Microglial activation involved in morphine tolerance is not mediated by toll-like receptor 4.

PURPOSE: Morphine is a powerful analgesic but its effect is often diminished owing to the development of tolerance. It has been suggested that morphine activates microglia through its action on the toll-like receptor 4 (TLR4) in the spinal cord, leading to suppression of the morphine effect. However, it has not been examined whether the development of morphine tolerance is affected by the deletion and mutation of the TLR4 gene. METHODS: Mice were treated with morphine (60 mg/kg) or vehicle once daily for five consecutive days to induce morphine tolerance, which was assessed by the tail-flick test before and after the treatment period. The effect of the microglial inhibitor minocycline, and the effect of TLR4 mutation (C3H/HeJ mouse) and deletion (TLR4-knockout mouse) on the development of morphine tolerance were tested. The expression of the microglial activation marker, CD11b, in the spinal cords of TLR4-knockout and wild-type mice after morphine treatment for 5 days was assessed by reverse-transcription polymerase chain reaction. RESULTS: Minocycline attenuated the development of morphine tolerance in mice. Mutation or deletion of the TLR4 gene did not significantly affect the development of morphine tolerance. CD11b mRNA expression was increased after morphine treatment both in TLR4-knockout and wild-type mice. CONCLUSION: Microglial activation caused by a mechanism independent of TLR4 is involved in the development of morphine tolerance. Further studies are necessary to clarify the cellular mechanisms of morphine-induced microglial activation.

[Safety in general anesthesia for ambulatory electroconvulsive therapy].

BACKGROUND: Ambulatory electroconvulsive therapy (ECT) is prevailing nowadays because of its lower cost and less disruption of the patient's social activity. We evaluated the safety and recovery profiles of general anesthesia for acute-phase or continuation/maintenance ambulatory ECT. METHODS: Forty outpatients with a mean age of 56 years for the management of mental disorders were reviewed. A total of 762 bilateral ECT procedures were performed under general anesthesia using propofol/ thiopental/sevoflurane and suxamethonium. RESULTS: During anesthesia, hypertension and tachycardia occurred in 281 (37%) and 214 procedures (28%), respectively. During post-anesthesia care unit stay, the medication most used was oxygen in 161 procedures (21%), and confusion and headache occurred in 54 procedures (7%) and 39 procedures (5%), respectively. No patients required unplanned hospital admission. Mean stay time in the day surgery unit was 172 min. Two ECT treatments (0.3%) in 2 patients needed unplanned return to our hospital within 24 hr after ECT due to worsening of their psychiatric conditions. CONCLUSIONS: General anesthesia for ambulatory ECT with our protocol was proven to be safe without causing serious complications.

Monitored anesthesia care with dexmedetomidine of a patient with severe pulmonary arterial hypertension for inguinal hernioplasty.

The presence of severe pulmonary arterial hypertension (PAH) is a significant risk factor of major perioperative cardiovascular complications in patients undergoing even non-cardiac surgery under anesthetic management. The most important aspect of perioperative care of PAH patients is to avoid pulmonary hypertensive crisis, which can be induced by alveolar hypoxia, hypoxemia, hypercarbia, metabolic acidosis, airway manipulations, and activation of the sympathetic nervous system by noxious stimuli. We report a case of successful monitored anesthesia care supplemented by dexmedetomidine for inguinal hernioplasty of a patient with severe PAH secondary to congenital heart disease.

Pituitary apoplexy during general anesthesia in beach chair position for shoulder joint arthroplasty.

Pituitary apoplexy is a rare but potentially life-threatening clinical syndrome caused by the sudden enlargement of pituitary adenoma secondary to infarction and/or hemorrhage. It may be the first presentation of previously undiagnosed pituitary adenoma. Although various precipitating factors of pituitary apoplexy are indicated, the pathogenesis remains unknown. In this report, we describe for the first time a case of pituitary apoplexy developed explicitly during general anesthesia supplemented with interscalene brachial plexus block in beach chair or barbershop position for shoulder joint arthroplasty.

[Morbidly obese patient with a huge ovarian tumor who was intubated while awake using airway scope in lateral decubitus position].

A morbidly obese woman with a huge ovarian tumor was scheduled to undergo tumor resection under general anesthesia. Under slight sedation with midazolam and fentanyl, a tracheal tube was inserted smoothly using Pentax-AWS Airway Scope, and general anesthesia was thereafter maintained by sevoflurane. To avoid circulatory collapse and reexpansion pulmonary edema, the content of the huge ovarian tumor was aspirated through a small drainage tube to reduce volume and weight of the tumor. Then resection of the ovarian tumor and abdominal wall tissue was performed in supine position. Periooperative course was uneventful.

The radical scavenger edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) reacts with a pterin derivative and produces a cytotoxic substance that induces intracellular reactive oxygen species generation and cell death.

Cytotoxic effects of the combined use of edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a radical scavenger and an approved medicine for acute brain infarction in Japan, with a pterin derivative, were examined in vitro. When pancreatic cancer cell line Panc-1 cells were incubated with 50 to 400 microM of a pterin derivative, 2-(N,N-dimethylaminomethyleneamino)-6-formyl-3-pivaloylpteridine-4-one (DFP), and the equivalent dose of edaravone, reactive oxygen species (ROS), were generated, and cell death was induced. ROS generation and the loss of mitochondrial membrane potential (MMP) preceding cell death were simultaneously monitored using time-lapse microscopy with an ROS-sensitive dye and a probe to monitor MMP, respectively. Cell death was also estimated quantitatively by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. ROS generation and cell death were prominent when more than 100 microM of each agent was used in combination, whereas the sole use of each agent did not show any effects even at the highest dose, 400 microM. Chemical analysis revealed that DFP and edaravone react immediately in aqueous solution and produce a new compound named DFP-E. DFP-E chemically reacted with NADH much faster than DFP and generated ROS, and biologically, it was much more cell-permeable than DFP. These findings collectively indicated that the combined use of DFP with edaravone produced DFP-E, which caused intracellular ROS generation and cell death. Cell death was observed in normal cells, and edaravone reacted with another pterin derivative to yield an ROS-generating compound. As a result, care should be taken with the clinical use of edaravone when pterin derivatives stay in the body.

Potentiation of cyclic AMP-mediated proopiomelanocortin gene promoter activity by calcium channel blockers in a pituitary cell line.

Although it is known that the expression of proopiomelanocortin, a precursor protein of adrenocorticotropic hormone, can be affected by a variety of drugs, the effects of calcium channel blockers have not been studied. This study examined the effect of calcium channel blockers on proopiomelanocortin gene expression. Mouse pituitary tumor cells stably transfected with approximately 0.7 kb of the rat proopiomelanocortin 5' promoter-luciferase fusion gene were stimulated by potassium chloride, corticotropin-releasing hormone (CRH) or forskolin, in the presence or absence of calcium channel blockers (nifedipine, verapamil and diltiazem). Assessments were made of proopiomelanocortin gene promoter activity and cyclic adenosine 3',5'-monophosphate (cyclic AMP) efflux. A dose-dependent enhancement of CRH- or forskolin-stimulated proopiomelanocortin promoter activity was observed with nifedipine and verapamil, but not diltiazem. Cyclic AMP efflux induced by CRH or forskolin was also enhanced by nifedipine and verapamil. In the presence of isobutylmethylxanthine, a phosphodiesterase inhibitor, enhancement of proopiomelanocortin promoter activity and cyclic AMP efflux by nifedipine and verapamil was not observed. It was concluded that the inhibition of phosphodiesterase is a probable mechanism for the effect of nifedipine and verapamil on CRH or forskolin induction of proopiomelanocortin gene expression.

Enhancement of proopiomelanocortin gene promoter activity by local anesthetics in a pituitary cell line.

BACKGROUND AND OBJECTIVES: Corticotropin-releasing hormone (CRH) induces gene expression of proopiomelanocortin, a precursor protein of adrenocorticotropic hormone and beta-endorphin, by elevating intracellular cyclic adenosine 3',5'-monophosphate (cyclic AMP) level in anterior pituitary cells and immune cells. CRH-induced proopiomelanocortin gene expression plays an important role in stress responses and is affected by a variety of drugs, but it is not known whether local anesthetics can directly affect the gene expression. We hypothesized that local anesthetics may directly affect proopiomelanocortin gene expression and can modulate production of adrenocorticotropic hormone and beta-endorphin. METHODS: The authors used mouse pituitary tumor cells stably transfected with approximately 0.7 kilobases of the rat proopiomelanocortin 5' promoter linked with the luciferase gene. In the presence or absence of local anesthetics (lidocaine, mepivacaine, bupivacaine, and ropivacaine), cells were stimulated by CRH or forskolin. After stimulation, proopiomelanocortin gene promoter activity was assessed as luciferase activity, and cyclic AMP efflux was measured by enzyme immunoassay. RESULTS: CRH- or forskolin-stimulated proopiomelanocortin promoter activity was significantly enhanced by local anesthetics. Cyclic AMP efflux induced by CRH was not significantly increased by local anesthetics. CONCLUSIONS: It was concluded that local anesthetics potentiate the effect of CRH or forskolin on proopiomelanocortin promoter activity without changing the intracellular cyclic AMP level. It might be possible that transcriptional regulation mediated by cyclic AMP is also enhanced by local anesthetics in the other cells.