Masseter muscle contraction and cervical muscle sensitization by nerve growth factor cause mechanical hyperalgesia in masticatory muscle with activation of the trigemino-lateral parabrachial nucleus system in female rats.

OBJECTIVE: To establish a new rat model of craniofacial myalgia, and to clarify which central nervous system pathways are activated in the model. BACKGROUND: Craniofacial myalgia, represented by myogenous temporomandibular disorder and tension-type headache with pericranial tenderness, is more common in female patients. The pain is thought to be a type of multifactorial disorder with several coexisting causes. To our knowledge, there are no models of craniofacial muscle hyperalgesia caused by multiple types of stimuli. METHODS: We injected nerve growth factor into the trapezius muscle of female and male rats and repeatedly stimulated the masseter muscle (MM) electrically for 10 days. We determined the mechanical head-withdrawal threshold of MM and extent of phosphorylated extracellular signal-related kinase 1/2 (pERK) immunoreactivity in various regions of the lower brainstem. We conducted retrograde tract-tracing to determine the projection of mechanosensitive MM-innervating secondary neurons to the lateral parabrachial nucleus. Finally, we administered morphine in rats to determine whether increases of pERK immunoreactivity were dependent on noxious inputs. RESULTS: In female rats, but not male rats, the mechanical head-withdrawal threshold was decreased significantly from days 9 to 12. The number of pERK-immunoreactive neurons in the brainstem was increased significantly in female rats in the group with both stimuli compared to rats in other groups with a single stimulus. Mechanosensitive MM-innervating neurons in the brainstem projected to the parabrachial nucleus. Morphine administration blocked the increase in the number of pERK-immunoreactive neurons in both the brainstem and parabrachial nucleus. CONCLUSIONS: We established a model of craniofacial myalgia by combining trapezius and MM stimuli in female rats. We found mechanical hyperalgesia of the MM and activation of the pain pathway from the brainstem to parabrachial nucleus. The model reflects the characteristics of patients with craniofacial myalgia and might be helpful to clarify the pathogenic mechanisms underlying these disorders.

Neural Subtype-dependent Cholinergic Modulation of Neural Activities by Activation of Muscarinic 2 Receptors and G Protein-activated Inwardly Rectifying Potassium Channel in Rat Periaqueductal Gray Neurons.

Acetylcholine plays a pivotal role in the regulation of functions such as pain and the sleep and wake cycle by modulating neural activities of the ventrolateral periaqueductal gray (vlPAG). Electrophysiological studies have shown that cholinergic effects are inconsistent among recorded neurons, particularly in the depolarization and hyperpolarization of the resting membrane potential (RMP). This discrepancy may be due to the neural subtype-dependent cholinergic modulation of the RMP. To examine this possibility, we performed whole-cell patch-clamp recordings from subtype-identified neurons using vesicular GABA transporter (VGAT)-Venus × ChAT-TdTomato rats and elucidated cellular mechanisms of cholinergic effects on the RMP. The application of carbachol hyperpolarized the RMP of cholinergic neurons in a dose-dependent manner but had much less of an effect on other neural subtypes, including GABAergic/glycinergic and glutamatergic neurons. Cholinergic hyperpolarization was accompanied by a decrease in input resistance. These cholinergic effects were blocked by AF-DX384 or gallamine and were mimicked by arecaidine but-2-ynyl ester tosylate, suggesting that the carbachol-induced hyperpolarization of the RMP in cholinergic neurons is mediated via M2 receptors. Tertiapin suppressed the carbachol-induced G protein-activated inwardly rectifying potassium channel (GIRK) currents and hyperpolarization of the RMP in cholinergic neurons. Intracellular application of GDP-ß-S blocked the carbachol-induced hyperpolarization of the RMP. Neostigmine slowly hyperpolarized the RMP in cholinergic neurons. These results suggest that neural firing of vlPAG cholinergic neurons is suppressed by GIRK currents induced via M2 receptor activation, and this negative feedback regulation of cholinergic neuronal activities can be induced by acetylcholine, which is intrinsically released in the vlPAG.

Synchronous inhibitory synaptic inputs to layer II/III pyramidal neurons in the murine barrel cortex.

The barrel cortex exhibits obvious columnar organization. Although GABAergic inhibition plays a critical role in regulating neural excitation in response to mechanical stimuli applied to whiskers, the profiles of synchronous events for inhibitory synaptic transmission in intracolumnar and transcolumnar pyramidal neurons remain unknown. To explore a functional mechanism of synchronous inhibition of pyramidal neurons, we performed paired whole-cell patch-clamp recordings and recorded spontaneous inhibitory postsynaptic currents (sIPSCs) from layer II/III pyramidal neurons. A cross-correlogram of sIPSCs (1 ms bin) was used to detect synchronous sIPSCs. Synchronous neuron pairs were defined as those whose peak number of sIPSCs between -3 and 3 ms exceeded the mean + 2 SD of the number of sIPSCs in the period of -50 to 50 ms minus the number in that of -3 to 3 ms period. In the recording of pyramidal neurons located in the same column (intracolumn), 61.5% of neuron pairs were classified as synchronous neuron pairs, while 52.6% of pyramidal neuron pairs in adjacent columns (transcolumn) were defined as synchronous neuron pairs. The amplitude of synchronous sIPSCs was comparable to that of asynchronous sIPSCs in asynchronous neuron pairs, whereas that of synchronous sIPSCs was larger than that of asynchronous sIPSCs in synchronous neuron pairs. Synchronicity of sIPSCs did not depend on the distance of neuron pairs. These results suggest that layer II/III pyramidal neurons receive synchronous inhibitory synaptic inputs generated by a certain type of GABAergic interneuron that induces large IPSCs in pyramidal neurons, likely to be fast-spiking cells.

Comparison of Cerebral Blood Flow Patterns in Patients with Phantom Bite Syndrome with Their Corresponding Clinical Features.

BACKGROUND: Phantom bite syndrome (PBS) is characterized by an uncomfortable sensation during occlusion without any evident abnormality. A recent case-control study with single-photon emission computed tomography (SPECT) using 99mTc-ethyl cysteinate dimer could not find the specific features of regional cerebral blood flow (rCBF), which might be due to the heterogeneity of PBS. We analyzed the brain images of PBS corresponding to the clinical features by studying PBS subgroups. METHODS: This study contributes to elucidating the pathophysiology of PBS by evaluating regional brain perfusion on SPECT and its clinical features. We performed SPECT using 99mTc-ethyl cysteinate dimer in 44 patients with PBS. The SPECT images were analyzed qualitatively and quantitatively. RESULTS: Asymmetrical rCBF patterns were detected, corresponding to symptom laterality. Patients with PBS with right-side symptoms showed right-side-predominant rCBF asymmetry in the parietal region and left-side-predominant rCBF asymmetry in the thalamus, and vice versa. Moreover, the analysis of the association between rCBF and patient behaviors revealed that patients who blamed their dentists for their symptoms tended to have a symmetrical rCBF pattern. CONCLUSION: Patients with PBS showed blood flow imbalance in the thalamus and parietal region corresponding to symptom laterality. There are two types of symmetrical and asymmetrical rCBF patterns in the pathophysiology of PBS despite similar clinical manifestations.

Suppression of Superficial Microglial Activation by Spinal Cord Stimulation Attenuates Neuropathic Pain Following Sciatic Nerve Injury in Rats.

We evaluated the mechanisms underlying the spinal cord stimulation (SCS)-induced analgesic effect on neuropathic pain following spared nerve injury (SNI). On day 3 after SNI, SCS was performed for 6 h by using electrodes paraspinally placed on the L4-S1 spinal cord. The effects of SCS and intraperitoneal minocycline administration on plantar mechanical sensitivity, microglial activation, and neuronal excitability in the L4 dorsal horn were assessed on day 3 after SNI. The somatosensory cortical responses to electrical stimulation of the hind paw on day 3 following SNI were examined by using in vivo optical imaging with a voltage-sensitive dye. On day 3 after SNI, plantar mechanical hypersensitivity and enhanced microglial activation were suppressed by minocycline or SCS, and L4 dorsal horn nociceptive neuronal hyperexcitability was suppressed by SCS. In vivo optical imaging also revealed that electrical stimulation of the hind paw-activated areas in the somatosensory cortex was decreased by SCS. The present findings suggest that SCS could suppress plantar SNI-induced neuropathic pain via inhibition of microglial activation in the L4 dorsal horn, which is involved in spinal neuronal hyperexcitability. SCS is likely to be a potential alternative and complementary medicine therapy to alleviate neuropathic pain following nerve injury.

Involvement of Satellite Cell Activation via Nitric Oxide Signaling in Ectopic Orofacial Hypersensitivity.

: The mechanical head-withdrawal threshold (MHWT) was significantly reduced following inferior alveolar nerve transection (IANX) in rats. Nitrate and nitrite synthesis was dramatically increased in the trigeminal ganglion (TG) at 6 h after the IANX. The relative number of neuronal nitric oxide synthase (nNOS)-immunoreactive (IR) cells was significantly higher in IANX rats compared to sham-operated and N-propyl-L-arginine (NPLA)-treated IANX rats. On day 3 after NPLA administration, the MHWT recovered considerably in IANX rats. Following L-arginine injection into the TG, the MHWT was significantly reduced within 15 min, and the mean number of TG cells encircled by glial fibrillary acidic protein (GFAP)-IR cells was substantially higher. The relative number of nNOS-IR cells encircled by GFAP-IR cells was significantly increased in IANX rats. In contrast, after NPLA injection into the TG, the relative number of GFAP-IR cells was considerably reduced in IANX rats. Fluorocitrate administration into the TG significantly reduced the number of GFAP-IR cells and prevented the MHWT reduction in IANX rats. The present findings suggest that following IANX, satellite glial cells are activated via nitric oxide (NO) signaling from TG neurons. The spreading satellite glial cell activation within the TG results in mechanical hypersensitivity of face regions not directly associated with the trigeminal nerve injury.

Differences in the Clinical Characteristics of Persistent Idiopathic Facial Pain (Atypical Odontalgia) Patients with or Without Neurovascular Compression of the Trigeminal Nerve.

BACKGROUND: Persistent idiopathic facial pain (PIFP) is the unexplained pain along the territory of the trigeminal nerve, including nonorganic tooth pain called atypical odontalgia (AO). Though PIFP is debilitating to patients' livelihood and well-being, its pathophysiology remains poorly understood. Although neurovascular compression (NVC) of the trigeminal nerve is known to be associated with trigeminal neuralgia (TN), the relationship between NVC and other orofacial pains has not been fully elucidated. METHODS: In this study, we investigated the differences in the characteristics of PIFP (primarily AO) patients in the presence or absence of NVC. A retrospective analysis was performed on data from 121 consecutive patients who had been diagnosed with unilateral PIFP according to the criteria of the International Classification of Headache Disorders (ICHD)-3 and underwent magnetic resonance imaging scans of the head. RESULTS: In the group without NVC, characteristic findings were significant for psychiatric morbidity, somatization, and pain disability, when compared with the group with NVC. Furthermore, the group without NVC exhibited significant headache, noncardiac chest pain, shortness of breath, and pain catastrophizing. CONCLUSIONS: These results suggest that PIFP patients can be divided into two groups: one consistent with a neuropathic pain phenotype when NVC is present and a functional somatic symptom phenotype when presenting without NVC. Our findings may enable a more precise understanding of pathophysiology of PIFP and lead to better treatment strategies.

Comorbid depressive disorders and left-side dominant occlusal discomfort in patients with phantom bite syndrome.

BACKGROUND: Phantom bite syndrome (PBS) is characterised by occlusal discomfort without corresponding dental abnormalities. Despite repeated, failed dental treatments, patients with PBS persist in seeking bite correction. PBS has been regarded as a mental disorder. However, we have reported that PBS patients with a dental trigger tend to have less psychiatric history than those without. Hence, the symptoms of PBS cannot be explained by a mental disorder alone, and it is unclear if mental disorders affect occlusal sensation. OBJECTIVE: To elucidate the pathophysiology of PBS, we analysed the dental history, PBS symptom laterality and psychiatric history of patients. METHODS: In this retrospective study, we reviewed outpatients with PBS who presented at our clinic between April 2012 and March 2017. Their medical records were reviewed for demographic data, medical history and laterality of occlusal discomfort. RESULTS: Approximately half of the 199 enrolled patients had bilateral occlusal discomfort. In the others, the side with occlusal discomfort generally tended to be the one that had received dental treatment. There was no significant relationship between the side chiefly affected by occlusal discomfort and whether dental treatment had been received; however, the affected side differed depending on whether the patient had comorbid psychiatric disorders (P = .041). CONCLUSIONS: The distributions of the side with symptoms of PBS were different between those with and without comorbid psychiatric disorders, suggesting that psychiatric disorders might affect occlusal sensation due to a subtle dysfunction in brain areas central to sensory integration. Central dysfunction might play an important role in PBS.

Increase in IGF-1 Expression in the Injured Infraorbital Nerve and Possible Implications for Orofacial Neuropathic Pain.

Insulin-like growth factor-1 (IGF-1) is upregulated in the injured peripheral nerve bundle and controls nociceptive neuronal excitability associated with peripheral nerve injury. Here, we examined the involvement of IGF-1 signaling in orofacial neuropathic pain following infraorbital nerve injury (IONI) in rats. IONI promoted macrophage accumulation in the injured ION, as well as in the ipsilateral trigeminal ganglion (TG), and induced mechanical allodynia of the whisker pad skin together with the enhancement of neuronal activities in the subnucleus caudalis of the spinal trigeminal nucleus and in the upper cervical spinal cord. The levels of IGF-1 released by infiltrating macrophages into the injured ION and the TG were significantly increased. The IONI-induced the number of transient receptor potential vanilloid (TRPV) subfamily type 4 (TRPV4) upregulation in TRPV subfamily type 2 (TRPV2)-positive small-sized, and medium-sized TG neurons were inhibited by peripheral TRPV2 antagonism. Furthermore, the IONI-induced mechanical allodynia was suppressed by TRPV4 antagonism in the whisker pad skin. These results suggest that IGF-1 released by macrophages accumulating in the injured ION binds to TRPV2, which increases TRPV4 expression in TG neurons innervating the whisker pad skin, ultimately resulting in mechanical allodynia of the whisker pad skin.

Upregulation of calcitonin gene-related peptide, neuronal nitric oxide synthase, and phosphorylated extracellular signal-regulated kinase 1/2 in the trigeminal ganglion after bright light stimulation of the eye in rats.

Bright light stimulation of the eye activates trigeminal subnucleus caudalis (Vc) neurons in rats. Sensory information is conveyed to the Vc via the trigeminal ganglion (TG). Thus, it is likely that TG neurons respond to photic stimulation and are involved in photic hypersensitivity. However, the mechanisms underlying this process are unclear. Therefore, the hypothesis in this study is bright light stimulation enhances the excitability of TG neurons involved in photic hypersensitivity. Expressions of calcitonin gene-related peptide (CGRP) and neuronal nitric oxide synthase (nNOS) were significantly higher in TG neurons from 5 min to 12 h after photic stimulation of the eye. Phosphorylation of extracellular signal-regulated kinase1/2 (pERK1/2) was enhanced in TG neurons within 5 min after photic stimulation, while pERK1/2 immunoreactivity in satellite glial cells (SGCs) persisted for more than 12 h after the stimulus. Activation of SGCs was observed from 5 min to 2 h. Expression of CGRP, nNOS, and pERK1/2 was observed in small and medium TG neurons, and activation of SGCs and pERK1/2-immunoreactive SGCs encircling large TG neurons was accelerated after stimulation. These results suggest that upregulation of CGRP, nNOS, and pERK1/2 within the TG is involved in photic hypersensitivity.

Pharmacotherapeutic outcomes in atypical odontalgia: determinants of pain relief.

OBJECTIVES: There has been considerable research which has focused on clarifying the origin of pain in patients with atypical odontalgia (AO), also known as "idiopathic toothache", and on identifying effective treatment, but there has been limited success so far. In this study, we assessed the outcomes of treatment and attempted to identify factors that could account for pain remission in patients with AO. PATIENTS AND METHODS: Data for 165 patients diagnosed with AO from June 2015 to August 2017 were retrospectively reviewed. The patients' sex, age, duration of pain, and psychiatric history were collected, along with information on pain intensity, depressive status, and catastrophizing scores. Responses at 4 and 16 weeks from the start of treatment were observed. The associations between potentially associated factors and outcome were investigated using Bayesian model averaging. RESULTS: A 30% reduction in pain was reported by 38 patients (46.3%) at 4 weeks and by 54 patients (65.9%) at 16 weeks. The pain intensity decreased as the depression and catastrophizing score improved; all of the changes were statistically significant (P<0.001). Four elements, that is, patient sex, depression score at baseline, pain score at 4 weeks, and change in the catastrophizing score, explained 52.5% of the variation in final outcome between individual patients. CONCLUSION: Our findings confirm the efficacy of tricyclic antidepressants (TCAs) as a treatment for AO and indicate that other medications, especially aripiprazole used in combination with a TCA, may be useful. A considerable number of patients, especially women, those with lower levels of depression at baseline, and those who responded to 4 weeks of treatment, achieved pain relief.

Clinical characteristics and course of oral somatic delusions: a retrospective chart review of 606 cases in 5 years.

OBJECTIVE: Oral cenesthopathy is characterized by foreign body sensations without medical and dental evidence for them. It is thought to be a rare disease in psychiatry, but many patients are visiting dental clinics seeking treatment to remove a foreign body. Even though the features of oral cenesthopathy might be different between a psychiatric clinic and a dental clinic, there has been no clinic-statistical study from dentists. In this study, we report a clinico-statistical study of patients with oral cenesthopathy in dentistry. METHODS: This is a retrospective chart review of 606 outpatients with oral cenesthopathy in Tokyo Medical and Dental University from April 2010 through to March 2015. RESULTS: A total of 159 male and 447 female patients were included in this study. The mean age was 62.08 years, and female patients were older than male patients. The trigger of the dental treatment and the acute phase of depression at the onset were significantly related (p=0.037). Only 128 patients (36%) had clinically significant improvement after 6 months of pharmacotherapy. No history of psychiatric disorders (odds ratio [OR] 0.479 [95% confidence interval {CI}: 0.262-0.875], p=0.017) and longer duration of illness (>18 months) (OR 2.626 [95% CI: 1.437-4.799], p=0.002) were significant factors for clinical outcomes. CONCLUSION: Patients with oral cenesthopathy in our clinic were predominantly elderly female patients. Dental treatment in the acute phase of depression might be a risk factor for oral cenesthopathy. Therefore, comprehending the situation of psychiatric disorder and obtaining adequate informed consent might be required to prevent the trouble concerning oral cenesthopathy.

[A Case Report of Surgery and Chemotherapy for a Patient with Rapidly Progressing Breast Cancer during Pregnancy].

A 33-year-old woman became aware of a right breast mass at her 28th week of pregnancy. From the biopsy results, we diagnosed her with right breast cancer. At her 33rd week of pregnancy, she underwent modified radical mastectomy (pT2N3aM0, Stage III C, ER-negative, PR-negative, HER2-positive), and she elected to receive adjuvant therapy after the surgery during her pregnancy. She received the first course of EC (epirubicin plus cyclophosphamide) therapy on the 13th postoperative day (35 weeks of gestation) and gave a natural, vaginal delivery at 36 weeks and 5 days of gestation. On the 4th day after birth, the patient noticed a contralateral left breast mass and was diagnosed with left breast cancer, after core needle biopsy. She received 4 courses of EC therapy and is currently undergoing PTX plus HER (paclitaxel plus trastuzumab) therapy. Regarding chemotherapy during pregnancy, we recommend that there is no need to perform artificial preterm birth, because chemotherapy has little influence on children after their second-trimester. After the second-trimester, chemotherapy can be safely performed.

Erratum: Low levels of linoleic acid and α-linolenic acid and high levels of arachidonic acid in plasma phospholipids are associated with hypertension.

[This corrects the article DOI: 10.3892/br.2017.1015.].

Low levels of linoleic acid and α-linolenic acid and high levels of arachidonic acid in plasma phospholipids are associated with hypertension.

Dietary fat is an important determinant in the development and progression of high blood pressure (BP), a major risk factor for cardiovascular diseases and mortality. The aim of the present study was to determine the association between plasma phospholipid fatty acids and hypertension in Japanese men. The plasma level of linoleic acid (LA) in the subjects with hypertension (systolic BP ≥140 mmHg and/or diastolic BP ≥90 mmHg) was identified to be significantly higher than that in the healthy controls. Following adjustment for age, body mass index, physical activity, smoking status, alcohol consumption, salt intake, and serum levels of glucose and hemoglobin A1c, higher plasma levels of LA and α-linolenic acid (ALA), and lower levels of arachidonic acid (AA) were significantly associated with a lower prevalence of hypertension. The odds ratio (OR) for the highest quartile (Q4) versus the lowest quartile (Q1) of LA was 0.17 (P=0.003), the OR for Q4 versus Q1 of ALA was 0.26 (P=0.042) and the OR for Q4 versus Q1 of AA was 2.04 (P=0.047). These results indicate that elevated levels of LA and ALA, and reduced levels of AA in the plasma prevent hypertension.

Psychiatric comorbidities in patients with Atypical Odontalgia.

OBJECTIVE: Atypical Odontalgia (AO) is a condition characterized by tooth pain with no apparent cause. Although psychiatric comorbidity seems to be very common, it has rarely been studied. To clarify the influence of psychiatric comorbidity on the clinical features in patients with AO, we retrospectively evaluated their examination records. METHODS: Clinical features and psychiatric diagnoses of 383 patients with AO were investigated by reviewing patients' medical records and referral letters. Psychiatric diagnoses were categorized according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). We also analyzed visual analogue scale (VAS), self-rating depression scale (SDS), and the short-form McGill pain questionnaire (SF-MPQ) scores. RESULTS: Of the 383 patients with AO, 177 (46.2%) had comorbid psychiatric disorders. The most common were depressive disorders (15.4%) and anxiety disorders (10.1%). Serious psychotic disorders such as bipolar disorder (3.0%) and schizophrenia (1.8%) were rare. Dental trigger of AO was reported in 217 (56.7%) patients. There were no significant correlations between psychiatric comorbidities and most of the demographic features. Higher VAS and SDS scores, higher frequency of sleep disturbance, and higher ratings of "Fearful" and "Punishing-cruel" descriptors of the SF-MPQ were found in patients with psychiatric comorbidity. CONCLUSIONS: About half of AO patients had comorbid psychiatric disorders. Dental procedures are not necessarily causative factors of AO. In AO patients with comorbid psychiatric disorders, pain might have a larger emotional component than a sensory one. VAS, SDS, and SF-MPQ scores might aid in the noticing of underlying comorbid psychiatric disorders in AO patients.

Evaluating Burning Mouth Syndrome as a Comorbidity of Atypical Odontalgia: The Impact on Pain Experiences.

OBJECTIVE: This study aimed (1) to investigate the differences in clinical characteristics of patients between 2 groups, those who have atypical odontalgia (AO) only and those who have AO with burning mouth syndrome (BMS), and (2) to assess the influence of psychiatric comorbidity factors on patients' experiences. METHOD: Medical records and psychiatric referral forms of patients visiting the Psychosomatic Dentistry Clinic of Tokyo Medical and Dental University between 2013 and 2016 were reviewed. The final sample included 2 groups of 355 patients: those who have AO only (n = 272) and those who have AO with BMS (AO-BMS; n = 83). Clinicodemographic variables (gender, age, comorbid psychiatric disorders, and history of headache or sleep disturbances) and pain variables (duration of illness, pain intensity, and severity of accompanying depression) were collected. Initial pain assessment was done using the Short-Form McGill Pain Questionnaire, and depressive state was determined using the Zung Self-Rating Depression Scale. RESULTS: The average age, female ratio, and sleep disturbance prevalence in the AO-only group were significantly lower than those in AO-BMS group. AO-BMS patients rated overall pain score and present pain intensity significantly higher than did the AO-only patients (P = 0.033 and P = 0.034, respectively), emphasizing sharp (P = 0.049), hot-burning (P = 0.000), and splitting (P = 0.003) characteristics of pain. Patients having comorbid psychiatric disorders had a higher proportion of sleep disturbance in both groups and a higher proportion of depressive state in the AO-only group. CONCLUSIONS: AO-BMS patients have different epidemiological characteristics, sleep quality, and pain experiences compared to AO-only patients. The presence of psychiatric comorbidities in both groups may exacerbate sleep quality. We suggest that BMS as a comorbid oral disorder in AO patients contributes to a more intensively painful experience.

Interaction between calcitonin gene-related peptide-immunoreactive neurons and satellite cells via P2Y12 R in the trigeminal ganglion is involved in neuropathic tongue pain in rats.

The P2Y12 receptor expressed in satellite cells of the trigeminal ganglion is thought to contribute to neuropathic pain. The functional interaction between neurons and satellite cells via P2Y12 receptors and phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) underlying neuropathic pain in the tongue was evaluated in this study. Expression of P2Y12 receptor was enhanced in pERK1/2-immunoreactive cells encircling trigeminal ganglion neurons after lingual nerve crush. The administration to lingual nerve crush rats of a selective P2Y12 receptor antagonist, MRS2395, attenuated tongue hypersensitivity to mechanical and heat stimulation and suppressed the increase in the relative numbers of calcitonin gene-related peptide (CGRP)-immunoreactive neurons and neurons encircled by pERK1/2-immunoreactive cells. Administration of the P2Y1,12,13 receptor agonist, 2-(methylthio)adenosine 5'-diphosphate trisodium salt hydrate (2-MeSADP), to naïve rats induced neuropathic pain in the tongue, as in lingual nerve crush rats. Co-administration of 2-MeSADP + MRS2395 to naïve rats did not result in hypersensitivity of the tongue. The relative number of CGRP-immunoreactive neurons increased following this co-administration, but to a lesser degree than observed in 2-MeSADP-administrated naïve rats, and the relative number of neurons encircled by pERK1/2-immunoreactive cells did not change. These results suggest that the interaction between activated satellite cells and CGRP-immunoreactive neurons via P2Y12 receptors contributes to neuropathic pain in the tongue associated with lingual nerve injury.

Clinical features of atypical odontalgia; three cases and literature reviews.

BACKGROUND: Atypical odontalgia (AO) is a disease characterized by continuous pain affecting the teeth or tooth sockets after extraction in the absence of any identifiable cause on clinical or radiographic examination. Antidepressants, such as amitriptyline, are reported to be effective in the treatment of AO; however, their efficacy varies depending on the case. In this article, we report three types of AO and discuss its heterogeneity and management. CASE PRESENTATION: In the first case, a 58-year-old woman presented with a heavy, splitting pain in the four maxillary front post-crown teeth, as if they were being pressed from the side. Her symptoms abated with 20 mg of amitriptyline. In the second case, a 39-year-old woman presented with a feeling of heaviness pain on the right side of maxillary and mandibular molar teeth, face, whole palate, and throat. She was unable to function because of her pain. Her symptoms drastically subsided with 3 mg of aripiprazole. In the third case, a 54-year-old woman presented with a tingling sensation on the left mandibular second premolar and first molar, and an uncomfortable feeling on her provisional prosthesis that made it unbearable to keep the caps on. Her symptoms diminished with 2 mg of aripiprazole added to 30 mg of mirtazapine. CONCLUSIONS: AO shows various features and responses to drugs. It is considered not only a purely sensory problem, but also a considerably complex psychological problem, such as rumination about the pain. Investigating the difference in pharmacotherapeutic responses might help to advance the treatment of AO.