Dual effects of melatonin on barbiturate-induced narcosis in rats

Melatonin affects the circadian sleep/wake cycle, but it is not clear whether it may influence drug-induced narcosis. Sodium thiopenthal was administered intraperitoneally into male rats pre-treated with melatonin (0.05, 0.5, 5 and 50 mg/kg). Melatonin pre-treatment affected in a dual manner barbiturate narcosis, however, no dose-effect correlation was found. In particular, low doses reduced the latency to and prolonged the duration of barbiturate narcosis. In contrast, the highest dose of melatonin (50 mg/kg) caused a paradoxical increase in the latency and produced a sustained reduction of the duration of narcosis, and a reduction in mortality rate. Melatonin 0.5 and 5 mg/kg influenced the duration but not the latency of ketamine- or diazepam-induced narcosis. Thus, the dual action of melatonin on pharmacological narcosis seems to be specific for the barbiturate mechanism of action.     

Inhibitory effect of ketamine on phosphorylation of the extracellular signal-regulated kinase1/2 following brain ischemia and reperfusion in rats with hyperglycemia

To determine if the inhibitory effects of ketamine on the extracellular signal-regulated kinase (ERK) 1/2 are involved in reduction of the hyperglycemia-exaggerated cerebral ischemic lesion, rats with normoglycemia, hyperglycemia, or hyperglycemia supplemented with ketamine were subjected to 15 min of forebrain ischemia, and then, reperfusion for 0.5, 1, and 3h. Phosphorylation of ERK1/2 in the brain tissues was assessed by immunohistochemistry and Western blot analysis. In rats with normoglycemia, we demonstrated a moderate increase of the ERK1/2 phosphorylation in the cingulum cortex and hippocampus CA3 following an ischemic intervention. It quickly dropped to control levels after reperfusion for 0.5h. In rats with hyperglycemia, however, the increase of the ERK1/2 phosphorylation in these areas was significantly higher in all animals reperfused. The neuronal death, detected by the TdT-mediated-dUTP nick end labeling assays, was found in the cingulum cortex (5.23+/-2.34, per high power feild) and hippocampus CA3 areas (6.29+/-3.68, per 1mm(2)) in hyperglycemic group after reperfusion for 3h. With ketamine treatment, the ERK1/2 phosphorylation in cingulum cortex and hippocampus CA1 and CA3 areas was found to be the same as that in normoglycemia rats. Our results suggest that hyperglycemia may increase the ischemic insult through modulation of the signal transduction pathways involving ERK1/2. The inhibitory effects of ketamine on the hyperglycemia-activated ERK1/2 phosphorylation are probably through inhibition of the N-methyl d-aspartate-mediated calcium influx, which subsequently reduce the hyperglycemia-exaggerated cerebral damage.     

Effect of ketamine on apoptosis by energy deprivation in astroglioma cells using flow cytometry system

Apoptosis is a programmed, physiologic mode of cell death that plays an important role in tissue homeostasis. As for the central nervous system, ischemic insults can induce pathophysiologic cascade of apoptosis in neurophils. Impairment of astrocyte functions during brain ischemia can critically influence neuron survival by neuronglia interactions. We aimed to elucidate the protective effect of ketamine on apoptosis by energy deprivation in astrocytes. Ischemic insults was induced with iodoacetate/ carbonylcyanide m-chlorophenylhydrazone (IAA/CCCP) 1.5 mM/20 microm or 150 microm/2 microm for 1 hr in the HTB-15 and CRL-1690 astrocytoma cells. Then these cells were reperfused with normal media or ketamine (0.1 mM) containing media for 1 hr or 24 hr. FITC-annexin-V staining and propidium iodide binding were determined by using flow cytometry. Cell size and granularity were measured by forward and side light scattering properties of flow cytometry system, respectively. An addition of ketamine during reperfusion increased the proportion of viable cells. Ketamine alleviated cell shrinkage and increased granularity during the early period, and ameliorated cell swelling during the late reperfusion period. Ketamine may have a valuable effect on amelioration of early and late apoptosis in the astrocytoma cells, even though the exact mechanism remains to be verified.     

Ketamine inhibits LPS-induced calcium elevation and NF-kappa B activation in monocytes

Objective:To investigate whether ketamine could inhibit lipopolysaccharide (LPS)-induced intracellular calcium elevation and NF-kappa B activation in monocytes. Materials and methods:Isolated rat monocytes were challenged with 10 g/ml LPS with or without the presence of various concentrations of ketamine (10, 100, 1000 M). Intracellular calcium was monitored by laser confocal microscopy. NF-kappa B activity of the nuclear extracts of monocytes was analyzed by electrophoretic mobility shift assay (EMSA). Results:LPS provoked a significant calcium elevation and enhanced NF-kappa B activity in monocytes. Ketamine above concentration of 100 M inhibited endotoxin-induced intracellular calcium elevation and NF-kappa B activity. Ketamine itself had no effect on either of them. Conclusions:These findings suggest that ketamine could suppress NF-kappa B in monocytes exposed to endotoxin, and this anti-inflammatory effect might act through attenuating intracellular calcium elevation.Received 31 October 2003; returned for revision 18 December 2003; accepted by I. Ahnfelt-Rønne 26 Januaryy 2004     

Involvement of opioid receptors in phencyclidine-induced enhancement of brain histamine turnover in mice

Summary When the histamine (HA) turnover in the brain of mice was estimated on the basis of the pargyline-induced accumulation of tele-methylhistamine (t-MH), a predominant metabolite of brain HA, the enhancing effect of phencyclidine (PCP) on the HA turnover was antagonized by a large dose of naloxone. However, a dopamine receptor antagonist haloperidol, which is also a potent receptor antagonist, did not inhibit the effect of PCP on the HA turnover. [abetd-Ala², abetd-Leu⁵]enkephalin, a prototypic opioid agonist, markedly enhanced the HA turnover. The effect of this peptide was demonstrated not only when the HA turnover was determined by the pargyline-induced t-MH accumulation but when it was estimated by the HA depletion induced by -fluoromethylhistidine, a specific inhibitor of histidine decarboxylase. A agonist, SKF-10047, and a agonist, ethylketazocine, had no PCP-like enhancing effect on the HA turnover. These results suggest that PCP enhances the brain HA turnover in mice by stimulating, probably indireclty, endogenous opioid systems. Send offprint requests to K. Saeki at the above address     

Gel tópico de amitriptilina al 2% y ketamina al 0,5% para el tratamiento de la eritromelalgia: reporte de un caso con respuesta positiva al dolor

Erythromelalgia (EM) is a rare autosomal dominant neuropathy characterized by the combination of severe burning pain and erythematous warm extremities. Chronic pain control is most often unsuccessful and a completely effective therapy is yet to be identified. Recent studies have reported significant improvements in pain management using a combination of amitriptyline and ketamine in a topical formulation. We describe a 1-year follow-up pain control success case of a male patient with EM, proposed for topical use of a 2% Amitriptyline and 0.5% Ketamine gel.     

Investigation of urinary components in rat model of ketamine-induced bladder fibrosis based on metabolomics

BackgroundKetamine abuse has been linked to the system''s damage, presenting with lower urinary tract symptoms (LUTS). While the pathogenesis of ketamine-induced urinary damage is not fully understood, fibrosis is believed to be a potential mechanism. A metabolomic investigation of the urinary metabolites in ketamine abuse was conducted to gain insights into its pathogenesis.MethodsA rat model of ketamine induced bladder fibrosis was established through tail vein injection of ketamine hydrochloride and control group was established through tail vein injection of the equivalent normal saline. Hematoxylin and eosin (H&E) staining and Masson trichrome staining were performed to evaluated bladder pathology. Urinary components were detected based on a metabolomic approach using ultra-high performance liquid tandem chromatography quadrupole time of flight mass spectrometry (UHPLC-QTOFMS platform). Orthogonal projections analyzed the data to latent structures discriminant analysis (OPLS-DA) and bioinformatics analysis.ResultsThe rat model of ketamine induced bladder fibrosis was confirmed through H&E and Masson trichrome staining. There were marked differences in the urinary metabolites between the experimental group and the control group. Compared to the control group, 16 kinds of differential metabolites were up-regulated and 102 differential metabolites were down-regulated in the urine samples of the ketamine group. Bioinformatics analysis revealed the related metabolic pathways.ConclusionsUsing a ketamine-induced bladder fibrosis rat model, this study identified the differential urinary metabolites expressed following ketamine treatment. These results provide vital clues for exploring the pathogenesis of ketamine-induced LUTS and may further contribute to the disease''s diagnosis and treatment.     

Block of the N-methyl-d-aspartate receptor by phenycyclidine-like drugs is influenced by alternative splicing

N-methyl-d-aspartate (NMDA) receptors were expressed in Xenopus oocytes from injected mRNA. The presence of an alternatively-spliced insertion encoding 21 amino acids at the N-terminus of the NMDAR1 (NR1₁₁₁) subunit, made homomeric assemblies of the receptor more sensitive to ketamine and MK-801 than receptors assembled from NMDAR1 subunits lacking this insert (NR1₀₁₁ and NR1₀₀₁). The influence of this insert was maintained when NR1 subunits were co-expressed in heteromeric combinations with NR2B. The increased sensitivity of the receptors containing the insert (NR1₀₀₁) was accompanied by a faster on-rate for drug action than was observed for receptors lacking the insert (NR1₀₁₁ and NR1₀₀₁). Our results suggest that the action of phencyclidine-like drugs is influenced by the presence of Insertion I in the NMDA isoforms, generated by alternative splicing.     

Interaction of ketamine with μ2 opioid receptors in SH-SY5Y human neuroblastoma cells

Purpose. Ketamine is known to interact with opioid receptors. However, because this agent does not produce opioid-like respiratory depression, it might not interact with μ₂ opioid receptors. Therefore, we have studied the interaction of ketamine with μ₂ opioid receptors expressed in SH-SY5Y cells. Methods. SH-SY5Y cells (passage 70–80) were used to obtain ketamine dose-response curves for inhibition of 0.4 nM [³H][d-Ala²,MePhe⁴,Gly(ol)⁵] enkephalin (DAMGO) binding to μ₂ opioid receptors and of forskolin (1 μM)-stimulated cyclic AMP (cAMP) formation. Results. Ketamine displaced [³H]DAMGO binding in SH-SY5Y cells with a K _i of 12.1 μM. However, this concentrations did not inhibit forskolin-stimulated cAMP formation, although at supraclinical concentrations, significant inhibition was observed with an estimated IC₅₀ of 700 μM. Conclusion. The present study indicates that a clinically relevant concentration of ketamine interacts with μ₂ opioid receptors. However, no agonist activity was observed. Received for publication on September 10, 1998; accepted on January 5, 1999     

丙泊酚及氯胺酮持续泵注与间断静注的静脉全麻比较

目的比较丙泊酚复合氯胺酮静脉泵注与间断静注的静脉全麻效果及安全性。方法　20例ASA　I～II级静脉全麻手术患者随机为I、II组,每组10例,I组为丙泊酚及氯胺酮分次静注组,II组为丙泊酚及氯胺酮持续静脉泵注组。两组术前3分钟静注丙珀酚0.6mg/kg,氯胺酮1mg/kg。I组术中当麻醉转浅时静注丙泊酚(0.6mg/kg)和(或)氯胺酮(1mg/kg),Ⅱ组术中以微泵泵注丙泊酚(1～3mg·kg-1·h-1),氯胺酮(2～4mg·kg-1·h-1)。记录麻醉前至手术进行1小时每隔5分钟测得的平均动脉压(MAP)、呼吸(R)及脉搏氧饱和度(SpO);整个手术过程中麻醉药用量。结果2麻醉期间I组MAP、R波动大,Ⅱ组较平稳;I组有4例SpO下降至88%～94%;Ⅱ组所有病人SpO达98%～100%以上,22两组比较差异有显著性。Ⅱ组人均氯胺酮及丙泊酚用量显著多于Ⅰ组。结论　氯胺酮及丙泊酚微泵泵注给药麻醉效果好,术中BP和R平稳,麻醉药用量少,安全性好。