Is Burning Mouth Syndrome Associated with Extraoral Dryness? A Systematic Review.

Burning mouth syndrome (BMS) is characterized by a persistent intraoral burning sensation, often experienced by postmenopausal women. The etiology of BMS remains partially understood, and consequently, treatments remain suboptimal. Extraoral manifestations of BMS, such as extraoral dryness, are less studied. However, it has been suggested that the identification of the frequency and patterns of extraoral dryness and potential underlying mechanisms are essential to optimize treatment strategies and reduce the burden of disease. Therefore, we conducted this systematic review to provide existing evidence about extraoral dryness in BMS. The guidelines for the conduction and reporting of systematic reviews were followed. An electronic search was conducted in four major databases-PubMed, Web of Science, COCHRANE Library, and EBSCOhost-and the grey literature was assessed through Google Scholar. From each included article, information on extraoral dryness in BMS was extracted, and odds ratios were calculated for extraoral dryness among BMS patients compared with non-BMS controls. The findings demonstrated higher odds of the prevalence of extraoral dryness in BMS, which was found to a high degree in the lips, eyes, skin, and genitalia. The pattern of spread and locations of extraoral dryness propose a potential central mechanism. Based on our findings, we encourage the standardization of the assessment, recording, and reporting of the extraoral characteristics of BMS, including extraoral dryness, which can lead to better management strategies and enhance the quality of life of the affected patients.

Presence of Small-Conductance Calcium-Activated Potassium (SK) Channels in the Central and Peripheral Nervous Systems and Their Role in Health and Disease.

Potassium (K+) channels establish and maintain the resting potential of most living cells. Their activity is predominantly regulated by the membrane voltage or the K+ gradient across the cell membrane. However, many cells also express small-conductance calcium-activated potassium (SK) channels, which have the unique ability to translate changes in the level of the intracellular second messenger, Ca2+ to changes in the membrane K+ conductance and, therefore, the resting membrane potential. This article reviews the structure, presence, distribution, and function of SK channels, their pharmacological modulation, and their role in health and disease, emphasizing nociception and pain.

The role of glial cells in Zika virus-induced neurodegeneration.

Zika virus (ZIKV) is a strongly neurotropic flavivirus whose infection has been associated with microcephaly in neonates. However, clinical and experimental evidence indicate that ZIKV also affects the adult nervous system. In this regard, in vitro and in vivo studies have shown the ability of ZIKV to infect glial cells. In the central nervous system (CNS), glial cells are represented by astrocytes, microglia, and oligodendrocytes. In contrast, the peripheral nervous system (PNS) constitutes a highly heterogeneous group of cells (Schwann cells, satellite glial cells, and enteric glial cells) spread through the body. These cells are critical in both physiological and pathological conditions; as such, ZIKV-induced glial dysfunctions can be associated with the development and progression of neurological complications, including those related to the adult and aging brain. This review will address the effects of ZIKV infection on CNS and PNS glial cells, focusing on cellular and molecular mechanisms, including changes in the inflammatory response, oxidative stress, mitochondrial dysfunction, Ca2+ and glutamate homeostasis, neural metabolism, and neuron-glia communication. Of note, preventive and therapeutic strategies that focus on glial cells may emerge to delay and/or prevent the development of ZIKV-induced neurodegeneration and its consequences.

Action of Hyaluronic Acid as a Damage-Associated Molecular Pattern Molecule and Its Function on the Treatment of Temporomandibular Disorders.

The temporomandibular joint is responsible for fundamental functions. However, mechanical overload or microtraumas can cause temporomandibular disorders (TMD). In addition to external factors, it is known that these conditions are involved in complex biological mechanisms, such as activation of the immune system, activation of the inflammatory process, and degradation of extracellular matrix (ECM) components. The ECM is a non-cellular three-dimensional macromolecular network; its most studied components is hyaluronic acid (HA). HA is naturally found in many tissues, and most of it has a high molecular weight. HA has attributed an essential role in the viscoelastic properties of the synovial fluid and other tissues. Additionally, it has been shown that HA molecules can contribute to other mechanisms in the processes of injury and healing. It has been speculated that the degradation product of high molecular weight HA in healthy tissues during injury, a low molecular weight HA, may act as damage-associated molecular patterns (DAMPs). DAMPs are multifunctional and structurally diverse molecules that play critical intracellular roles in the absence of injury or infection. However, after cellular damage or stress, these molecules promote the activation of the immune response. Fragments from the degradation of HA can also act as immune response activators. Low molecular weight HA would have the ability to act as a pro-inflammatory marker, promoting the activation and maturation of dendritic cells, the release of pro-inflammatory cytokines such as interleukin 1 beta (IL-1ß), and tumor necrosis factor α (TNF-α). It also increases the expression of chemokines and cell proliferation. Many of the pro-inflammatory effects of low molecular weight HA are attributed to its interactions with the activation of toll-like receptors (TLRs 2 and 4). In contrast, the high molecular weight HA found in healthy tissues would act as an anti-inflammatory, inhibiting cell growth and differentiation, decreasing the production of inflammatory cytokines, and reducing phagocytosis by macrophages. These anti-inflammatory effects are mainly attributed to the interaction of high-weight HA with the CD44 receptor. In this study, we review the action of the HA as a DAMP and its functions on pain control, more specifically in orofacial origin (e.g., TMD).

Development of core outcome sets for clinical trials in temporomandibular disorders: A study protocol.

BACKGROUND: Temporomandibular Disorder (TMD) is a generic term applied to describe musculoskeletal disorders that affect the temporomandibular joint (TMJ), the masticatory muscles and the related structures. TMD comprises two groups of disorders, namely intra-articular TMD and masticatory muscle disorders. There is still difficulty in establishing the effectiveness of different therapeutic modalities for TMD with robust evidence, despite the large volume of publications in the area. The lack of outcomes standardization may represent a limiting factor in the search for scientific evidence. OBJECTIVE: This study aims to develop a core outcome sets (COS) for clinical trials in intra-articular TMD and masticatory muscle disorders. METHODS: The protocol for determining the COS-TMD will consist of three phases: 1. Synthesis of TMD Management Intervention Outcomes. The identification of outcomes will be carried out through a systematic review, which will include randomized clinical trials that evaluated the effectiveness of interventions used in TMD management. 2. Through a two-round international Delphi survey, the list of outcomes will be scored by three panels of stakeholders. 3. A representative sample of key stakeholders will be invited to participate in a face-to-face meeting where they can discuss the results of the Delphi survey and determine the final core set. CONCLUSIONS: The implementation of this protocol will determine the COS-TMD, which will be made available for use in all TMD clinical studies. The use of COS when planning and reporting TMD clinical trials will reduce the risk of publication bias and enable proper comparison of results found by different studies.

Role of lysophosphatidic acid and its receptors in health and disease: novel therapeutic strategies.

Lysophosphatidic acid (LPA) is an abundant bioactive phospholipid, with multiple functions both in development and in pathological conditions. Here, we review the literature about the differential signaling of LPA through its specific receptors, which makes this lipid a versatile signaling molecule. This differential signaling is important for understanding how this molecule can have such diverse effects during central nervous system development and angiogenesis; and also, how it can act as a powerful mediator of pathological conditions, such as neuropathic pain, neurodegenerative diseases, and cancer progression. Ultimately, we review the preclinical and clinical uses of Autotaxin, LPA, and its receptors as therapeutic targets, approaching the most recent data of promising molecules modulating both LPA production and signaling. This review aims to summarize the most update knowledge about the mechanisms of LPA production and signaling in order to understand its biological functions in the central nervous system both in health and disease.

Impact of the COVID-19 Pandemic on Stress, Sleep, and Oral Health in University Students.

Background: The COVID-19 pandemic, a disease caused by Sars-CoV-2, has become a worldwide stressor, especially as it represents a new viral infection, which spreads quickly and easily, without prior knowledge about vaccination, and absence, to this moment, of a medication that is totally effective against the disease. Objective: The aim of this observational study was to provide a general evaluation, through a questionnaire applied to students in the health field of the Federal University of Rio de Janeiro, on the psychological impacts and behavioral changes generated by the COVID-19 pandemic on oral health, especially the triggering or exacerbation of bruxism and temporomandibular disorders (TMD). Methods: In order to verify the impacts of the pandemic on the health of UFRJ healthcare students, a non-randomized survey was performed with 370 students. Results: It was found that 72% of the students had their sleep routine altered, 65% had greater difficulty in keeping their spirits up, there was a statistically significant increase in emotional stress, headaches, and daytime teeth clenching. Conclusion: It was possible to conclude that the outbreak of COVID-19 resulted in psychological, physiological and behavioral impacts on students.

Sensory-Discriminative Three-Dimensional Body Pain Mobile App Measures Versus Traditional Pain Measurement With a Visual Analog Scale: Validation Study.

BACKGROUND: To quantify pain severity in patients and the efficacy treatments, researchers and clinicians apply tools such as the traditional visual analog scale (VAS) that leads to inaccurate interpretation of the main sensory pain. OBJECTIVE: This study aimed to validate the pain measurements of a neuroscience-based 3D body pain mobile app called GeoPain. METHODS: Patients with temporomandibular disorder (TMD) were assessed using GeoPain measures in comparison to VAS and positive and negative affect schedule (PANAS), pain and mood scales, respectively. Principal component analysis (PCA), scatter score analysis, Pearson methods, and effect size were used to determine the correlation between GeoPain and VAS measures. RESULTS: The PCA resulted in two main orthogonal components: first principal component (PC1) and second principal component (PC2). PC1 comprises a combination score of all GeoPain measures, which had a high internal consistency and clustered together in TMD pain. PC2 included VAS and PANAS. All loading coefficients for GeoPain measures in PC1 were above 0.70, with low loadings for VAS and PANAS. Meanwhile, PC2 was dominated by a VAS and PANAS coefficient >0.4. Repeated measure analysis revealed a strong correlation between the VAS and mood scores from PANAS over time, which might be related to the subjectivity of the VAS measure, whereas sensory-discriminative GeoPain measures, not VAS, demonstrated an association between chronicity and TMD pain in locations spread away from the most commonly reported area or pain epicenter (P=.01). Analysis using VAS did not detect an association at baseline between TMD and chronic pain. The long-term reliability (lag >1 day) was consistently high for the pain area and intensity number summation (PAINS) with lag autocorrelations averaging between 0.7 and 0.8, and greater than the autocorrelations for VAS averaging between 0.3 and 0.6. The combination of higher reliability for PAINS and its objectivity, displayed by the lack of association with PANAS as compared with VAS, indicated that PAINS has better sensitivity and reliability for measuring treatment effect over time for sensory-discriminative pain. The effect sizes for PAINS were larger than those for VAS, consequently requiring smaller sample sizes to assess the analgesic efficacy of treatment if PAINS was used versus VAS. The PAINS effect size was 0.51 SD for both facial sides and 0.60 SD for the right side versus 0.35 SD for VAS. Therefore, the sample size required to detect such effect sizes with 80% power would be n=125 per group for VAS, but as low as n=44 per group for PAINS, which is almost a third of the sample size needed by VAS. CONCLUSIONS: GeoPain demonstrates precision and reliability as a 3D mobile interface for measuring and analyzing sensory-discriminative aspects of subregional pain in terms of its severity and response to treatment, without being influenced by mood variations from patients.

Human dental follicle cells express embryonic, mesenchymal and neural stem cells markers.

OBJECTIVE: This study was conducted to identify and characterize dental follicle stem cells (DFSCs) by analyzing expression of embryonic, mesenchymal and neural stem cells surface markers. Design Dental follicle cells (DFCs) were evaluated by immunocytochemistry using embryonic stem cells markers (OCT4 and SOX2), mesenchmal stem cells (MSCs) markers (Notch1, active Notch1, STRO, CD44, HLA-ABC, CD90), neural stem cells markers (Nestin and ß-III-tubulin), neural crest stem cells (NCSCs) markers (p75 and HNK1) and a glial cells marker (GFAP). RT-PCR was performed to identify the expression of OCT4 and NANOG in DFCs and dental follicle tissue. RESULTS: Immunocytochemistry and RT-PCR analysis revealed that a significant proportion of the DFCs evaluated expressed human embryonic stem cells marker OCT4 (75%) whereas NANOG was weakly expressed. A considerable amount of MSCs (90%) expressed Notch1, STRO, CD44 and HLA-ABC. However, they were weakly positive for CD90. Moreover, it was possible to demonstrate that dental follicle contains a significant proportion of neural stem/progenitors cells, expressing ß-III-tubulin (90%) and nestin (70%). Interestingly, immunocytochemistry showed DFCs positive for p75 (50%), HNK1 (<10%) and a small proportion (<20%) of GFAP-positive cells. This is the first study reporting the presence of NCSCs and glial-like cells in the dental follicle. CONCLUSIONS: The results of the present study suggest the occurrence of heterogeneous populations of stem cells, particularly neural stem/progenitor cells, in the dental follicle, Therefore, the human dental follicle might be a promising source of adult stem cells for regenerative purposes.

A novel method for intraoral access to the superior head of the human lateral pterygoid muscle.

BACKGROUND: The uncoordinated activity of the superior and inferior parts of the lateral pterygoid muscle (LPM) has been suggested to be one of the causes of temporomandibular joint (TMJ) disc displacement. A therapy for this muscle disorder is the injection of botulinum toxin (BTX), of the LPM. However, there is a potential risk of side effects with the injection guide methods currently available. In addition, they do not permit appropriate differentiation between the two bellies of the muscle. Herein, a novel method is presented to provide intraoral access to the superior head of the human LPM with maximal control and minimal hazards. METHODS: Computational tomography along with digital imaging software programs and rapid prototyping techniques were used to create a rapid prototyped guide to orient BTX injections in the superior LPM. RESULTS: The method proved to be feasible and reliable. Furthermore, when tested in one volunteer it allowed precise access to the upper head of LPM, without producing side effects. CONCLUSIONS: The prototyped guide presented in this paper is a novel tool that provides intraoral access to the superior head of the LPM. Further studies will be necessary to test the efficacy and validate this method in a larger cohort of subjects.

Immediate effects of tDCS on the µ-opioid system of a chronic pain patient.

We developed a unique protocol where transcranial direct current stimulation (tDCS) of the motor cortex is performed during positron emission tomography (PET) scan using a µ-opioid receptor (µOR) selective radiotracer, [(11)C]carfentanil. This is one of the most important central neuromechanisms associated with pain perception and regulation. We measured µOR non-displaceable binding potential (µOR BP(ND)) in a trigeminal neuropathic pain patient (TNP) without creating artifacts, or posing risks to the patient (e.g., monitoring of resistance). The active session directly improved in 36.2% the threshold for experimental cold pain in the trigeminal allodynic area, mandibular branch, but not the TNP patient's clinical pain. Interestingly, the single active tDCS application considerably decreased µORBP(ND) levels in (sub)cortical pain-matrix structures compared to sham tDCS, especially in the posterior thalamus. Suggesting that the µ-opioidergic effects of a single tDCS session are subclinical at immediate level, and repetitive sessions are necessary to revert ingrained neuroplastic changes related to the chronic pain. To our knowledge, we provide data for the first time in vivo that there is possibly an instant increase of endogenous µ-opioid release during acute motor cortex neuromodulation with tDCS.

Reduced basal ganglia µ-opioid receptor availability in trigeminal neuropathic pain: a pilot study.

BACKGROUND: Although neuroimaging techniques have provided insights into the function of brain regions involved in Trigeminal Neuropathic Pain (TNP) in humans, there is little understanding of the molecular mechanisms affected during the course of this disorder. Understanding these processes is crucial to determine the systems involved in the development and persistence of TNP. FINDINGS: In this study, we examined the regional µ-opioid receptor (µOR) availability in vivo (non-displaceable binding potential BPND) of TNP patients with positron emission tomography (PET) using the µOR selective radioligand [11C]carfentanil. Four TNP patients and eight gender and age-matched healthy controls were examined with PET. Patients with TNP showed reduced µOR BPND in the left nucleus accumbens (NAc), an area known to be involved in pain modulation and reward/aversive behaviors. In addition, the µOR BPND in the NAc was negatively correlated with the McGill sensory and total pain ratings in the TNP patients. CONCLUSIONS: Our findings give preliminary evidence that the clinical pain in TNP patients can be related to alterations in the endogenous µ-opioid system, rather than only to the peripheral pathology. The decreased availability of µORs found in TNP patients, and its inverse relationship to clinical pain levels, provide insights into the central mechanisms related to this condition. The results also expand our understanding about the impact of chronic pain on the limbic system.

tDCS-induced analgesia and electrical fields in pain-related neural networks in chronic migraine.

OBJECTIVE: We investigated in a sham-controlled trial the analgesic effects of a 4-week treatment of transcranial direct current stimulation (tDCS) over the primary motor cortex in chronic migraine. In addition, using a high-resolution tDCS computational model, we analyzed the current flow (electric field) through brain regions associated with pain perception and modulation. METHODS: Thirteen patients with chronic migraine were randomized to receive 10 sessions of active or sham tDCS for 20 minutes with 2 mA over 4 weeks. Data were collected during baseline, treatment and follow-up. For the tDCS computational analysis, we adapted a high-resolution individualized model incorporating accurate segmentation of cortical and subcortical structures of interest. RESULTS: There was a significant interaction term (time vs group) for the main outcome (pain intensity) and for the length of migraine episodes (ANOVA, P < .05 for both analyses). Post-hoc analysis showed a significant improvement in the follow-up period for the active tDCS group only. Our computational modeling studies predicted electric current flow in multiple cortical and subcortical regions associated with migraine pathophysiology. Significant electric fields were generated, not only in targeted cortical regions but also in the insula, cingulate cortex, thalamus, and brainstem regions. CONCLUSIONS: Our findings give preliminary evidence that patients with chronic migraine have a positive, but delayed, response to anodal tDCS of the primary motor cortex. These effects may be related to electrical currents induced in pain-related cortical and subcortical regions.