and intra-rater reliability using the modified QualST protocol and in the side-to-side differences. METHODS: Thirty healthy adult female participants underwent three sessions of sensitivity testing as per the modified QualST protocol. Stimuli were applied bilaterally to the facial skin, and participants provided separate yes/no responses for presence of stimulus-evoked pleasantness, unpleasantness and/or differences between sides. RESULTS: The stimuli were able to evoke sensations of pleasantness and unpleasantness with little differences in responses between the Q-tip and goat hair brush for the perceptions. Side-to-side differences in evoked perceptions were observed and greatest, when evaluating for pinprick-evoked unpleasantness (range between sessions = 18-19 participants). Acceptable percentage (≥90%) and excellent Cohen's Kappa (≥0.762) inter- and intra-rater agreements were identified for one or more positive responses for each stimulus modality and the targeted perception. CONCLUSION: The modified QualST protocol provides a simple, reproducible method for the investigation of perceptions of pleasantness and unpleasantness, with readily accessible instrumentation to dental professionals and allowing for a more holistic approach in somatosensory testing.

Ultrasound-guided trigeminal nerve approach at the level of the pterygopalatine fossa in cat cadavers.

OBJECTIVE: To describe an ultrasound-guided suprazygomatic approach to the trigeminal nerve block in cat cadavers. STUDY DESIGN: Prospective descriptive study. ANIMALS: Ten feline cadaver heads. METHODS: A 25:75 methylene blue-iopamidol mixture (0.1 mL cm-1 cranium length) was injected into 10 cadaver heads using an ultrasound-guided suprazygomatic approach. A computed tomography (CT) scan was performed to identify contrast presence at the orbital fissure, foramen rotundum and ovale, followed by anatomical dissection to identify staining of the pterygopalatine fossa (PPF), extraconal retrobulbar area, mandibular and maxillary nerves. Descriptive statistics were used to summarize results. RESULTS: A total of 20 injections were performed. Of these, 1/20 misinjection occurred and excluded from further reporting. The volume of injectate was 0.9 (0.9-1.1) mL [median (range)]. Staining of the PPF, extraconal space, maxillary and mandibular nerves over more than 6 mm was achieved in 19/19 (100%), 18/19 (95%), 17/19 (89%) and 19/19 (100%) of injections, respectively. CT showed presence of contrast within 5 mm of the orbital fissure, foramen rotundum and ovale in 18/19 (95%), 19/19 (100%) and 19/19 (100%) of the injections, respectively. No intracranial migration was observed. CONCLUSIONS AND CLINICAL RELEVANCE: This cadaver study illustrates that the suprazygomatic ultrasound-guided trigeminal nerve injection technique can successfully stain the PPF, retrobulbar cone extraconally, mandibular and maxillary nerves. Consequently, this technique has the potential to be used in vivo in cats to desensitize areas innervated by the trigeminal nerve.

A new and simplified extraoral approach for inferior alveolar nerve block: a cadaveric study and clinical case reports.

PURPOSE: Inferior alveolar nerve (IAN) and lingual nerve (LN) blocks are commonly performed using the intraoral landmark techniques. However, these methods have a risk of unanticipated nerve and arterial injury or a higher failure rate. We developed a novel extraoral approach for the IAN and LN blocks, the "inferior alveolar nerve block mandibular angle approach (IANB-MA)," using ultrasound guidance. The mechanism of action of this nerve block was examined anatomically, and its clinical feasibility was reported. METHODS: We performed the IANB-MA on four cadavers using different dye volumes (2, 4, 6 and 8 mL). The ultrasound probe was placed on the lower edge of the mandibula of each cadaver, and the needle was advanced to the mandibular inner surface. Blue acrylic paint solution was injected, and its spread was evaluated by dissection. RESULTS: Our study showed that the medial pterygoid muscle fascia was stained in all cadavers. The dye reached the LN consistently, and the IAN was stained with higher volumes (6 mL and 8 mL). The pterygomandibular space was filled with 6 mL and 8 mL of the dye. The IANB-MA successfully reduced pain in three patients with trigeminal neuralgia, tongue or jaw pain. CONCLUSIONS: The IANB-MA is a novel ultrasound-guided approach to the IAN and the LN. The clinical feasibility and effectiveness of this technique were confirmed in our patients. It may be a good alternative analgesic approach to other conventional approaches.

Rare presentation of maxillary osteonecrosis and tooth exfoliation induced by herpes zoster infection in a 29-year-old Chinese male: a case report and literature review.

BACKGROUND: We present a case of a 29-year-old male patient without immunodeficiency who suffered from rapid osteonecrosis and tooth exfoliation resulting from herpes zoster (HZ) infection in the left maxillary branch of the trigeminal nerve. Various complications associated with shingles infections have been reported, cases of osteonecrosis and tooth exfoliation due to HZ infection among young people without immunodeficiency are rare. In this case, we focus on the particular manifestation of HZ infection. CASE PRESENTATION: The patient presented with clusters of erythema and papules, along with non-hemorrhagic blisters on the left face and the loss of the left upper incisor. All lesions were localized to the left side of the face without exceeding the midline. After receiving antibacterial and antiviral treatment, successful control over the infection was achieved; however, he experienced the loss of all upper teeth on the left side except for the first and second upper left molars. CONCLUSION: This case highlights that rapid osteonecrosis and tooth exfoliation may occur among young individuals without immunodeficiency after HZ infection. HZ infection of the face should be taken very seriously to obtain prompt treatment to prevent the rare complications of bone necrosis and tooth loss as much as possible.

Transient bradycardia during local anaesthesia to the oral cavity under intravenous sedation and its associate factors: a prospective observational study.

BACKGROUND: Local anaesthesia in dental procedures is generally safe, although the occurrence of transient bradycardia (TB) has occasionally been reported. TB is often associated with two reflexes, the trigeminal cardiac reflex (TCR) and the vasovagal reflex (VVR) and is characterised by a rapid decrease in heart rate (HR) and blood pressure (BP). The prevalence of TCR is considered low, and its predictors have not been thoroughly investigated, although an association with the gag reflex has been suggested in recent years. METHODS: This prospective study assessed TB occurrence during local anaesthesia and its potential associated factors. A comprehensive questionnaire was used to categorise discomforts during dental treatment, and various anxiety scales were used to measure patients' anxiety levels. We investigated HR variability during local anaesthesia administration under sedation and the association between the incidence of TB and gag reflex. Subsequently, logistic regression analysis was performed to assess factors associated with TB occurrence. RESULTS: The prospective analysis included 188 patients of 234 initial patients. The analysis revealed a high TB incidence rate of 41% during local anaesthesia administration under sedation. No severe hypotensive events occurred, indicating a relatively benign nature of TB during local anaesthesia. TB occurrence was significantly higher in the group of patients with the gag reflex. Further analysis revealed that both gag reflex and trait anxiety were significantly associated with TB occurrence, whereas dental phobia did not directly correlate with TB. CONCLUSION: This study highlights the prominent occurrence of TB during local anaesthesia in dental treatment, which is primarily attributed to TCR activation. The identification of gag reflex and trait anxiety as independent factors associated with TB development may pave the way for TB prevention measures. Further research is required to clarify the mechanisms of TCR and perform safer dental procedures under sedation. Future studies should also aim to elucidate the precise mechanisms underlying TB during local anaesthesia through direct measurements of neural activity. A better understanding of TB in dentistry is crucial for improving patient safety and optimising dental practice protocols.

Deciphering the functional role of insular cortex stratification in trigeminal neuropathic pain.

Trigeminal neuropathic pain (TNP) is a major concern in both dentistry and medicine. The progression from normal to chronic TNP through activation of the insular cortex (IC) is thought to involve several neuroplastic changes in multiple brain regions, resulting in distorted pain perception and associated comorbidities. While the functional changes in the insula are recognized contributors to TNP, the intricate mechanisms underlying the involvement of the insula in TNP processing remain subjects of ongoing investigation. Here, we have overviewed the most recent advancements regarding the functional role of IC in regulating TNP alongside insights into the IC's connectivity with other brain regions implicated in trigeminal pain pathways. In addition, the review examines diverse modulation strategies that target the different parts of the IC, thereby suggesting novel diagnostic and therapeutic management of chronic TNP in the future.

[Left mandibular osteonecrosis following herpes zoster of the third branch of left trigeminal nerve: A case report].

Herpes zoster of trigeminal nerve was a common skin disease caused by varicella-zoster virus infection. Simple involvement of the third branch of trigeminal nerve was rare, and so were oral complications such as pulpitis, periodontitis, spontaneous tooth loss, bone necrosis, etc. This article presented a case of herpes zoster on the third branch of the left trigeminal nerve complicated with left mandibular osteonecrosis. We reported the case of a 64-year-old man with sudden pain in the left half of the tongue 1 month ago, and then herpes on the left facial skin appeared following with acute pain.The local hospital diagnosed it as herpes zoster and treated it with external medication. A few days later, he developed gum pain in the left mandibular posterior tooth area. He was admitted to Peking University School and Hospital of Stomatology one week ago with loose and dislodged left posterior tooth accompanied by left mandibular bone surface exposure. Clinical examination showed bilateral symmetry and no obvious restriction of mouth opening. Visible herpes zoster pigmentation and scarring on the left side of the face appeared. The left mandibular posterior tooth was missing, the exposed bone surface was about 1.5 cm×0.8 cm, and the surrounding gingiva was red and swollen, painful under pressure, with no discharge of pus. The remaining teeth in the mouth were all Ⅲ degree loosened. Imageological examination showed irregular low-density destruction of the left mandible bone, unclear boundary, and severe resorption of alveolar bone. The patient was diagnosed as left mandibular osteonecrosis. Under general anesthesia, left mandibular lesion exploration and curettage + left mandibular partial resection + adjacent flap transfer repair were performed. The patient was re-exmained 6 months after surgery, there was no redness, swelling or other abnormality in the gums and the herpes pigmentation on the left face was significantly reduced. Unfortunately, the patient had complications of postherpetic neuralgia. This case indicate that clinicians should improve their awareness of jaw necrosis, a serious oral complication of trigeminal zoster, and provide early treatment. After the inflammation was initially controlled, surgical treatment could be considered to remove the necrotic bone, curettage the inflammatory granulation tissue, and extraction of the focal teeth to avoid further deterioration of the disease.

Trigeminal n eu ra l gia diagnosis - a c ha l lenge - a cros s-se ct ional sur ve y to a ssess the k nowledge and a ttit ud e among t he dentists of S au di A ra bia.

OBJECTIVE: To analyse the knowledge level and attitude of Saudi dentists regarding trigeminal neuralgia. METHODS: The cross-sectional study was conducted from 17/12/ 2020 - 9/2/2021 at Prince Sat t am Bin Abdulaziz University, Al-Kharj, Riyadh Elm University, Riyadh, and Dar Al-Uloom University, Riyadh, Kingdom of Saud i Arabia. The sample comprised dentists and postgraduate dental students from every speciality. Data was collected online using a predesigned self-structured questionnaire consisting of three par ts, assessing knowledge, practice and attitude of the subjects. Data was analysed using SPSS 22. RESULTS: A total of 202 questionnaire about the knowledge level and attitude of Saudi dentists regarding trigeminal neuralgia were completed. The knowledge level was significantly higher in those senior age group compared to the young dentists with respect to the type of pain observed in TN, the unilateral pain of TN, and the abrupt, unexpected and transient nature of TN pain, local anaesthetic, the first-line treatment for TN, and the effect of TN on oral hygiene. CONCLUSIONS: Older and experienced dentists had more knowledge than younger and less experienced ones.

Maxillary Osteonecrosis Related with Herpes Zoster: A Case Report and Review of the Literature.

Osteonecrosis of the jaw (ONJ) can occur through various mechanisms including radiation, medication, and viral infections such as herpes zoster. Although herpes zoster is a varicella-zoster virus infection that can affect the trigeminal nerve, it rarely causes oral complications. The author reports a rare case of herpes zoster-related ONJ, followed by a review of the relevant literature pertaining to herpes zoster-related oral complications, including ONJ. A 73-year-old woman presented with a scarred skin lesion on her left midface with an exposed alveolar bone of the left maxilla. Based on her medical records, she received a diagnosis and treatment for herpes zoster six months prior and experienced a few teeth loss in the left maxilla following a fall preceding the onset of herpes zoster. Sequestrectomy of the left maxilla was performed and ONJ was diagnosed. The operative site recovered favorably. Although unusual, several cases of localized extensive ONJ in herpes zoster-infected patients have been reported. This case illustrates the possibility of a rare occurrence of unilateral widespread osteonecrosis of the jaw (ONJ) even in the maxilla associated with herpes zoster. The exact mechanism has not been elucidated; nevertheless, surgeons should consider the possibility of oral and dental complications, including ONJ, related to a history of herpes zoster.

Pulsed Radiofrequency of the Auriculotemporal Nerve to Reduce the Intensity of Tinnitus.

INTRODUCTION: Stimulation of the nonauditory nervous systems via the trigeminal nerve pathways can be a promising intervention for patients with tinnitus refractory to medical, conservative, and other treatment options. Therapy of the mandibular division of the trigeminal nerve through the auriculotemporal nerve has been reported as useful for patients with tinnitus. OBJECTIVES: The objective of our study was to study the long-term effects of pulsed radiofrequency of the auriculotemporal nerve in a large group of tinnitus sufferers and to find predictors for a prosperous result. DESIGN: A monocenter backward-looking group study. RESULTS: In a two-year period, 67 tinnitus patients had pulsed radiofrequency of the auriculotemporal nerve. Twentythree (35%) reported reduced tinnitus loudness at the 7-week post-treatment follow-up. These patients valued the improvements as: 61% good, 22% moderate, and 17% slight. In 3% of patients, tinnitus magnified after the treatment. The odds of permanent tinnitus relief after successful pulsed radiofrequency of the auriculotemporal nerve are 68% at 1 year postoperative. In tinnitus patients without cervical pain 62% had an improvement following pulsed radiofrequency of the auriculotemporal nerve compared to 28% in those not fulfilling this criterion (p=0.024). CONCLUSIONS: Neuromodulation of the auriculotemporal nerve is an uncomplicated remedy for tinnitus. In a select group of tinnitus patients this treatment can a good relief of their tinnitus for a long period. Especially, tinnitus sufferers without cervical pain will benefit of this therapy.

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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.

Early deficits in GABA inhibition parallels an increase in L-type Ca2+ currents in the jaw motor neurons of SOD1G93A mouse model for ALS.

Amyotrophic Lateral Sclerosis (ALS) involves protracted pre-symptomatic periods of abnormal motor neuron (MN) excitability occurring in parallel with central and peripheral synaptic perturbations. Focusing on inhibitory control of MNs, we first compared longitudinal changes in pre-synaptic terminal proteins for GABA and glycine neurotransmitters around the soma of retrogradely identified trigeminal jaw closer (JC) MNs and ChAT-labeled midbrain extraocular (EO) MNs in the SOD1G93A mouse model for ALS. Fluorescence immunocytochemistry and confocal imaging were used to quantify GAD67 and GlyT2 synaptic bouton density (SBD) around MN soma at pre-symptomatic ages ∼P12 (postnatal), ∼P50 (adult) and near disease end-stage (∼P135) in SOD1G93A mice and age-matched wild-type (WT) controls. We noted reduced GAD67 innervation in the SOD1G93A trigeminal jaw closer MNs around P12, relative to age-matched WT and no significant difference around P50 and P135. In contrast, both GAD67 and GlyT2 innervation were elevated in the SOD1G93A EO MNs at the pre-symptomatic time points. Considering trigeminal MNs are vulnerable in ALS while EO MNs are spared, we suggest that upregulation of inhibition in the latter might be compensatory. Notable contrast also existed in the innate co-expression patterns of GAD67 and GlyT2 with higher mutual information (co-dependency) in EO MNs compared to JC in both SOD1G93A and WT mice, especially at adult stages (P50 and P135). Around P12 when GAD67 terminals expression was low in the mutant, we further tested for persistent GABA inhibition in those MNs using in vitro patch-clamp electrophysiology. Our results show that SOD1G93A JC MNs have reduced persistent GABA inhibition, relative to WT. Pharmacological blocking of an underlying tonically active GABA conductance using the GABA-α5 subunit inverse agonist, L-655-708, disinhibited WT JC MNs and lowered their recruitment threshold, suggesting its role in the control of intrinsic MN excitability. Quantitative RT-PCR in laser dissected JC MNs further supported a reduction in GABA-α5 subunit mRNA expression in the mutant. In light of our previous report that JC MNs forming putative fast motor units have lower input threshold in the SOD1G93A mice, we suggest that our present result on reduced GABA-α5 tonic inhibition provides for a mechanism contributing to such imbalance. In parallel with reduced GABA inhibition, we noted an increase in voltage-gated L-type Ca2+ currents in the mutant JC MNs around P12. Together these results support that, early modifications in intrinsic properties of vulnerable MNs could be an adaptive response to counter synaptic deficits.

The interleukin-6 signal regulates orthodontic tooth movement and pain.

Orthodontic tooth movement (OTM) is accomplished by controlling the mechanical loading onto the bone around the roots of target teeth. The precise orthodontic force induces osteoclastic bone resorption on the compression side and osteoblastic bone formation on the tension side of the alveolar bone. Orthodontic intervention causes inflammation in the periodontal ligament (PDL), which manifests as acute pain. Because inflammation is deeply connected to bone remodeling, it has been indicated that the inflammation after orthodontic intervention affects both the movement of teeth and generation of pain. However, the precise mechanisms underlying the immune regulation of OTM and the related pain are not well elucidated. Here, we found from the search of a public database that the interleukin (IL)-6 family of cytokines are highly expressed in the PDL by mechanical loading. The IL-6 signal was activated in the PDL after orthodontic intervention. The signal promoted OTM by inducing osteoclastic bone resorption. IL-6 was found to increase the number of osteoclasts by suppressing apoptosis and increasing their responsiveness to macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL). Furthermore, IL-6 signal was shown to elicit orthodontic pain by inducing neuroinflammation in the trigeminal ganglion (TG). Taken together, it was demonstrated that the IL-6 signal regulates tooth movement and pain during orthodontic treatment. It was also indicated that local blockade of the IL-6 signal is a promising therapeutic option in orthodontic treatment, targeting both tooth movement and pain.