Voltage-gated sodium channels gene expression in Burning Mouth Syndrome: a case-control study.

Burning mouth syndrome (BMS) is a condition characterized by painful symptoms of the oral mucosa, despite the absence of any clinical signs. Its etiology is unknown, and there is still no effective treatment to date. Current evidence has shown neuropathic impairment in BMS patients. Neuropathic pain can be related to the dysfunction of voltage-gated sodium channels, considering that these receptors regulate the induction of action potentials in nociceptive neurons. This study evaluated the gene expression of voltage-gated sodium channels Na v 1.7, Na v 1.8 and Na v 1.9 in these patients. The gene expressions of these channels were assessed by real time RT-PCR analysis of fresh-frozen tongue biopsies in a case-control study composed of 12 patients with BMS, and 5 healthy control patients, proportionally matched by sex and age, and analyzed using the 2^(-Delta Delta CT) method. There was no statistically significant difference between the analyzed groups, despite the increase in Na v 1.7 (fold-change = 3.13, p = 0.52) and decrease in Na v 1.9 (fold-change = 0.45, p = 0.36) gene expression in the BMS group. The Na v 1.8 gene was not expressed in any of the samples analyzed. Although the gene expression in the voltage-gated sodium channels in BMS under study seems to be comparable with that of the normal oral mucosa, the functionality of these channels in BMS has not yet been identified, thus suggesting that further research is needed to better understand these voltage-gated sodium channels.

Evaluation of IL-6 levels and +3954 polymorphism of IL-1ß in burning mouth syndrome: A systematic review and meta-analysis.

This study evaluated IL-6 salivary levels as well as the +3954 polymorphism of IL-1ß in patients with burning mouth syndrome and healthy individuals, through case-control studies. This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We conducted this research in PubMed/MEDLINE, Cochrane Library and Web of Science databases. The risk of bias was measured based in the Newcastle-Ottawa Scale. Researches with a group of patients with burning mouth syndrome and a control group in which the presence of the +3954 polymorphism of IL-1ß and/ or IL-6 salivary levels through non-stimulated saliva were evaluated to detect if this interleukin concentrations are increased in patients and if the polymorphism is a risk factor for this syndrome. We identified seven studies with total of 440 participants, 229 patients with burning mouth syndrome and 211 healthy controls, ages 24-84 years old. The female gender was predominant. Patients in the majority of studies did not present increased levels of IL-6 and the +3954 polymorphism of IL-1ß is not a risk factor for this syndrome. A few studies researched biomarkers in this pathology and more investigations are required not only to identify salivary levels and the polymorphism evaluated, but also other interleukins and polymorphisms in order to clarify the etiopathogenesis of this syndrome as well as for propose new diagnostic methods and treatments.

Reduced sialyl-Lewisx on salivary MUC7 from patients with burning mouth syndrome.

We analysed and compared MUC7 O-glycosylation and inflammatory biomarkers in saliva from female patients with burning mouth syndrome (BMS) and gender/age-matched controls. Oligosaccharides from salivary MUC7 from BMS and controls were released. Inflammatory mediators were measured by multiplex proximity extension assay. Presence of sialyl-Lewisx (Si-Lex) epitope on MUC7 was confirmed using Western blot. MUC7 O-glycans and measured inflammatory biomarkers were found to be similar between BMS and controls. However, oligosaccharides sialyl-Lewisx (Si-Lex) was found to be reduced in samples from BMS patients. Positive correlation (combined patients and controls) was found between levels of C-C motif chemokine 19 (CCL-19) and the amount of core-2 oligosaccharides on MUC7 as well as fractalkine (CX3CL1) and level of sialylation. Patients with BMS were shown to represent a heterogeneous group in terms of inflammatory biomarkers. This indicates that BMS patients could be further stratified on the basis of low-level inflammation. The results furthermore indicate that reduced sialylation of MUC7, particularly Si-Lex, may be an important feature in patients with BMS. However, the functional aspects and potential involvement in immune regulation of Si-Lex remains unclear. Our data suggests a chemokine driven alteration of MUC7 glycosylation.

Proteomic profiling of whole-saliva reveals correlation between Burning Mouth Syndrome and the neurotrophin signaling pathway.

Burning mouth syndrome (BMS) is characterized by a spontaneous and chronic sensation of burning in the oral mucosa, with no apparent signs. The underlying pathophysiological and neuropathic mechanisms remain unclear. Here, we attempt to elucidate some of these mechanisms using proteomic profiling and bioinformatic analyses of whole-saliva (WS) from BMS patients compared to WS from healthy individuals. Qualitative and quantitative proteomic profiling was performed using two dimensional gel electrophoresis (2-DE) and quantitative mass spectrometry (q-MS). In order to improve protein visibility, 21 high abundance proteins were depleted before proteomic profiling. Quantitative proteomic analysis revealed 100 BMS specific proteins and an additional 158 proteins up-regulated by more than threefold in those with BMS. Bioinformatic analyses of the altered protein expression profile of BMS group indicated high correlations to three cellular mechanisms including the neurotrophin signaling pathway. Based on this finding, we suggest that neurotrophin signaling pathway is involved in the pathophysiology of BMS by amplifying P75NTR activity, which in turn increases neural apoptosis thereby reducing sub-papillary nerve fiber density in the oral mucosa.

Neurophysiology and genetics of burning mouth syndrome.

BACKGROUND AND AIMS: Neuropathic mechanisms are involved in burning mouth syndrome (BMS), and variation of the dopamine D2 receptor (DRD2) gene contributes to experimental pain perception. We investigated whether neurophysiologic findings differ in BMS patients compared to healthy controls, and whether 957C>T polymorphism of the DRD2 gene influences thermal sensitivity or pain experience in BMS. METHODS: Forty-five BMS patients (43 women), mean age 62.5 years, and 32 healthy controls (30 women), mean age 64.8 years, participated. Patients estimated pain intensity, interference, suffering and sleep with Numeric Rating Scale. Blink reflex tests of the supraorbital (SON), mental (MN) and lingual (LN) nerves, and thermal quantitative sensory testing were done. The results were analysed with ANOVA. DRD2 gene 957C>T polymorphism was determined in 31 patients, and its effects on neurophysiologic and clinical variables were analysed. RESULTS: Cool (p = 0.0090) and warm detection thresholds (p = 0.0229) of the tongue were higher in BMS patients than controls. The stimulation threshold for SON BR was higher in patients than in controls (p = 0.0056). The latencies of R2 component were longer in BMS patients than in controls (p = 0.0005) at the SON distribution. Habituation of SON BR did not differ between the groups. The heat pain thresholds were highest (p = 0.0312) in homozygous patients with 957TT, who also reported most interference (p = 0.0352) and greatest suffering (p = 0.0341). Genotype 957CC associated with sleep disturbances (p = 0.0254). CONCLUSIONS: Burning mouth syndrome patients showed thermal hypoesthesia within LN distribution compatible with small fibre neuropathy. The DRD2 957C>T genotype influences perception and experience of BMS pain. SIGNIFICANCE: The results confirm earlier findings of neuropathic pain in BMS. The DRD2 957 C>T genotype influences perception and experience of clinical pain in BMS.

Polymorphisms of interleukin-1ß and MUC7 genes in burning mouth syndrome.

OBJECTIVE: The objectives of the present study are to compare polymorphisms of the IL-1ß and MUC7 genes between patients with burning mouth syndrome (BMS) and controls and to investigate relationships between these polymorphisms and clinical characteristics in BMS patients. MATERIALS AND METHODS: Forty female BMS patients and 40 gender- and age-matched controls were included. Genomic DNA was extracted from saliva samples. Single-nucleotide polymorphisms of IL-1ß -511 and +3954 and variation in number of tandem repeat (VNTR) polymorphism of MUC7 were analyzed. Relationships between genotypic polymorphism data and clinical characteristics in BMS patients were also analyzed. RESULTS: There were no significant differences in the genotypes of IL-1ß -511 and +3954 and of MUC7 between the groups. There were no significant differences in symptom duration and intensity of BMS patients according to their IL-1ß and MUC7 genotypes. The T allele of IL-1ß -511 showed associations with psychometry results in BMS patients: paranoid ideation (P = 0.014), Global Severity Index (P = 0.025), and Positive Symptom Total (P = 0.008). CONCLUSIONS: The genotypic polymorphisms of IL-1ß -511 and +3954, and of MUC7 VNTR, had no direct associations with the development of BMS. However, the T allele of IL-1ß -511 may increase the risk of BMS by increasing psychological asthenia. CLINICAL RELEVANCE: The genotypic polymorphisms of IL-1ß -511 may increase the risk for the development of BMS by increasing psychological asthenia.

Comparative Analysis of Psychological, Hormonal, and Genetic Factors Between Burning Mouth Syndrome and Secondary Oral Burning.

OBJECTIVE: The objective of this study was to evaluate the association between psychological, hormonal, and genetic factors with the development of burning mouth syndrome (BMS) and secondary oral burning (SOB) in order to provide a better characterization and classification of these conditions. DESIGN: Cross sectional study. SETTING: Patients with complaints of mouth burning registered at the Oral Diagnostic Service of the Federal University of Rio Grande do Norte between 2000 and 2013. SUBJECTS: The sample consisted of 163 subjects divided into a group of patients with BMS (n = 64) and a group of subjects with SOB (n = 99). METHODS: The following variables were analyzed: passive and stimulated saliva flow, stress levels and phase, depression, anxiety, serum cortisol and dehydroepiandrosterone (DHEA) levels, and the presence of polymorphisms in the interleukin 6 (IL-6) gene. RESULTS: The results showed significant differences in the presence of xerostomia (p = 0.01), hyposalivation at rest (p < 0.001) and symptoms of depression (p = 0.033) between the two groups, which were more prevalent in the BMS group. DHEA levels were lower in the BMS group (p = 0.003) and were sensitive and specific for the diagnosis of this condition. Genetic analysis revealed no significant association between the polymorphisms analyzed and the development of BMS. CONCLUSION: These results suggest a possible role of depression, as well as of reduced DHEA levels, as associated factors for development of BMS.

Síndrome de boca ardiente secundario a pregabalina en un paciente con atrofia frontal leve / Burning mouth syndrome secondary to pregabaline in a patient with mild frontal lobes atrophy

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Involvement of peripheral artemin signaling in tongue pain: possible mechanism in burning mouth syndrome.

Burning mouth syndrome is characterized by altered sensory qualities, namely tongue pain hypersensitivity. We found that the mRNA expression of Artemin (Artn) in the tongue mucosa of patients with burning mouth syndrome was significantly higher than that of control subjects, and we developed a mouse model of burning mouth syndrome by application of 2,4,6-trinitrobenzene sulfonic acid (TNBS) diluted with 50% ethanol to the dorsum of the tongue. TNBS treatment to the tongue induced persistent, week-long, noninflammatory tongue pain and a significant increase in Artn expression in the tongue mucosa and marked tongue heat hyperalgesia. Following TNBS treatment, the successive administration of the transient receptor potential vanilloid 1 (TRPV1) antagonist SB366791 or neutralizing anti-Artn antibody completely inhibited the heat hyperalgesia. The number of glial cell line-derived neurotrophic factor family receptor α3 (GFRα3)-positive and TRPV1-positive trigeminal ganglion (TG) neurons innervating the tongue significantly increased following TNBS treatment and was significantly reduced by successive administration of neutralizing anti-Artn antibody. The capsaicin-induced current in TG neurons innervating the tongue was enhanced following TNBS treatment and was inhibited by local administration of neutralizing anti-Artn antibody to the tongue. These results suggest that the overexpression of Artn in the TNBS-treated tongue increases the membrane excitability of TG neurons innervating the tongue by increasing TRPV1 sensitivity, which causes heat hyperalgesia. This model may be useful for the study of tongue pain hypersensitivity associated with burning mouth syndrome.

Peculiar alexithymic traits in burning mouth syndrome: case-control study.

OBJECTIVES: The present case-control study aims to assess the occurrence of alexithymic traits in burning mouth syndrome (BMS) subjects and to correlate alexithymic traits to anxious and depressive traits in BMS subjects. MATERIALS AND METHODS: Prospectively enrolled BMS and control subjects were administered the 20-item Toronto Alexithymia Scale (TAS-20). Anxiety and depressive traits were assessed using the Hamilton Anxiety Rating Scale and the Montgomery and Asberg Depression Rating Scale. Occurrence of alexithymic traits was compared between BMS and control subjects. Correlation tests were used to measure the importance of alexithymic traits related to demographic characteristics, pain intensity (VAS score), and to the other psychometric scores. RESULTS: Fifty-eight BMS subjects (46 females and 12 males) had a mean TAS-20 score significantly higher when compared to controls (p < 0.001; r = 0.72), corresponding to an occurrence rate of alexithymic traits of 79.3 versus 6.9%. Alexithymic traits in BMS subjects were just related to depressive traits (p = 0.02; ρ = 0.31). CONCLUSIONS: The high occurrence of alexithymia in BMS is an adjunctive issue in favor of its multifactorial pathogenesis, with a not negligible role for somatization. CLINICAL RELEVANCE: Clinicians should be aware of the high occurrence of alexithymic traits among BMS subjects as such traits may affect the doctor-patient relationship.

Interleukin-1beta and serotonin transporter gene polymorphisms in burning mouth syndrome patients.

UNLABELLED: Burning mouth syndrome (BMS) is a chronic pain syndrome that encompasses all forms of burning sensations in the oral cavity when the oral mucosa is clinically normal. Neural, psychologic, and cytokine factors may be implicated in the pathogenesis of BMS. There are no studies of genetic factors associated with psychologic behavior and cytokine pain sensitivity in BMS patients. The purpose of the present study was to investigate a possible association between functional genetic polymorphisms, +3,954 (C/T) interleukin-1beta, and the polymorphic site on promoter region of the serotonin transporter gene (5-HTTLPR) in a sample of Brazilian patients. Thirty patients affected by BMS and 31 healthy volunteers were genotyped for 5-HTTLPR and IL-1beta gene. The chi-squared test was used for statistical analysis. There was no statistical difference in 5-HTTLPR genotypes between the case and control groups (P = .60), however a significant increase was observed in the IL-1beta high production genotype CT in BMS subjects (P = .005). In conclusion, the present study shows association between BMS and IL-1beta high producer genotype. PERSPECTIVE: This article shows evidence that genetic polymorphisms associated with IL-1beta high production genotype are implicated on the pathogenesis of BMS. The modulation of IL1beta production may be an interesting tool in BMS management.