Effect of cisplatin on oral ulcer-induced nociception in rats.

OBJECTIVE: The aim of this study is to investigate effects of cisplatin preadministration on oral ulcerative mucositis-induced nociception by using an experimental model of rats. DESIGN: After two rounds of cisplatin administration, oral ulcers developed with topical acetic acid treatment in rats. Spontaneous mouth rubbing behavior was observed as spontaneous nociceptive behavior in a plastic cage. Head-withdrawal behavior was observed as mechanical allodynia by using von Frey test in the oral mucosa of conscious rats. Bacterial invasion and inflammatory cell infiltration into oral ulcerative region and systemic leukocyte phagocytic activity were assessed. RESULTS: Following cisplatin preadministration, oral ulcerative mucositis-induced spontaneous nociceptive behavior was not observed in the model. The preadministration enhanced leukocyte phagocytic activity, leading to reduce bacterial invasion and inflammatory cell infiltration in the oral ulcerative region. In contrast, oral ulcerative mucositis-induced mechanical allodynia was induced. The exaggerated mechanical allodynia in the oral ulcerative region was largely inhibited by topical treatment with the antioxidative drug, ɑ-lipoic acid, or the blocker of N-formyl peptide receptor 1, N-t-butoxycarbonyl-methionyl-leucyl-phenylalanine. CONCLUSIONS: These results suggest that cisplatin preadministration suppresses spontaneous nociception in oral ulcerative region, due to antiinflammatory effects by enhancement of leukocyte phagocytic activity, but exaggerates mechanical allodynia due to oxidative stress with N-formyl peptide receptor 1 activation. The suppression of spontaneous nociception is one of the advantages of cisplatin treatment for head and neck cancer patients although the exaggerated allodynia is a serious symptom.

Cisplatin induces TRPA1-mediated mechanical allodynia in the oral mucosa.

OBJECTIVE: Cisplatin, a platinum-based anticancer drug, produces reactive oxygen species (ROS) in many cell types and induces mechanical allodynia in the hands and/or feet (chemotherapy-induced painful neuropathy: CIPN). In this study, we examined the possibility of inducing neuropathy in the oral region using oral keratinocytes and rats. METHODS: Human oral keratinocytes (HOKs) were used to evaluate ROS generation after cisplatin application by a ROS-reactive fluorescent assay. In rats, after cisplatin administrations (two times), the trigeminal ganglion (TG) was investigated by electron microscopy and quantitative RT-PCR. Using our proprietary assay system, oral pain-related behaviors were observed in cisplatin-treated rats. RESULTS: In rats, cisplatin administration reduced food intake and body weight. In electron microscopic analysis, glycogen granules in the TG were depleted following administration, although organelles were intact. In HOK cells, cisplatin significantly increased ROS generation with cell death, similar to glycolysis inhibitors. Cisplatin administration did not show any effects on Trpa1 mRNA levels in the TG. However, the same procedure induced hypersensitivity to mechanical stimulation and the TRPA1 agonist allyl isothiocyanate in the oral mucosa. Mechanical hypersensitivity was inhibited by the antioxidative drug α-lipoic acid and the TRPA1 antagonist HC-030031, similar to that of the hind paw. CONCLUSION: The present findings suggest that cisplatin induces TRPA1-mediated CIPN due to ROS generation in the oral region. This study will provide a better understanding of persistent oral pain in cancer patients.

Association between sensory processing and dental fear among female undergraduates in Japan.

Objectives: The aim of cross-sectional study was to investigate the association between sensory processing patterns and dental fear among female undergraduates. Material and methods: Three hundred and ten female university students were included in the present study. Dental fear and sensory processing patterns were measured using the Dental Fear Survey and Adolescent/Adult Sensory Profile with other possible confounders, respectively. Sensory processing patterns were categorized into sensory sensitivity, sensory avoidance, low registration and sensation seeking. We conducted structural equation modelling based on the hypothesis that sensory processing directly affects dental fear, including the confounding role of negative experiences with dentistry, autistic traits and the mediating role of trait anxiety. Results: Based on our proposed model, sensory processing patterns, excluding sensation seeking and negative experiences significantly contributed to dental fear (ß = 0.33, p < .001 and ß = 0.32, p < .001, respectively) and autistic traits and trait anxiety did not significantly contribute to dental fear. Conclusions: Extreme sensory processing patterns seem to be associated with a high level of dental fear; thus, the difference in sensory processing might play an important role in the aetiology of dental fear.

Characteristics of diffusion-weighted images and apparent diffusion coefficients of ranulas and other masses in and around the floor of the mouth.

OBJECTIVE: The aim of this study was to evaluate the characteristics of diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) values of ranulas. In addition, to elucidate DWI findings and ADC values of other representative masses in and around the floor of the mouth. STUDY DESIGN: DWI findings and ADC values in 35 patients with ranulas and 33 patients with other masses were retrospectively reviewed with a central focus on cystic masses or lesions that may have cyst-like components in and around the floor of the mouth based on the diagnosis of each respective disease. RESULTS: Ranulas were all well-defined, homogeneous masses with high signal intensity on DWI. The mean ± standard deviation ADC value of the 35 ranulas was 2.59 ± 0.31 × 10-3 mm2/s. There was a significant difference in ADC values between simple and plunging ranulas. On DWI, most other masses were heterogeneous, and most ADC values, except those for thyroglossal duct cysts, hemangiomas, and pleomorphic adenomas, were significantly lower than those for ranulas. CONCLUSIONS: The characteristic DWI and ADC findings of ranulas can be determined accurately, and these data can be significantly useful in the differential diagnosis of many kinds of diseases in and around the oral floor.

Prostanoid-dependent spontaneous pain and PAR2-dependent mechanical allodynia following oral mucosal trauma: involvement of TRPV1, TRPA1 and TRPV4.

Abstract: During dental treatments, intraoral appliances frequently induce traumatic ulcers in the oral mucosa. Such mucosal injury-induced mucositis leads to severe pain, resulting in poor quality of life and decreased cooperation in the therapy. To elucidate mucosal pain mechanisms, we developed a new rat model of intraoral wire-induced mucositis and investigated pain mechanisms using our proprietary assay system for conscious rats. A thick metal wire was installed in the rats between the inferior incisors for one day. In the mucosa of the mandibular labial fornix region, which was touched with a free end of the wire, traumatic ulcer and submucosal abscess were induced on day 1. The ulcer was quickly cured until next day and abscess formation was gradually disappeared until five days. Spontaneous nociceptive behavior was induced on day 1 only, and mechanical allodynia persisted over day 3. Antibiotic pretreatment did not affect pain induction. Spontaneous nociceptive behavior was sensitive to indomethacin (cyclooxygenase inhibitor), ONO-8711 (prostanoid receptor EP1 antagonist), SB-366791, and HC-030031 (TRPV1 and TRPA1 antagonists, respectively). Prostaglandin E2 and 15-deoxyΔ12,14-prostaglandin J2 were upregulated only on day 1. In contrast, mechanical allodynia was sensitive to FSLLRY-NH2 (protease-activated receptor PAR2 antagonist) and RN-1734 (TRPV4 antagonist). Neutrophil elastase, which is known as a biased agonist for PAR2, was upregulated on days 1 to 2. These results suggest that prostanoids and PAR2 activation elicit TRPV1- and TRPA1-mediated spontaneous pain and TRPV4-mediated mechanical allodynia, respectively, independently of bacterial infection, following oral mucosal trauma. The pathophysiological pain mechanism suggests effective analgesic approaches for dental patients suffering from mucosal trauma-induced pain.

Anesthetic Management of a Patient With Takayasu Arteritis.

Takayasu arteritis is a rare chronic progressive panendarteritis involving the aorta and its main branches. Anesthesia in patients with this disease can be complicated by severe uncontrolled hypertension, end-organ dysfunction, and stenosis of major blood vessels. In this case, general anesthesia was induced with sevoflurane and remifentanil without complications. To prevent intraoperative complications, we conducted intubation with a rigid video laryngoscope with careful consideration of the concentrations of analgesics and sedatives used. This case demonstrates the importance of anesthetic techniques for maintaining adequate tissue perfusion without hemodynamic changes in the anesthetic management of patients with Takayasu arteritis.

Distinct TRPV1- and TRPA1-based mechanisms underlying enhancement of oral ulcerative mucositis-induced pain by 5-fluorouracil.

In many patients with cancer, chemotherapy-induced severe oral ulcerative mucositis causes intractable pain, leading to delays and interruptions in therapy. However, the pain mechanism in oral ulcerative mucositis after chemotherapy has not been extensively studied. In this study, we investigated spontaneous pain and mechanical allodynia in a preclinical model of oral ulcerative mucositis after systemic administration of the chemotherapy drug 5-fluorouracil, using our proprietary pain assay system for conscious rats. 5-Fluorouracil caused leukopenia but did not induce pain-related behaviors. After 5-fluorouracil administration, oral ulcers were developed with topical acetic acid treatment. Compared with saline-treated rats, 5-fluorouracil-exposed rats showed more severe mucositis with excessive bacterial loading due to a lack of leukocyte infiltration, as well as enhancements of spontaneous pain and mechanical allodynia. Antibacterial drugs, the lipid A inhibitor polymyxin B and the TRPV1/TRPA1 channel pore-passing anesthetic QX-314, suppressed both the spontaneous pain and the mechanical allodynia. The cyclooxygenase inhibitor indomethacin and the TRPV1 antagonist SB-366791 inhibited the spontaneous pain, but not the mechanical allodynia. In contrast, the TRPA1 antagonist HC-030031 and the N-formylmethionine receptor FPR1 antagonist Boc MLF primarily suppressed the mechanical allodynia. These results suggest that 5-fluorouracil-associated leukopenia allows excessive oral bacterial infection in the oral ulcerative region, resulting in the enhancement of spontaneous pain through continuous TRPV1 activation and cyclooxygenase pathway, and mechanical allodynia through mechanical sensitization of TRPA1 caused by neuronal effects of bacterial toxins. These distinct pain mechanisms explain the difficulties encountered with general treatments for oral ulcerative mucositis-induced pain in patients with cancer and suggest more effective approaches.

Comparison of pain tolerance thresholds of upper limb to identify the most appropriate venipuncture site.

PURPOSE: Venipuncture is often accompanied by pain, which can compromise dental care and foment distrust toward dental care providers. The aim of the present study was to identify sites on the forearm and hand that have the greatest pain tolerance threshold (PTT) during venipuncture. MATERIALS AND METHODS: The PTT was estimated in 20 healthy volunteers using a noninvasive nerve conduction threshold device. The subjects self-stimulated 5 sites (median cubital vein, cephalic vein at the cubitus, basilic vein, cephalic vein at the carpus, and superficial dorsal vein) at 2 kHz, 250 Hz, and 5 Hz. We measured the stimulation intensity before the subject deactivated the device. Differences in the average PTT values at each site were compared using the Kruskal-Wallis and Scheffé tests. P <.05 was considered to indicate statistical significance. RESULTS: The PTT was significantly greater at the superficial dorsal vein than at the basilic vein for all 3 noninvasive nerve conduction threshold frequencies (P < .05). The estimated PTT was significantly greater at the superficial dorsal vein than at the median cubital vein and cephalic vein at the carpus in response to 250-Hz stimulation (P < .05). CONCLUSIONS: The greater PTT of the superficial dorsal vein suggests that venipuncture at this site should result in the lowest pain intensity among all upper limb sites.

A nasal high-flow system prevents hypoxia in dental patients under intravenous sedation.

PURPOSE: Hypoxia is a major complication in dental patients under intravenous sedation (IVS). A nasal high-flow (NHF) system has been reported to achieve effective oxygenation in patients with sleep apnea syndrome. This study investigated the ability of the NHF system to prevent hypoxia in dental patients under IVS. MATERIALS AND METHODS: Thirty patients scheduled for dental treatment under IVS were enrolled. Patients were randomly divided into 3 groups: patients spontaneously breathing oxygen at 5 L/minute through a nasal cannula (NC5 group), patients administered oxygen at 30 L/minute through the NHF system, and patients administered oxygen at 50 L/minute through the NHF system. Hypnosis was induced by bolus administration of midazolam (0.05 mg/kg) followed by continuous administration of propofol (target blood concentration, 1.2 to 2 µg/mL). Noninvasive blood pressure, peripheral capillary oxygen saturation (SpO2), heart rate, and bispectral index values were recorded every 2.5 minutes before the induction of anesthesia. Interventions, such as jaw lifting, were recorded during IVS and arterial blood gas analysis was performed at the end of sedation. Patient and surgeon satisfaction with IVS was evaluated by interview. RESULTS: Minimum SpO2 was lowest in and surgeons were least satisfied with the NC5 group. In addition, interventions were required most frequently in the NC5 group (P < .05). Compared with the NC5 group, use of the NHF system improved partial pressures of oxygen and carbon dioxide in dental patients under IVS (P < .05). CONCLUSIONS: These results suggest that use of the NHF system can prevent hypoxia in dental patients under IVS. Further studies are necessary to determine the appropriate flow rate and indications for NHF in obese patients.

Novel methods of applying direct chemical and mechanical stimulation to the oral mucosa for traditional behavioral pain assays in conscious rats.

BACKGROUND: Stomatitis induces severe and painful hypersensitivity to pungency and physical contact during meals. Many studies have used anesthetized animals to examine evoked nociception in the oral mucosa, but no reports have used traditional behavioral assays to evaluate nociception in conscious animals. NEW METHODS: We developed two new methods of applying chemical or mechanical stimulation directly to the oral mucosa of the mandibular vestibule of conscious rats. Nociceptive evaluations were performed by measuring facial grooming time and the head withdrawal threshold to von Frey stimulations. (1) For the intraoral dropping method, rat mucosa was transiently exposed by hand, and a drop of a pungent solution was applied. (2) For the stable intraoral opening method, rat mucosa was long-term exposed following piercing surgery of the mental skin after habitual training for 2-3 weeks. RESULTS: In the intraoral dropping method, the application of 100 µM capsaicin or 100 mM allyl isothiocyanate prolonged mouth-rubbing time. Capsaicin-induced mouth-rubbing time was further enhanced following the development of an acetic acid-induced ulcer. The stable intraoral opening method enabled stable measurements of the mechanical withdrawal threshold in the oral mucosa of conscious rats. Ulcer development decreased the mechanical threshold, whereas topical lidocaine treatment increased the threshold. COMPARISON WITH EXISTING METHODS: These new methods enable the evaluations of motivational nocifensive behaviors in response to intraoral stimulations without any anesthetic effects. CONCLUSIONS: The intraoral dropping and stable intraoral opening methods can be used in combination with traditional behavioral assays to evaluate nociception in the oral mucosa of conscious rats.

Distinct time courses of microglial and astrocytic hyperactivation and the glial contribution to pain hypersensitivity in a facial cancer model.

Although recent evidence suggests that central glial hyperactivation is involved in cancer-induced persistent pain, the time course of this hyperactivation and the glial contribution to pain hypersensitivity remain unclear. The present study investigated the time-dependent spatial changes of microglial and astrocytic hyperactivation in the trigeminocervical complex, which consists of the medullary (MDH) and upper cervical (UCDH) dorsal horns, and pain-related behaviors in a rat facial cancer model in which Walker 256B-cells are inoculated into the vibrissal pad. In this model, the tumors grew within the vibrissal pad, from which sensory nerve fibers project into the MDH, but did not expand into the infraorbital region, from which fibers project into the UCDH. Nevertheless, mechanical allodynia and thermal hyperalgesia were observed not only in the vibrissal pad but also in the infraorbital region. Western blotting and immunofluorescence studies indicated that microglia were widely activated in the trigeminocervical complex on day 4 and gradually inactivated by day 11. In contrast, astrocytes were only activated in the MDH on day 4; the hyperactivation later expanded into the UCDH. Daily administration of the glial hyperactivation inhibitor propentofylline beginning on day 4 suppressed the glial hyperactivation on later days. Propentofylline treatment largely prevented allodynia/hyperalgesia in the infraorbital region beginning on day 5, although established allodynia/hyperalgesia in the vibrissal pad was less sensitive to the treatment. These results suggest that central glial hyperactivation, transient microglial hyperactivation and persistent astrocytic hyperactivation, contributes to the development of pain hypersensitivity but not to the maintenance of pain in this model.

A rat pain model of facial cancer.

Cancer pain is a very severe problem for patients with advanced or terminal cancer. However, the induction mechanism remains unknown. Orofacial cancer patients often report difficulties in eating and swallowing, different from patients with cancer in other regions. Although several cancer pain animal models have been reported, these models have focused on the sciatic nerve areas. To understand the mechanisms of pain associated with orofacial cancer, we recently created a rat facial cancer model by inoculation of cancer cells into the vibrissal pad. This model provides mechanical allodynia, thermal hyperalgesia, and feeding disorder characteristics, similar to orofacial cancer patients. Hence, this model is useful for the evaluation of cancer pain of the trigeminal nerve area. In this chapter, we describe in detail the generation of a facial cancer pain model of rats by inoculation of Walker carcinosarcoma 256B cells.

Behavioral characteristics and c-Fos expression in the medullary dorsal horn in a rat model for orofacial cancer pain.

It is well known that patients with orofacial cancer suffer from cancer-induced pain which produces feeding difficulties. To understand the mechanisms of pain associated with orofacial cancer, we have recently created a model for rat orofacial cancer by inoculation with Walker carcinosarcoma 256B-cells into the vibrissal pads. The present study used both behavioral and immunohistochemical techniques to investigate changes in pain-related and ingestive behavior, along with c-Fos expression in the medullary dorsal horn which is a site for processing orofacial pain. The tumor mass grew gradually and contacted the nerve trunks within days after the inoculation of tumor cells. Physical difficulties in ingestion were observed after day 10 post-inoculation and facial grooming periods were prolonged. Sensitivities of the inoculated vibrissal pads to mechanical and thermal stimuli were increased on days 4 and 7, suggesting the development of mechanical allodynia and thermal hyperalgesia. Although hyposensitivity to mechanical and thermal stimulation was observed in the inoculated region after day 10, hyperalgesia developed on the margin of the tumor, suggesting that the hypersensitive region spread with growth of tumor mass. In the medullary dorsal horn, the levels of c-Fos immunoreactivity of the ipsilateral side increased significantly on days 4, 7 and 10, supporting the behavioral observations. These results indicate that the rat model shows symptoms similar to those in patients with orofacial cancer, for example, induction of feeding disorder and neuropathic pain.