Akira Toyofuku

Satellite glial cell P2Y12 receptor in the trigeminal ganglion is involved in lingual neuropathic pain mechanisms in rats

BackgroundIt has been reported that the P2Y12 receptor (P2Y12R) is involved in satellite glial cells (SGCs) activation, indicating that P2Y12R expressed in SGCs may play functional roles in orofacial neuropathic pain mechanisms. However, the involvement of P2Y12R in orofacial neuropathic pain mechanisms is still unknown. We therefore studied the reflex to noxious mechanical or heat stimulation of the tongue, P2Y12R and glial fibrillary acidic protein (GFAP) immunohistochemistries in the trigeminal ganglion (TG) in a rat model of unilateral lingual nerve crush (LNC) to evaluate role of P2Y12R in SGC in lingual neuropathic pain.ResultsThe head-withdrawal reflex thresholds to mechanical and heat stimulation of the lateral tongue were significantly decreased in LNC-rats compared to sham-rats. These nocifensive effects were apparent on day 1 after LNC and lasted for 17 days. On days 3, 9, 15 and 21 after LNC, the mean relative number of TG neurons encircled with GFAP-immunoreactive (IR) cells significantly increased in the ophthalmic, maxillary and mandibular branch regions of TG. On day 3 after LNC, P2Y12R expression occurred in GFAP-IR cells but not neuronal nuclei (NeuN)-IR cells (i.e. neurons) in TG. After 3 days of successive administration of the P2Y12R antagonist MRS2395 into TG in LNC-rats, the mean relative number of TG neurons encircled with GFAP-IR cells was significantly decreased coincident with a significant reversal of the lowered head-withdrawal reflex thresholds to mechanical and heat stimulation of the tongue compared to vehicle-injected rats. Furthermore, after 3 days of successive administration of the P2YR agonist 2-MeSADP into the TG in naïve rats, the mean relative number of TG neurons encircled with GFAP-IR cells was significantly increased and head-withdrawal reflex thresholds to mechanical and heat stimulation of the tongue were significantly decreased in a dose-dependent manner compared to vehicle-injected rats.ConclusionsThe present findings provide the first evidence that the activation of P2Y12R in SGCs of TG following lingual nerve injury is involved in the enhancement of TG neuron activity and nocifensive reflex behavior, resulting in neuropathic pain in the tongue.

Psychiatric diagnoses in patients with burning mouth syndrome and atypical odontalgia referred from psychiatric to dental facilities

Background Burning mouth syndrome (BMS) and atypical odontalgia (AO) are two conditions involving chronic oral pain in the absence of any organic cause. Psychiatrically they can both be considered as “somatoform disorder”. From the dental point of view, however, the two disorders are quite distinct. BMS is a burning or stinging sensation in the mouth in association with a normal mucosa whereas AO is most frequently associated with a continuous pain in the teeth or in a tooth socket after extraction in the absence of any identifiable cause. Because of the absence of organic causes, BMS and AO are often regarded as psychogenic conditions, although the relationship between oral pain and psychologic factors is still unclear. Some studies have analyzed the psychiatric diagnoses of patients with chronic oral pain who have been referred from dental facilities to psychiatric facilities. No study to date has investigated patients referred from psychiatric facilities to dental facilities. Objective To analyze the psychiatric diagnoses of chronic oral pain patients, diagnosed with BMS and AO, and referred from psychiatric facilities to dental facilities. Study design Psychiatric diagnoses and disease conditions of BMS or AO were investigated in 162 patients by reviewing patients’ medical records and referral forms. Psychiatric diagnoses were categorized according to the International Statistical Classification of Disease and Related Health Problems, Tenth Revision. Results The proportion of F4 classification (neurotic, stress-related, and somatoform disorders) in AO patients was significantly higher than in BMS patients. BMS patients were more frequently given a F3 classification (mood/affective disorders). However, 50.8% of BMS patients and 33.3% of AO patients had no specific psychiatric diagnoses. Conclusion Although BMS and AO are both chronic pain disorders occurring in the absence of any organic cause, the psychiatric diagnoses of patients with BMS and AO differ substantially.

Efficacy of milnacipran for glossodynia patients.

Pain and depression are thought to arise from a common neurochemical dysfunction at the level of noradrenergic and serotonergic neurons, and antidepressants are used to treat chronic pain. The dual action tricyclic antidepressants are more potent in relieving pain than the selective serotonin reuptake inhibitors. Glossodynia is chronic pain and burning sensation in the tongue often associated with depression. Patients suffering from glossodynia were treated with the serotonin and noradrenaline reuptake inhibitor, milnacipran, which has been recently launched in Japan. Milnacipran was found to be effective in the relief of the chronic glossodynia and well tolerated.

Milnacipran dose-effect study in patients with burning mouth syndrome.

Objective:The object of this study was to evaluate the dose-dependent efficacy and tolerability of milnacipran in patients with burning mouth syndrome (BMS) with inadequate response at low doses. Methods:A 12-week open-label dose-escalation study was conducted in 56 female patients (aged 20-83 years, with a mean age of 60.8 years). The initial dosage of milnacipran was 30 mg/d, and the dosage was raised up to 60 mg and 90 mg/d every 4 weeks until an improvement of at least 50% reduction of visual analog scale was achieved. Results:The mean ± SD effective daily dose of milnacipran was 63.9 ±16.7 mg. The cumulative improvement rate for the daily dose of 30 mg was 28.6%, and this rate rose (50.8%-67.9%) as the daily dose was increased (from 60 to 90 mg, respectively). The cumulative proportion of responders was significantly greater, with maximal daily doses of 60 and 90 mg, compared with that of 30 mg (P < 0.05, &khgr;2 test). Most adverse events appeared at the low dose, and there was little evidence for dose-dependence of adverse effects. No serious safety issues were observed. Conclusion:From the result of this study, dose escalation of milnacipran for patients with burning mouth syndrome with inadequate response at low doses may be helpful if the 30-mg daily dose has been tolerated well.

Current Evidence on Atypical Odontalgia: Diagnosis and Clinical Management

Patients with atypical odontalgia (AO) complain of medically unexplained toothache. No evidence-based diagnostic criteria or treatment guidelines are yet available. The present paper addresses seven clinical questions about AO based on current knowledge in the literature and discusses diagnostic criteria and guidelines for treatment and management. The questions are (i) What is the prevalence of AO in the community? (ii) What psychological problems are experienced by patients with AO? (iii) Are there any comorbidities of AO? (iv) Is local anesthesia effective for the relief of pain in AO? (v) Are there any characteristic symptoms of AO other than spontaneous pain? (vi) Are antidepressants effective for treatment of AO? (vii) Are anticonvulsants effective for treatment of AO? Our literature search provided answers for these questions; however, there is insufficient evidence-based data to establish guidelines for the diagnosis and treatment of AO. Overall, some diagnostic criteria for neuropathic pain and persistent dentoalveolar pain disorder may be applied to AO patients. The patients psychogenic background should always be considered in the treatment and/or management of AO. The clinicians may need to treat AO patients using Patient-Oriented Evidence that Matters approach.

Psychosomatic problems in dentistry

Many dental patients complain of oral symptoms after dental treatment, such as chronic pain or occlusal discomfort, for which the cause remains undetermined. These symptoms are often thought to be mental or emotional in origin, and patients are considered to have an “oral psychosomatic disorder”. Representative medically unexplained oral symptoms/syndromes (MUOS) include burning mouth syndrome, atypical odontalgia, phantom bite syndrome, oral cenesthopathy, or halitophobia. With an increasing prevalence of these MUOS, dentists are being asked to develop new approaches to dental treatment, which include taking care of not only the patient’s teeth but also the patient’s suffering. Progress in the understanding of mind-body interactions will lead to investigations on the pathophysiology of MUOS and the development of new therapeutic approaches.

Psychiatric comorbidities and psychopharmacological outcomes of phantom bite syndrome

OBJECTIVE Phantom bite syndrome (PBS) is characterized by a persistent uncomfortable sensation of occlusion without an evident occlusal discrepancy. The aims of this retrospective cross-sectional study were to assess psychiatric comorbidities and evaluate psychopharmacological outcomes of PBS. METHODS The database of the Psychosomatic Dentistry Clinic of Tokyo Medical and Dental University Dental Hospital was reviewed for cases of PBS diagnosed between April 2009 and March 2012. Clinical Global Impression indices were used to assess psychopharmacological outcomes. RESULTS The review revealed 130 patients (107 women, 23 men) with a mean age of 53.0 ±13.1 years. They previously visited 4.4 ±3.4 dental clinicsand had a mean symptom duration of 5.3 ±5.4 years. Only 24 (18.5%) of 63 (48.5%) patients with psychiatric comorbidities had schizophrenia, major depressive disorder, or bipolar disorder. The frequency of psychiatric comorbidities was significantly lower in PBS with a dental trigger than that without a specific trigger. Moreover, patients without a psychiatric comorbidity showed significantly better outcomes than those with a psychiatric comorbidity. Forty patients (30.8%) showed remarkable clinical improvement after receiving amitriptyline, mirtazapine, or aripiprazole. CONCLUSION PBS is generally not associated with severe psychiatric disorders. Absence of a dental trigger predicts a psychiatric comorbidity, which affects the psychopharmacological outcome. Antidepressant or antipsychotic therapy may be effective for symptom management in PBS.

Phenotypic change in trigeminal ganglion neurons associated with satellite cell activation via extracellular signal-regulated kinase phosphorylation is involved in lingual neuropathic pain

Iatrogenic trigeminal nerve injuries remain a common and complex clinical problem. Satellite glial cell (SGC) activation, associated phosphorylation of extracellular signal‐regulated kinase (ERK), and neuropeptide expression in the trigeminal ganglion (TG) are known to be involved in trigeminal neuropathic pain related to trigeminal nerve injury. However, the involvement of these molecules in orofacial neuropathic pain mechanisms is still unknown. Phosphorylation of ERK1/2 in lingual nerve crush (LNC) rats was observed in SGCs. To evaluate the role of neuron–SGC interactions under neuropathic pain, calcitonin gene‐related peptide (CGRP)‐immunoreactive (IR), phosphorylated ERK1/2 (pERK1/2)‐IR and glial fibrillary acidic protein (GFAP)‐IR cells in the TG were studied in LNC rats. The number of CGRP‐IR neurons and neurons encircled with pERK1/2‐IR SGCs was significantly larger in LNC rats compared with sham rats. The percentage of large‐sized CGRP‐IR neurons was significantly higher in LNC rats. The number of CGRP‐IR neurons, neurons encircled with pERK1/2‐IR SGCs, and neurons encircled with GFAP‐IR SGCs was decreased following CGRP receptor blocker CGRP8‐37 or mitogen‐activated protein kinase/ERK kinase 1 inhibitor PD98059 administration into the TG after LNC. Reduced thresholds to mechanical and heat stimulation to the tongue in LNC rats were also significantly recovered following CGRP8‐37 or PD98059 administration. The present findings suggest that CGRP released from TG neurons activates SGCs through ERK1/2 phosphorylation and TG neuronal activity is enhanced, resulting in the tongue hypersensitivity associated with lingual nerve injury. The phenotypic switching of large myelinated TG neurons expressing CGRP may account for the pathogenesis of tongue neuropathic pain.

Comparison of cerebral blood flow in oral somatic delusion in patients with and without a history of depression: a comparative case series

BackgroundA significant number of patients visit dental clinics because of unusual oral sensations for which no physical cause can be found. Such patients are recognized as having oral somatic delusion (OSD). OSD may be either primary (monosymptomatic) or secondary to another disease, such as depression or cerebral infarction. Although the presenting complaints of patients with primary and secondary OSD are nearly indistinguishable, symptoms in patients with secondary OSD seem to be resistant to treatment compared with those in patients with primary OSD. Moreover, right dominant cerebral blood flow (CBF) has been reported in patients with primary OSD, but the difference in CBF between patients with primary and secondary OSD remains unclear. The aim of this study was to assess the differences in clinical characteristics and CBF distribution between patients with monosymptomatic OSD (non-depression group) and OSD in conjunction with remitted depression (depression group).MethodsParticipants were 27 patients of a psychosomatic dentistry clinic, all diagnosed with OSD. They were categorized into either the non-depression group (17 patients) or the depression group (10 patients) on the basis of assessments by their personal medical providers. CBF was examined using single-photon emission computed tomography.ResultsThere was no difference in clinical presentation between the two groups. A significant right dominant asymmetry in the temporal and posterior cerebral regions was observed in both groups. In the central region, a right dominance was seen in the non-depression group, while a left dominance was seen in the depression group. Moreover, the mean regional CBF values for patients in the depression group were significantly lower in several regions (including bilateral callosomarginal, precentral, angular, temporal, posterior cerebral, pericallosal, lenticular nucleus, thalamus, and hippocampus; and right central and cerebellum) than for patients in the non-depression group.ConclusionThese results suggest that the temporal and posterior cerebral regions are involved in in the pathophysiology of OSD, regardless of depression history, and that widespread CBF reduction is a characteristic of remitted depression.

Oral Dysesthesia Rating Scale: a tool for assessing psychosomatic symptoms in oral regions

BackgroundThe concept of cenesthopathy was first introduced by Dupré and Camus in 1907 to describe clinically unexplainable bodily sensations mainly attributed to psychiatric pathology. If it occurs in oral regions, it is termed oral cenesthopathy and it has been of special interest to psychiatrists and dentists. While there is no independently defined criteria for this condition, which is classified as either a delusional or a somatoform disorder, clinical practice and research require a standard scale to measure and rate its symptoms. In this study, we included any types of psychosomatic symptoms in oral regions as oral dysesthesia, and developed an Oral Dysesthesia Rating Scale (Oral DRS) and evaluated its validity and reliability as an assessment tool.MethodsThe scale was developed based on literature review and extensive clinical experience. Twelve reviewers assessed relevancy of each item to oral dysesthesia symptoms by 1–4 scoring scale and item content validity index was computed. To evaluate the inter-rater reliability of Oral DRS, pairs of raters administered the scale to 40 randomly selected patients with complaints of oral dysesthesia symptoms and Cohen’s weighted kappa coefficient was determined for each item.ResultsThe scale assesses the severity of feelings of foreign body [A1], exudation [A2], squeezing-pulling [A3], movement [A4], misalignment [A5], pain [A6], and spontaneous thermal sensation or tastes [A7], and the degree of impairment in eating [B1], articulation [B2], work [B3], and social activities [B4] on a scale of 0–5. Items A1, A2, A3, A4, B3, and B4 demonstrated acceptable content validity. Inter-rater reliabilities were good or excellent for all items evaluated.ConclusionThe Oral DRS can help define the nosography of clinically unexplainable oral dysesthesia through further case evaluation and clinical research and facilitate devising of treatment modalities.