Antagonist of transient receptor potential melastatin 2 suppresses mechanical hypersensitivity and activation of microglia induced by infraorbital nerve ligation in male rats.

Activation of microglia is known to be involved in neuropathic pain. However, the pathway that regulates the microglial activation is not completely understood. Transient receptor potential (TRP) melastatin 2 (TRPM2), which is part of the TRP superfamily, is reportedly expressed on microglia and is suggested to be involved in neuropathic pain. To explore the effect of a TRPM2 antagonist on orofacial neuropathic pain and the relationship between TRPM2 and the activation of microglia, experiments were conducted using male rats that underwent infraorbital nerve (ION) ligation as orofacial neuropathic pain models. TRPM2 expression was detected on microglia in the trigeminal spinal subnucleus caudalis (Vc). The immunoreactivity of TRPM2 in the Vc increased after ION ligation. Mechanical threshold for head-withdrawal response was measured using von Frey filament, and it decreased after ION ligation. When the TRPM2 antagonist was administered to the ION-ligated rats, the low mechanical threshold for head-withdrawal response increased, and the number of phosphorylated extracellular signal-regulated kinase (pERK)-immunoreactive cells in the Vc decreased. The number of CD68-immunoreactive cells in the Vc also decreased after the administration of the TRPM2 antagonist in the ION-ligated rats. These findings suggest that TRPM2 antagonist administration suppresses hypersensitivity to mechanical stimulation induced by ION ligation and microglial activation, and TRPM2 is also involved in microglial activation in orofacial neuropathic pain.

Estrogen modulation of cortical spreading depression.

BACKGROUND AND AIMS: Cortical spreading depression (CSD), a transient neuronal and glial depolarization that propagates slowly across the cerebral cortex, is the putative electrophysiological event underlying migraine aura and a headache trigger. Migraine is three times more prevalent in women than men, linked to circulating female hormones. High estrogen levels or estrogen withdrawal may be a migraine trigger for many women. We, therefore, aimed to examine whether sex, gonadectomy, and female hormone supplementation and withdrawal affect the susceptibility to CSD. METHODS: To determine CSD susceptibility, we recorded the frequency of CSDs triggered during 2-h topical KCl application in intact or gonadectomized female and male rats, without or with estradiol or progesterone supplementation via daily intraperitoneal injections. Estrogen or progesterone treatment followed by withdrawal was studied in a separate cohort. To take the first step towards identifying potential mechanisms, we studied glutamate and GABAA receptor binding using autoradiography. RESULTS: The CSD frequency in intact female rats was higher than intact male and ovariectomized rats. We did not detect a change in CSD frequency during different stages of the estrous cycle in intact females. Daily estrogen injections for three weeks did not change CSD frequency. However, one-week estrogen withdrawal after two weeks of treatment significantly increased CSD frequency compared with the vehicle group in gonadectomized females. The same protocol of estrogen treatment and withdrawal was ineffective in gonadectomized males. In contrast to estrogen, daily progesterone injections for three weeks elevated CSD susceptibility, and one-week withdrawal after two weeks of treatment partially normalized this effect. Autoradiography did not reveal significant changes in glutamate or GABAA receptor binding density after estrogen treatment and withdrawal. CONCLUSIONS: These data suggest that females are more susceptible to CSD, and sexual dimorphism is abrogated by gonadectomy. Moreover, estrogen withdrawal after prolonged daily treatment enhances CSD susceptibility. These findings may have implications for estrogen-withdrawal migraine, although the latter tends to be without aura.

Anti-calcitonin gene-related peptide antibody attenuates orofacial mechanical and heat hypersensitivities induced by infraorbital nerve injury.

Currently, limited information regarding the role of calcitonin gene-related peptide (CGRP) in neuropathic pain is available. Intracerebroventricular administrations of an anti-CGRP antibody were performed in rats with infraorbital nerve ligation. Anti-CGRP antibody administration attenuated mechanical and heat hypersensitivities induced by nerve ligation and decreased the phosphorylated extracellular signal-regulated kinase expression levels in the trigeminal spinal subnucleus caudalis (Vc) following mechanical or heat stimulation. An increased CGRP immunoreactivity in the Vc appeared after nerve ligation. A decreased CGRP immunoreactivity resulted from anti-CGRP antibody administration. Our findings suggest that anti-CGRP antibody administration attenuates the symptoms of trigeminal neuropathic pain by acting on CGRP in the Vc.

WJOG10517G: a multicenter Phase II study of mFOLFOX6 in gastric cancer patients with severe peritoneal metastases.

Gastric cancer patients with severe peritoneal metastases, defined as massive ascites and/or inadequate oral intake, have been excluded from clinical trials of new treatments due to poor prognosis and tumor-related complications, such as ileus. Based on the results of the JCOG1108/WJOG7312G study, their prognosis when treated with 5-fluorouracil/l-leucovorin or 5-fluorouracil/l-leucovorin plus paclitaxel remained extremely poor in this setting. Retrospective studies have shown the promising efficacy of the modified FOLFOX6 (mFOLFOX6) regimen, with improved ascites and oral intake. Therefore, we planned a Phase II study of mFOLFOX6 in gastric cancer patients with severe peritoneal metastases (jRCTs041180007). The primary end point is overall survival, with an exploratory analysis comparing the findings with those of the JCOG1108/WJOG7312G study using Bayes' theorem. Trial registration Identifier: jRCTs041180007 (jRCTs: the Japan Registry of Clinical Trials).

Dopaminergic Modulation of Orofacial Mechanical Hypersensitivity Induced by Infraorbital Nerve Injury.

While the descending dopaminergic control system is not fully understood, it is reported that the hypothalamic A11 nucleus is its principle source. To better understand the impact of this system, particularly the A11 nucleus, on neuropathic pain, we created a chronic constriction injury model of the infraorbital nerve (ION-CCI) in rats. ION-CCI rats received intraperitoneal administrations of quinpirole (a dopamine D2 receptor agonist). ION-CCI rats received microinjections of quinpirole, muscimol [a gamma-aminobutyric acid type A (GABAA) receptor agonist], or neurotoxin 6-hydroxydopamine (6-OHDA) into the A11 nucleus. A von Frey filament was used as a mechanical stimulus on the maxillary whisker pad skin; behavioral and immunohistochemical responses to the stimulation were assessed. After intraperitoneal administration of quinpirole and microinjection of quinpirole or muscimol, ION-CCI rats showed an increase in head-withdrawal thresholds and a decrease in the number of phosphorylated extracellular signal-regulated kinase (pERK) immunoreactive (pERK-IR) cells in the superficial layers of the trigeminal spinal subnucleus caudalis (Vc). Following 6-OHDA microinjection, ION-CCI rats showed a decrease in head-withdrawal thresholds and an increase in the number of pERK-IR cells in the Vc. Our findings suggest the descending dopaminergic control system is involved in the modulation of trigeminal neuropathic pain.

Age-based prediction of uncuffed tracheal tube size in children to prevent inappropriately large tube selection: a retrospective analysis.

BACKGROUND: This study aims to validate our previously reported prediction technique for uncuffed tracheal tube (TT) sizes in children younger than 2 years of age based on a calculated outer diameter (ODCal, mm) in each patient according to the regression equation ODCal = 0.00223 × age (day) + 4.88 and to investigate a better method to select initial TT sizes to decrease re-intubation frequency, especially since large tubes can damage the trachea. METHODS: We included patients younger than 2 years of age who underwent oral surgery under general anesthesia with tracheal intubation between July 2011 and December 2016 at the Osaka University Dental Hospital. The OD of the actual TT and the age in days were extracted from anesthesia records. Agreement rates, estimated numbers of required tubes, and size reduction frequencies were compared to obtain recommended OD (ODRec) values in 2 selection groups: "average selection" in the range "nearest to the ODCal value (ODCal - 0.35 < ODRec ≤ ODCal + 0.35)" and "safe selection" in the range "nearest to the value below ODCal (ODCal - 0.7 < ODRec ≤ ODCal)". RESULTS: The agreement rates for an ODRec in the average selection and safe selection groups were 60.8 and 55.1%, respectively (P = 0.001). The estimated number of required tubes per patient were 1.40 ± 0.51 and 1.47 ± 0.55 (P < 0.001), respectively. The estimated frequencies of size reductions were 13.3 and 4.0% (P < 0.001), respectively. CONCLUSIONS: Because the size reduction frequency is lower despite a slightly higher number of required TTs, selecting an ODRec based on "safe selection" parameters is desirable to avoid complications due to intubation with larger TTs.

Trigeminal nervous system sensitization by infraorbital nerve injury enhances responses in a migraine model.

Background Although the peripheral and central sensitizations of trigeminal nervous system may be one of the important factors of migraine, the precise mechanism is not fully understood. In this study, we examined the influence of the sensitization of the second division of the trigeminal nerve (V2) by chronic constriction injury (CCI) of the infraorbital nerve (ION) on migraine headache, using the capsaicin-induced migraine model. Methods Male Sprague-Dawley rats were assigned to four groups: (a) sham surgery and topical-dural vehicle application (Sham + Vehicle) group, (b) CCI-ION and topical-dural vehicle application (CCI-ION + Vehicle) group, (c) sham surgery and topical-dural capsaicin application (Sham + Capsaicin) group, (d) CCI-ION and topical-dural capsaicin application (CCI-ION + Capsaicin) group. Behavioral testing and immunohistochemical staining were performed. Results In the behavioral test, the Sham + Capsaicin group showed significantly longer duration of immobilization and shorter duration of exploration compared with the Sham + Vehicle group, which is similar to clinical features of migraine patients. Moreover, CCI-ION enhanced these effects in the CCI-ION + Capsaicin group. Immunohistochemical staining for phospho-extracellular signal-related kinase (pERK) in the trigeminal ganglion (TG) containing first and second divisions of the trigeminal nerve and the trigeminocervical complex (TCC) revealed that pERK expression was significantly increased in the CCI-ION + Capsaicin group compared with the other groups. However, comparing between effects of the peripheral and central sensitizations (in the TG and TCC), from our results, peripheral sensitization would play a much less or not significant role. Conclusions These data demonstrate that the sensitization of V2 could influence the activation and the sensitization of the first division of the trigeminal nerve in the TCC, subsequently exacerbating pain sensation and pain-related behaviors. We have shown for the first time that the existence of the central sensitization of V2 can be an exacerbating factor for migraine related nociceptive thresholds/activation.

Effective Dosage of Midazolam to Erase the Memory of Vascular Pain During Propofol Administration.

Intravenous sedation with propofol is often administered to anxious patients in dental practice. Pain on injection of propofol is a common adverse effect. This study aimed to determine the age-adjusted doses of midazolam required to erase memory of vascular pain of propofol administration and assess whether the Ramsay Sedation Scale (RSS) after the pretreatment of midazolam was useful to predict amnesia of the vascular pain of propofol administration. A total of 246 patients with dental phobia requiring dental treatment under intravenous sedation were included. Patients were classified according to their age: 30s, 40s, 50s, and 60s. Three minutes after administration of a predetermined dose of midazolam, propofol was infused continuously. After completion of the dental procedure, patients were interviewed about the memory of any pain or discomfort in the injection site or forearm. The dosage of midazolam was determined using the Dixon up-down method. The first patient was administered 0.03 mg/kg, and if memory of vascular pain remained, the dosage was increased by 0.01 mg/kg for the next patient, and then if the memory was erased, the dosage was decreased by 0.01 mg/kg. The effective dosage of midazolam in 95% of each age group for erasing the memory of propofol vascular pain (ED95) was determined using logistic analysis. The accuracy of RSS to predict the amnesia of injection pain was assessed by receiver operating characteristic (ROC) analysis. The ED95 of midazolam to erase the memory of propofol vascular pain was 0.061 mg/kg in patients in their 30s, 0.049 mg/kg in patients in their 40s, 0.033 mg/kg in patients in their 50s, and 0.033 mg/kg in patients in their 60s. The area under the ROC curve was 0.31. The ED95 of midazolam required to erase the memory of propofol vascular pain demonstrated a downward trend with age. On the other hand, it was impossible to predict the amnesia of propofol vascular pain using the RSS.

Appropriate sevoflurane concentration to stabilize autonomic activity during intubation with rocuronium in infants: a randomized controlled trial.

BACKGROUND: In infants, sevoflurane is commonly used for induction of anesthesia, following which a muscle relaxant is administered to facilitate tracheal intubation. When rocuronium is used as the muscle relaxant, intubation may be performed before reaching an adequate depth of anesthesia because of its rapid onset. The purpose of this study was to investigate the optimal sevoflurane concentration that would minimize the impact of intubation on hemodynamics and autonomic nervous system (ANS) activity in infants. METHODS: Sixty-one infants aged 1-6 months, undergoing cleft lip repair, were enrolled. Patients were randomly assigned to three end-tidal sevoflurane concentration (E'Sevo) groups, 3%, 4% and 5%. Anesthesia was induced with 5% sevoflurane with 100% oxygen, and rocuronium (0.6 mg/kg) was administered. The concentration of sevoflurane was adjusted to the predetermined concentration in each group. Mechanical pressure control ventilation via a face mask was commenced. Five minutes after E'Sevo became stable at the predetermined concentration, tracheal intubation was performed. Immediately after tracheal intubation, ventilation was restarted at the same ventilator settings and continued for 150 seconds. Heart rate (HR) and mean arterial pressure (MAP) were measured 5 times in the 150 seconds after intubation. Normalized units (nu) of high frequency (HF: 0.04-0.15 Hz) and the ratio of low frequency (LF: 0.15-0.4 Hz) to HF components (LF/HF) of HR variability were calculated by MemCalc/Tonam2C™. Normalized units of HF (HFnu) and LF/HF reflect cardiac parasympathetic and sympathetic activity, respectively. RESULTS: After intubation, HR increased slightly in all groups and MAP increased by 9.2% in the E'Sevo-3% group. LF/HF increased (p < 0.01) and HFnu decreased (p < 0.01) in all groups 30 seconds after intubation. HFnu was lower (p < 0.001) and LF/HF was higher (p = 0.007) in the E'Sevo-3% group than in E'Sevo-5% group. ANS responses to intubation were reduced in a dose-dependent manner. CONCLUSIONS: Sympathomimetic and parasympatholytic responses to intubation in the E'Sevo-3% group were much greater than those in the E'Sevo-5% group. During tracheal intubation in infants, 4% or 5% sevoflurane is appropriate for prevention of sympathetic hyperactivation and maintenance of ANS balance as compared to 3% sevoflurane, when a muscle relaxant is co-administered. TRIAL REGISTRATION: The study was registered at UMIN-CTR ( UMIN000009933).

A prospective, randomized controlled trial of conscious sedation using propofol combined with inhaled nitrous oxide for dental treatment.

PURPOSE: Adverse reactions during propofol sedation include a decrease in arterial blood pressure, propofol-induced pain on injection, and airway complications. The purpose of this study was to investigate whether combined use of intravenous propofol and inhaled nitrous oxide could decrease the hypotensive and other adverse effects of propofol. PATIENTS AND METHODS: We designed and implemented a prospective, randomized controlled trial. Patients undergoing dental procedures requiring intravenous sedation were randomly allocated to 2 groups: group P comprised those receiving sedation with propofol alone, and group N+P comprised those receiving sedation with 40% nitrous oxide inhalation and propofol. During the dental procedures, the sedation level was maintained at an Observer's Assessment of Alertness/Sedation scale score of 4 by adjusting propofol's target plasma concentration. Nitrous oxide inhalation was the predictor variable, whereas the hemodynamic changes, amount and concentration of propofol, and adverse events were the outcome variables. RESULTS: Eighty-eight patients were successfully analyzed without any complications. The total amount of propofol was significantly less in group N+P (249.8 ± 121.7 mg) than in group P (310.3 ± 122.4 mg) (P = .022), and the mean concentration of propofol was significantly less in group N+P (1.81 ± 0.34 µg/mL) than in group P (2.05 ± 0.44 µg/mL) (P = .006). The mean blood pressure reduction in group N+P (11.0 ± 8.0 mm Hg) was significantly smaller than that in group P (15.8 ± 10.2 mm Hg) (P = .034). Pain associated with the propofol injection and memory of the procedure were less in group N+P (P = .011 and P = .048, respectively). Nitrous oxide did not affect respiratory conditions or recovery characteristics. CONCLUSIONS: The results of this study suggest that nitrous oxide inhalation combined with propofol sedation attenuates the hypotensive effect and pain associated with propofol injections, along with potentiating the amnesic effect.

Considerations during intravenous sedation in geriatric dental patients with dementia.

OBJECTIVES: We retrospectively assessed the usability and precautions required during intravenous sedation (IVS) for dental treatment in geriatric outpatients with dementia. MATERIALS AND METHODS: We investigated the intraoperative complications in 65 cases (25 geriatric dental patients with dementia) under IVS, from the standpoint of local anesthesia usage, water usage during treatment, and content of treatment. RESULTS: Circulatory complications occurred in 46.2 % and respiratory complications in 52.3 % of all cases (n = 65). Bradycardia occurred in 13.8 % and hypotension in 12.3 % of cases in the former, while coughing spells occurred in 41.5 % and snoring in 16.9 % of cases in the latter. Many of the local anesthesia usage cases did not require water usage, such as during tooth extraction (p < 0.0001). Water usage cases, such as for caries treatment, needed longer sedation and treatment times, resulting in more propofol usage (p < 0.001, p < 0.0001, and p < 0.01, respectively). Many coughing spells developed in the water usage cases (p < 0.05). 81.8 % of snoring and 63.3 % of circulatory complications, such as hypotension and bradycardia, developed in the tooth extraction cases (p < 0.05). CONCLUSIONS: All the scheduled dental treatments in dementia patients were smoothly performed under IVS. However, stringent attention should be paid to the prevention of aspiration of fluids retained in the pharynx, airway obstruction due to therapeutic maneuvers, respiratory inhibition by sedatives, and hemodynamic fluctuations caused by invasive procedures under local anesthesia. CLINICAL RELEVANCE: In the future, with the growing need for dental procedures in dementia patients, dentists will require training in the general management of such patients.

Effects of hippocampal damage on pain perception in a rat model of Alzheimer's disease induced by amyloid-ß and ibotenic acid injection into the hippocampus.

Patients with Alzheimer's disease (AD) present with a variety of symptoms, including core symptoms as well as behavioral and psychological symptoms. Somatosensory neural systems are generally believed to be relatively unaffected by AD until late in the course of the disease; however, somatosensory perception in patients with AD is not yet well understood. One factor that may complicate the assessment of somatosensory perception in humans centers on individual variations in pathological and psychological backgrounds. It is therefore necessary to evaluate somatosensory perception using animal models with uniform status. In the current study, we focused on the hippocampus, the primary site of AD. We first constructed a rat model of AD model using bilateral hippocampal injections of amyloid-ß peptide 1-40 and ibotenic acid; sham rats received saline injections. The Morris water maze test was used to evaluate memory impairment, and the formalin test (1 % or 4 % formalin) and upper lip von Frey test were performed to compare pain perception between AD model and sham rats. Finally, histological and immunohistochemical methods were used to evaluate tissue damage and neuronal activity, respectively, in the hippocampus. AD model rats showed bilateral hippocampal damage and had memory impairment in the Morris water maze test. Furthermore, AD model rats exhibited significantly less pain-related behavior in phase 2 (the last 50 min of the 60-minute observation) of the 4 % formalin test compared with the sham rats. However, no significant changes were observed in the von Frey test. Immunohistochemical observations of the trigeminal spinal subnucleus caudalis after 4 % formalin injection revealed significantly fewer c-Fos-immunoreactive cells in AD model rats than in sham rats, reflecting reduced neuronal activity. These results indicate that AD model rats with hippocampal damage have reduced responsiveness to persistent inflammatory chemical stimuli to the orofacial region.

Changes in the analgesic mechanism of oxytocin can contribute to hyperalgesia in Parkinson's disease model rats.

Pain is a major non-motor symptom of Parkinson's disease (PD). Alterations in the descending pain inhibitory system (DPIS) have been reported to trigger hyperalgesia in PD patients. However, the underlying mechanisms remain unclear. In the current study, dopaminergic nigrostriatal lesions were induced in rats by injecting 6-hydroxydopamine (6-OHDA) into their medial forebrain bundle. The neural mechanisms underlying changes in nociception in the orofacial region of 6-OHDA-lesioned rats was examined by injecting formalin into the vibrissa pad. The 6-OHDA-lesioned rats were seen to exhibit increased frequency of face-rubbing and more c-Fos immunoreactive (c-Fos-IR) cells in the trigeminal spinal subnucleus caudalis (Vc), confirming hyperalgesia. Examination of the number of c-Fos-IR cells in the DPIS nuclei [including the midbrain ventrolateral periaqueductal gray, the locus coeruleus, the nucleus raphe magnus, and paraventricular nucleus (PVN)] showed that 6-OHDA-lesioned rats exhibited a significantly lower number of c-Fos-IR cells in the magnocellular division of the PVN (mPVN) after formalin injection compared to sham-operated rats. Moreover, the 6-OHDA-lesioned rats also exhibited significantly lower plasma oxytocin (OT) concentration and percentage of oxytocin-immunoreactive (OT-IR) neurons expressing c-Fos protein in the mPVN and dorsal parvocellular division of the PVN (dpPVN), which secrete the analgesic hormone OT upon activation by nociceptive stimuli, when compared to the sham-operated rats. The effect of OT on hyperalgesia in 6-OHDA-lesioned rats was examined by injecting formalin into the vibrissa pad after intracisternal administration of OT, and the findings showed a decrease in the frequency of face rubbing and the number of c-Fos-IR cells in the Vc. In conclusion, these findings confirm presence of hyperalgesia in PD rats, potentially due to suppression of the analgesic effects of OT originating from the PVN.

Cough reflex under intravenous sedation during dental implant surgery is more frequent during procedures in the maxillary anterior region.

PURPOSE: The present study was performed to evaluate the incidence of cough episodes and the association between cough episodes and patient-related and site-specific parameters during implant surgery when performed under intravenous sedation. MATERIALS AND METHODS: One hundred forty-seven patients scheduled for dental implant surgeries under intravenous sedation were enrolled in this study. Heart rate, blood pressure, percutaneous oxygen saturation, and bispectral index were monitored. Sedation was induced intravenously by a bolus administration of midazolam and maintained by a continuous administration of propofol. Sedation level was adjusted to achieve scores of 3 to 4 on the Ramsay Sedation Scale. Surgical procedures were divided into 11 stages. Implant sites were labeled as right maxillary molar, maxillary anterior, left maxillary molar, right mandibular molar, mandibular anterior, and left mandibular molar sites. When coughing occurred, heart rate, blood pressure, percutaneous oxygen saturation, bispectral index, procedure being performed, and surgical site being stimulated were recorded. RESULTS: One hundred seventy-two cough episodes were observed in 97 patients (66%). Cough episodes occurred during all stages of surgery but were substantially more frequent during preparation of the implant site. The incidence of cough episodes was significantly higher at the maxillary anterior site and lowest at the right mandibular molar areas. CONCLUSION: These findings suggest that difficulties in swallowing and in the suction of intraoral fluids have variable effects at different surgical sites. Careful suction of intraoral water and an appropriate sedation level are required, especially in procedures in the maxillary anterior region.

Initial loading of dexmedetomidine and continuous propofol sedation for prevention of delayed recovery: A randomized controlled trial.

BACKGROUND: Sedation with continuous dexmedetomidine and bolus midazolam administration provides a lower incidence of unacceptable patient movement during procedures but requires a longer recovery time. The authors aimed to compare recovery time and unacceptable patient movement during sedation with initial loading of dexmedetomidine followed by continuous propofol infusion with those during sedation with continuous dexmedetomidine and bolus midazolam administration. METHODS: In this prospective randomized controlled trial, 54 patients undergoing dental surgery and requiring intravenous sedation were assigned to either the dexmedetomidine and propofol group (n = 27, dexmedetomidine administered at 6 µg/kg/h for 5 minutes, followed by continuous propofol infusion using a target-controlled infusion) or the dexmedetomidine and midazolam group (n = 27, dexmedetomidine administered at 0.2-0.7 µg/kg/h continuously after the same initial loading dose with bolus midazolam). A bispectral index of 70 through 80 was maintained during the procedure. Patient movement that interfered with the procedure and time from the end of sedation to achieving a negative Romberg sign were assessed. RESULTS: Times from the end of sedation to achieving a negative Romberg sign in the dexmedetomidine and propofol group (median, 14 minutes [interquartile range, 12-15 minutes]) were significantly shorter (P < .001) than in the dexmedetomidine and midazolam group (median, 22 minutes [interquartile range, 17.5-30.5 minutes]). The incidence of unacceptable patient movement was comparable between groups (n = 3 in the dexmedetomidine and propofol group, n = 4 in the dexmedetomidine and midazolam group; P = .999). CONCLUSIONS: Sedation with a single loading dose of dexmedetomidine followed by continuous propofol infusion can prevent delayed recovery without increasing unacceptable patient movement. PRACTICAL IMPLICATIONS: The combination of dexmedetomidine and propofol may provide high-quality sedation for ambulatory dental practice. This clinical trial was registered in the University Hospital Medical Information Network Clinical Trials Registry. The registration number is UMIN000039668.

Genetic and hormonal factors modulate spreading depression and transient hemiparesis in mouse models of familial hemiplegic migraine type 1.

Familial hemiplegic migraine type 1 (FHM1) is an autosomal dominant subtype of migraine with aura that is associated with hemiparesis. As with other types of migraine, it affects women more frequently than men. FHM1 is caused by mutations in the CACNA1A gene, which encodes the alpha1A subunit of Cav2.1 channels; the R192Q mutation in CACNA1A causes a mild form of FHM1, whereas the S218L mutation causes a severe, often lethal phenotype. Spreading depression (SD), a slowly propagating neuronal and glial cell depolarization that leads to depression of neuronal activity, is the most likely cause of migraine aura. Here, we have shown that transgenic mice expressing R192Q or S218L FHM1 mutations have increased SD frequency and propagation speed; enhanced corticostriatal propagation; and, similar to the human FHM1 phenotype, more severe and prolonged post-SD neurological deficits. The susceptibility to SD and neurological deficits is affected by allele dosage and is higher in S218L than R192Q mutants. Further, female S218L and R192Q mutant mice were more susceptible to SD and neurological deficits than males. This sex difference was abrogated by ovariectomy and senescence and was partially restored by estrogen replacement, implicating ovarian hormones in the observed sex differences in humans with FHM1. These findings demonstrate that genetic and hormonal factors modulate susceptibility to SD and neurological deficits in FHM1 mutant mice, providing a potential mechanism for the phenotypic diversity of human migraine and aura.

Small bolus of esmolol effectively prevents sodium nitroprusside-induced reflex tachycardia without adversely affecting blood pressure.

PURPOSE: Hypotensive anesthesia with sodium nitroprusside (SNP) often is associated with reflex tachycardia. The purpose of this study was to investigate whether a small bolus of esmolol could counteract SNP-induced reflex tachycardia and sympathetic activation without affecting blood pressure. MATERIALS AND METHODS: Using a time-series study design, 27 healthy young patients scheduled for mandibular osteotomy were enrolled in this study. General anesthesia was maintained with 2% sevoflurane and 67% nitrous oxide in oxygen. SNP was administered to decrease the mean arterial pressure to 55 to 65 mm Hg. When heart rate (HR) increased reflexively to higher than 95 beats/min from SNP-induced hypotension, esmolol 0.5 mg/kg was given. Blood pressure and HR were measured, and the low-frequency component (0.04 to 0.15 Hz) of systolic blood pressure variability and high-frequency component (0.15 to 0.4 Hz) of HR variability were calculated to evaluate the autonomic condition. Data were analyzed using 1-way analysis of variance after multiple comparisons or t test. P < .05 was considered statistically significant. RESULTS: Of the 27 patients analyzed, 19 patients (70%) required esmolol. In these patients, SNP caused an increase in the low-frequency component of systolic blood pressure variability and a decrease in the high-frequency component of HR variability, leading to tachycardia (HR range, 95.9 ± 7.3 to 106.7 ± 7.4 beats/min; P < .001). Esmolol suppressed the effects of SNP on the low-frequency component of systolic blood pressure variability and high-frequency component of HR variability, resulting in an immediate decrease in HR to 86.9 ± 6.2 beats/min (P < .001), whereas mean arterial pressure remained unchanged. CONCLUSIONS: A small bolus of esmolol can suppress reflex tachycardia without significantly changing mean arterial pressure. Thus, esmolol restores the autonomic imbalance induced by SNP during hypotensive anesthesia.

Oxcarbazepine does not suppress cortical spreading depression.

BACKGROUND: Cortical spreading depression is the electrophysiological substrate of migraine aura, and may trigger headache. Recently, chronic treatment with five migraine prophylactic drugs was shown to suppress cortical spreading depression, implicating spreading depression as a common therapeutic target in migraine prophylaxis. MATERIALS AND METHODS: In order to assess the negative predictive value of spreading depression susceptibility as a preclinical drug screening tool, we tested oxcarbazepine, an anti-epileptic ineffective in migraine prophylaxis. Valproate served as the positive control. Cortical spreading depression susceptibility was measured in rats using topical KCl or electrical stimulation. RESULTS: Oxcarbazepine did not suppress spreading depression either after a single dose or after daily treatment for 5 weeks. As previously shown, valproate suppressed spreading depression susceptibility after chronic dosing, while a single dose was ineffective. CONCLUSIONS: These data provide further support for spreading depression as a relevant target in migraine prophylaxis, and demonstrate the predictive utility of employed spreading depression models.

Adiponectin prevents cerebral ischemic injury through endothelial nitric oxide synthase dependent mechanisms.

BACKGROUND: Adiponectin is a fat-derived plasma protein that has beneficial actions on cardiovascular disorders. A low level of plasma adiponectin is associated with increased mortality after ischemic stroke; however, the causal role of adiponectin in ischemic stroke is unknown. METHODS AND RESULTS: To explore the role of adiponectin in the development of acute cerebral injury, we subjected adiponectin-deficient (APN-KO) and wild-type (WT) mice to 1 hour of middle cerebral artery occlusion followed by 23 hours of reperfusion. APN-KO mice exhibited enlarged brain infarction and increased neurological deficits after ischemia-reperfusion compared with WT mice. Conversely, adenovirus-mediated supplementation of adiponectin significantly reduced cerebral infarct size in WT and APN-KO mice. APN-KO mice showed decreased cerebral blood flow during ischemia by laser speckle flowmetry methods. Adiponectin colocalized within the cerebral vascular endothelium under transient ischemic conditions by immunohistochemical analysis. Phosphorylation of endothelial nitric oxide synthase in ischemic brain tissues and the production of nitric oxide metabolites in plasma were attenuated in APN-KO mice compared with WT mice. Adenovirus-mediated administration of adiponectin stimulated endothelial nitric oxide synthase phosphorylation and nitric oxide metabolites during cerebral ischemia in both WT and APN-KO mice. Neuronal nitric oxide synthase expression during ischemia did not differ between WT and APN-KO mice. Adenovirus-mediated delivery of adiponectin did not affect brain infarction in mice deficient in endothelial nitric oxide synthase. CONCLUSIONS: These data provide causal evidence that adiponectin exerts a cerebroprotective action through an endothelial nitric oxide synthase-dependent mechanism. Adiponectin could represent a molecular target for the prevention of ischemic stroke.

Bilateral Parkinson's disease model rats exhibit hyperalgesia to subcutaneous formalin administration into the vibrissa pad.

We bilaterally injected 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle of rats and developed bilateral Parkinson's disease (PD) model rats in order to experimentally investigate the neural mechanisms underlying the alteration of nociception in the orofacial region of patients with PD. We explored the effects of dopamine depletion on nociception by investigating behavioral responses (face rubbing) triggered by subcutaneous administration of formalin into the vibrissa pad. We also assessed the number of c-Fos-immunoreactive (c-Fos-IR) cells in the superficial layers of the trigeminal spinal subnucleus caudalis (Vc). Subcutaneous formalin administration evoked a two-phase increase in face rubbing. We observed the first increase 0-5 min after formalin administration (first phase) and the second increase 10-60 min after administration (second phase). The number of face rubbing behaviors of 6OHDA-injected rats did not significantly change compared with saline-injected rats in both phases. Significant increase of c-Fos-IR cells in the Vc was found in 6-OHDA-injected rats after formalin administration compared with those in saline-injected rats after formalin administration. We also assessed expression of c-Fos-IR cells in the paraventricular nucleus (PVN), and significant decrease of c-Fos-IR cells in the PVN of 6-OHDA-injected rats was found. Taken together, these findings suggest that bilateral dopaminergic denervation evoked by 6-OHDA administration causes hyperalgesia in the trigeminal region and the PVN may be involved in the hyperalgesia.