PAR2-dependent phosphorylation of TRPV4 at the trigeminal nerve terminals contributes to tongue cancer pain.

OBJECTIVE: This study aimed to clarify the interactions between the tongue and primary afferent fibers in tongue cancer pain. METHODS: A pharmacological analysis was conducted to evaluate mechanical hypersensitivity of the tongues of rats with squamous cell carcinoma (SCC). Changes in trigeminal ganglion (TG) neurons projecting to the tongue were analyzed using immunohistochemistry and western blotting. RESULTS: SCC inoculation of the tongue caused persistent mechanical sensitization and tumor formation. Trypsin expression was significantly upregulated in cancer lesions. Continuous trypsin inhibition or protease-activated receptor 2 (PAR2) antagonism in the tongue significantly inhibited SCC-induced mechanical sensitization. No changes were observed in PAR2 and transient receptor potential vanilloid 4 (TRPV4) levels in the TG or the number of PAR2-and TRPV4-expressing TG neurons after SCC inoculation. In contrast, the relative amount of phosphorylated TRPV4 in the TG was significantly increased after SCC inoculation and abrogated by PAR2 antagonism in the tongue. TRPV4 antagonism in the tongue significantly ameliorated the mechanical sensitization caused by SCC inoculation. CONCLUSIONS: Our findings indicate that tumor-derived trypsin sensitizes primary afferent fibers by PAR2 stimulation and subsequent TRPV4 phosphorylation, resulting in severe tongue pain.

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.

Síndrome de boca ardiente / Burning-mouth syndrome

El “Sindrome de la boca ardiente” comprende “Glosodynia o Glosalgia”. Significa dolor de la lengua.“Glosopyrosis”, sensación de quemazón. Disestesia o parestesia es una experiencia de malestar dentro de laboca. “Glosodynia” es usado también cuando está involucrada toda la cavidad bucal.Objetivo. Realizar una revisión del tema y establecer la hipótesis que, este sindrome tendría un fondo psiconeuroinmunoendócrino relevante en el campo de las enfermedades autoinmunes. Promediando datos obtenidos, 80% de las mujeres sufren o han sufrido alguna vez de Glosodynia. Con un rango de 40 a 81 años de edad, media de 60 años, correspondiendo 2,9% al masculino y 15,7% al femenino. Localización: bordes de lengua 46%, dorso de lengua 46%, labios 50% y paladar 46%. La etiología permanece desconocida. La revisión está centrada en describir varios aspectos clínicos, inmunológicos, endocrinológicos y neuronales involucrados en la génesis, enfocando principalmente la relación con: la noradrenalina y las fibras amielínicas, los beta receptores, la histamina, la bradiquinina, las prostaglandinas, el eje hipotálamo-hipófisis-suprarrenal(HHS), el factor librador de corticotrofina (CRF) y la adrenocorticotropina (ACTH), las Interleuquinas 1, 6, 8, 10y 12, el factor de necrosis tumoral alfa (TNF alfa), el factor de agregación plaquetaria (PAF), los adenocorticoides(AGC), los mastocitos, la proteína A1 (AP-1), factores locales y sitémicos, la respuesta celular inmune y una base psicológica alterada. Conclusiones. Debería realizarse un diagnóstico a través de la actividad del eje hipotálamo-pituitaria-adrenal del stress, investigando valores de la respuesta inmune celular. Bajo desórdenes psicológicos serios, el paciente debe ser referido a un especialista apropiado (AU)

The “Burning-Mouth-Syndrome” comprise “Glosodynia or Glosalgia” that means pain of the tongue.“Glosopyrosis”: burning sensation.” Dysesthesia or Paresthesia is a disconfortable experience inside the mouth. Glosodynia is used when the entire oral cavity is involved as well. The objective is to make a rewire about this syndrome and to postulate an hypothesis about etiology and diagnosis. Generally, about 80% of women suffer or once have suffered from Glosodynia. With a range of 40-81 years old, mean age 60 years old, correspond 2.9% male and 15.7% female. Localization: borders of tongue 46%,dorsum of tongue 46%, lips 50% and palate 46%. The etiology remains unknown. The hypothesis establish that this syndrome has a psychoneuroimmunoendocrinology background, relevant in the field of autoimmune diseases. The present review is centered in describing clinical, immumologic, endocrinologycal and neurologyc pathways involved in its genesis, and to focus its relationship with the role of noradrenalin and amyelinic fibers, the Betareceptors, histamine, bradiquinin, prostaglandins, HHS, CRF and ACTH, Il-1, IL-6,IL-8, IL-10,IL-2, TNFalpha,PAF, TGF-B, GHRH, PRL, glucocorticoids, mast cells, NK AP-1, local and systemic factors and an altered psychological base. Conclusions: Diagnosis could be made through the hypothalamic pituitary-adrenal axis activity by stress, Investigating the cellular immune response. Under a serious underlying psychogenic disorder, patient must be referred to an appropriated specialist (AU)

Chondroitin sulfate and kallikrein in saliva: markers for glossodynia.

Glossodynia or burning mouth syndrome is a multifunctional disorder. The oral mucosa is apparently normal but patients report burning and dried mouth and painful tongue and lips. The present study reports biochemical and physiological markers in saliva of patients presenting glossodynia compared to normal subjects. Saliva-buffering capacity and contents of protein and hyaluronic (HA) acid were similar in both groups. In contrast, chondroitin sulfate (CS) concentration was decreased in the saliva of patients with glossodynia when compared to control group (p=0.0036). On the other hand glandular kallikrein showed increased activity in the saliva of patients compared to normal subjects (p<0.0001). The data suggest involvement of the kinin system, possibly related to the low levels of CS. Depression could explain the low level of serotonin in patient serum (p=0.0478).

Defensin-1, an antimicrobial peptide present in the saliva of patients with oral diseases.

OBJECTIVES AND DESIGN: A preceding paper has noted a detection of defensin-1 (HNP-1), a peptide with antimicrobial and cytotoxic properties, in the saliva of patients with oral squamous cell carcinoma. The present study deals with the presence of HNP-1 in the saliva of patients with various oral diseases. METHODS: Whole saliva samples were obtained from the patients. HNP-1 in the saliva was isolated and purified by HPLC and the amino acid sequence of the peptide was determined. The molecular weight of HNP-1 was measured by mass spectrometry. The concentration of HNP-1 in saliva was determined by comparing the height of eluted HNP-1 with that of a synthetic HNP-1 standard. RESULTS: The concentrations of HNP-1 in the saliva of patients with oral lichen planus (n = 5), leukoplakia (n = 4), and glossitis associated with iron deficiency (n = 4) were 8.3 +/- 4.3 micrograms ml-1, 13.2 +/- 7.9 micrograms ml-1, and 11.4 +/- 4.9 micrograms ml-1, (mean +/- s.d.), respectively. These concentrations were significantly higher than those in healthy subjects (0.8 microgram ml-1) (P < 0.01). In contrast, salivary HNP-1 concentrations in patients with glossodynia (n = 4) and oral discomfort (n = 4) were similar to those in healthy subjects. CONCLUSIONS: Since HNP-1 is a non-specific defensive peptide present in neutrophils, it may play an important role in the protection against diseases such as oral lichen planus, leukoplakia, and glossitis associated with iron deficiency.

Relation between idiopathic glossodynia and salivary flow rate and content.

From a series of 50 patients complaining of sore tongue, 13 were found to be suffering from idiopathic glossodynia. All were women in the postmenopausal stage. The salivary flow rate, protein, phosphate, and electrolyte content (Na, K, Ca, Mg) were measured in unstimulated saliva of these patients. Protein, potassium and phosphate concentrations were significantly higher than in the control group. The results indicate that hormonal disbalance might be a factor in the etiology of this type of sore tongue.