Recent advances in the understanding of the aetiology and therapeutic strategies in burning mouth syndrome: Focus on the actions of cannabinoids.

Burning mouth syndrome (BMS) is a neuropathic pain disorder associated with a burning sensation on oral mucosal surfaces with frequently reported xerostomia, dysgeusia and tingling or paraesthetic sensations. However, patients present no clinically evident causative lesions. The poor classification of the disorder has resulted in a diagnostic challenge, particularly for the clinician/dentist evaluating these individuals. Major research developments have been made in the BMS field in recent years to address this concern, principally in terms of the pathophysiological mechanisms underlying the disorder, in addition to therapeutic advancements. For the purpose of this review, an update on the pathophysiological mechanisms will be discussed from a neuropathic, immunological, hormonal and psychological perspective. This review will also focus on the many therapeutic strategies that have been explored for BMS, including antidepressants/antipsychotics, non-steroidal anti-inflammatories, hormone replacement therapies, phytotherapeutic compounds and non-pharmacological interventions, overall highlighting the lack of controlled clinical studies to support the effectiveness of such therapeutic avenues. Particular focus is given to the cannabinoid system and the potential of cannabis-based therapeutics in managing BMS patients.

Development and Assessment of a Three-Dimensional Tooth Morphology Quiz for Dental Students.

Tooth morphology has a pivotal role in the dental curriculum and provides one of the important foundations of clinical practice. To supplement tooth morphology teaching a three-dimensional (3D) quiz application (app) was developed. The 3D resource enables students to study tooth morphology actively by selecting teeth from an interactive quiz, modify their viewpoint and level of zoom. Additionally, students are able to rotate the tooth to obtain a 3D spatial understanding of the different surfaces of the tooth. A cross-over study was designed to allow comparison of students' results after studying with the new application or traditionally with extracted/model teeth. Data show that the app provides an efficient learning tool and that students' scores improve with usage (18% increase over three weeks, P < 0.001). Data also show that student assessment scores were correlated with scores obtained while using the app but were not influenced by the teaching modality initially accessed (r2  = 0.175, P < 0.01). Comparison of the 2016 and 2017 class performance shows that the class that had access to the app performed significantly better on their final tooth morphology assessment (68.0% ±15.0 vs. 75.3% ±13.4, P < 0.01). Furthermore, students reported that the 3D application was intuitive, provided useful feedback, presented the key features of the teeth, and assisted in learning tooth morphology. The 3D tooth morphology app thus provides students with a useful adjunct teaching tool for learning dental anatomy. Anat Sci Educ 00: 000-000. © 2018 American Association of Anatomists.

Fast-slow analysis of the Integrated Oscillator Model for pancreatic ß-cells.

Insulin-secreting pancreatic ß-cells are electrically excitable cells that are unusual because their electrical activity is influenced directly by metabolism via ATP-sensitive K+ channels. At the same time, changes in the intracellular Ca2+concentration that result from the cell's electrical activity influence metabolism in several ways. Thus, there is bidirectional coupling between the electrical dynamics and the metabolic dynamics in ß-cells. A mathematical model has been previously developed, called the Integrated. Oscillator Model (IOM), to highlight the bidirectional coupling involved in the oscillation mechanism. In this study, we show how this coupling can produce oscillations in ß-cell activity. These oscillations have period similar to that of insulin secretion pulses observed in rats, mice, dogs, and humans, which has been shown to facilitate the action of the liver in maintaining glucose homeostasis. In a companion paper we show that the IOM can produce oscillations using two distinct mechanisms, depending on the values of electrical and metabolic parameters. In the present article, we use fast-slow analysis to understand the mechanisms underlying each of these oscillations. In particular, we show why a key variable in the glycolytic pathway generates a pulsatile time course in one type of oscillation, while it generates a sawtooth time course in the other type. The significance of these patterns is that the time course is a reflection of whether an intrinsic glycolytic oscillator is active, or whether the oscillations are a direct consequence of Ca2+ feedback onto glycolysis.

Plasma N-acylethanolamine and endocannabinoid levels in burning mouth syndrome: Potential role in disease pathogenesis.

OBJECTIVE: The objective was to measure endocannabinoid (eCB) ligands and non-cannabinoid N-acylethanolamine (NAE) molecules in plasma from individuals with burning mouth syndrome (BMS) and to determine whether plasma eCB/NAE levels correlated with pain, inflammation and depressive symptomatology in this cohort. STUDY DESIGN: Plasma content of the eCBs, anandamide (AEA) and 2-arachidonoyl-glycerol (2-AG), and the NAE molecules, palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) were assessed in healthy subjects (n = 8) and in a cohort of newly diagnosed BMS patients (n = 9) using liquid chromatography-tandem mass spectrometry. Plasma eCBs and NAE profiles were correlated with self-rated oral cavity pain intensities, depressive symptomatology and plasma IL-8 levels. RESULTS: Plasma levels of PEA, but not OEA, AEA or 2-AG, were significantly elevated in patients with BMS, when compared to plasma from healthy individuals. Plasma PEA, OEA and AEA levels correlated with depressive symptomatology. CONCLUSIONS: This is the first evidence to indicate that circulating eCB/NAE levels are altered in BMS.

Plasma IL-8 signature correlates with pain and depressive symptomatology in patients with burning mouth syndrome: Results from a pilot study.

BACKGROUND: Burning mouth syndrome (BMS) is a neuropathic orofacial pain condition of unknown aetiology that encompasses intra-oral burning pain without abnormal clinical findings. Psychological, neural and inflammatory processes are associated with BMS pathogenesis. Currently, studies characterising plasma cytokine/chemokine profiles with pain and depression in patients with BMS are lacking. Considering that inflammation is associated with the pathophysiology of BMS, and that inflammation is closely associated with pain and depression, we aimed to correlate depressive symptomatology and oral cavity pain with plasma cytokine/chemokine signatures in a cohort of patients with BMS. METHODS: In this study, plasma protein levels of Th1 cytokines (IFN-γ, IL-2, IL-12p70, TNF-α), Th2 cytokines (IL-4, IL-10, IL-6, IL-13) and the chemokine IL-8 were assessed in patients with BMS (n = 10) and healthy volunteers (n = 10), using pro-inflammatory-10-plex assays. Clinical histories, alongside self-rated oral cavity pain intensities and depressive symptomatology were assessed using a visual analogue scale and the 16-item Quick Inventory of Depressive Symptomatology questionnaires, respectively. RESULTS: We present evidence that BMS is associated with increased depressive symptomatology and enhanced oral cavity pain. Plasma isolated from BMS patients display enhanced expression of the pro-inflammatory chemokine IL-8, when compared to plasma from healthy individuals. Plasma IL-8 signature correlates with pain and depressive symptomatology in the study cohort. CONCLUSIONS: Overall, these findings indicate that plasma IL-8 profiles are dysregulated in BMS and that modulation of IL-8 production in the disorder may be a tool in the management of BMS symptomatology.

Assessment of Thiel-Embalmed Cadavers as a Teaching Tool for Oral Anatomy and Local Anesthesia.

The aim of this study was to determine whether Thiel-embalmed cadavers would provide a useful anatomy teaching tool for topics that cannot be approached using formalin-fixed cadavers such as oral cavity examination and maxillary anesthesia. The suitability of Thiel-embalmed bodies for performing oral examinations was assessed by asking first-year dental and dental hygiene students at a dental school in Ireland to identify oral structures on a classmate and on a Thiel-embalmed body. The study was conducted in 2016. The ease of location was compared in the two settings, and their quality was assessed on the cadavers. The suitability of Thiel-embalmed cadavers to teach maxillary anesthesia was assessed by students' performing mock injections at five adjacent sites daily for five consecutive days, followed by inspection of the gingival surface by experienced anatomists and dentists. Data were obtained from 57 students, but only the 54 forms that were fully completed were analyzed, for an overall response rate of 85.7%. The results showed that most oral structures were more difficult to locate on cadavers. The texture and appearance of features in the cadavers were rated at a midpoint between realistic and unrealistic. The relative inexperience of the participants, the accumulation of fixative in the oral cavity, and discoloration were mentioned as potential confounding factors. Visual analysis of images obtained following repeated injections revealed no deterioration of the tissue. Importantly, the puncture marks appeared to reduce over time, suggesting that the gingival tissue maintains some elasticity following Thiel fixation. These findings suggest that Thiel-embalmed cadavers may be a useful tool to provide students more time to localize and study aspects of the oral cavity. Likewise, the recoiling capacity of gingival tissue suggests that Thiel-embalmed cadavers may provide an ideal tool for teaching injection technique of local anesthetics.

Glucose Oscillations Can Activate an Endogenous Oscillator in Pancreatic Islets.

Pancreatic islets manage elevations in blood glucose level by secreting insulin into the bloodstream in a pulsatile manner. Pulsatile insulin secretion is governed by islet oscillations such as bursting electrical activity and periodic Ca2+ entry in ß-cells. In this report, we demonstrate that although islet oscillations are lost by fixing a glucose stimulus at a high concentration, they may be recovered by subsequently converting the glucose stimulus to a sinusoidal wave. We predict with mathematical modeling that the sinusoidal glucose signal's ability to recover islet oscillations depends on its amplitude and period, and we confirm our predictions by conducting experiments with islets using a microfluidics platform. Our results suggest a mechanism whereby oscillatory blood glucose levels recruit non-oscillating islets to enhance pulsatile insulin output from the pancreas. Our results also provide support for the main hypothesis of the Dual Oscillator Model, that a glycolytic oscillator endogenous to islet ß-cells drives pulsatile insulin secretion.

Phase Analysis of Metabolic Oscillations and Membrane Potential in Pancreatic Islet ß-Cells.

Metabolism in islet ß-cells displays oscillations that can trigger pulses of electrical activity and insulin secretion. There has been a decades-long debate among islet biologists about whether metabolic oscillations are intrinsic or occur in response to oscillations in intracellular Ca(2+) that result from bursting electrical activity. In this article, the dynamics of oscillatory metabolism were investigated using five different optical reporters. Reporter activity was measured simultaneously with membrane potential bursting to determine the phase relationships between the metabolic oscillations and electrical activity. Our experimental findings suggest that Ca(2+) entry into ß-cells stimulates the rate of mitochondrial metabolism, accounting for the depletion of glycolytic intermediates during each oscillatory burst. We also performed Ca(2+) clamp tests in which we clamped membrane potential with the KATP channel-opener diazoxide and KCl to fix Ca(2+) at an elevated level. These tests confirm that metabolic oscillations do not require Ca(2+) oscillations, but show that Ca(2+) plays a larger role in shaping metabolic oscillations than previously suspected. A dynamical picture of the mechanisms of oscillations emerged that requires the restructuring of contemporary mathematical ß-cell models, including our own dual oscillator model. In the companion article, we modified our model to account for these new data.

Ca2+ Effects on ATP Production and Consumption Have Regulatory Roles on Oscillatory Islet Activity.

Pancreatic islets respond to elevated blood glucose by secreting pulses of insulin that parallel oscillations in ß-cell metabolism, intracellular Ca(2+) concentration, and bursting electrical activity. The mechanisms that maintain an oscillatory response are not fully understood, yet several models have been proposed. Only some can account for experiments supporting that metabolism is intrinsically oscillatory in ß-cells. The dual oscillator model (DOM) implicates glycolysis as the source of oscillatory metabolism. In the companion article, we use recently developed biosensors to confirm that glycolysis is oscillatory and further elucidate the coordination of metabolic and electrical signals in the insulin secretory pathway. In this report, we modify the DOM by incorporating an established link between metabolism and intracellular Ca(2+) to reconcile model predictions with experimental observations from the companion article. With modification, we maintain the distinguishing feature of the DOM, oscillatory glycolysis, but introduce the ability of Ca(2+) influx to reshape glycolytic oscillations by promoting glycolytic efflux. We use the modified model to explain measurements from the companion article and from previously published experiments with islets.

Neuropathic orofacial pain: cannabinoids as a therapeutic avenue.

Neuropathic orofacial pain (NOP) exists in several forms including pathologies such as burning mouth syndrome (BMS), persistent idiopathic facial pain (PIFP), trigeminal neuralgia (TN) and postherpetic neuralgia (PHN). BMS and PIFP are classically diagnosed by excluding other facial pain syndromes. TN and PHN are most often diagnosed based on a typical history and presenting pain characteristics. The pathophysiology of some of these conditions is still unclear and hence treatment options tend to vary and include a wide variety of treatments including cognitive behaviour therapy, anti-depressants, anti-convulsants and opioids; however such treatments often have limited efficacy with a great amount of inter-patient variability and poorly tolerated side effects. Analgesia is one the principal therapeutic targets of the cannabinoid system and many studies have demonstrated the efficacy of cannabinoid compounds in the treatment of neuropathic pain. This review will investigate the potential use of cannabinoids in the treatment of symptoms associated with NOP.