A study of a topiramate pre-treatment on the effects induced by a subanaesthetic dose of ketamine on human reaction time

Ketamine, a N-methyl-D-aspartate (NMDA) receptor antagonist, impairs reaction time performance and interacts with foreperiod duration, thereby suggesting that ketamine alters motor preparation. These effects can be attributed either to the blockade of NMDA receptors or to the stimulation of alpha-amino-3-hydroxy-5-methylisoxasole-4-proprionic acid (AMPA) and kainate receptors. The purpose of the present study was: (i) to replicate previous findings and (ii) to study the effect of a pre-treatment with topiramate, an AMPA/kainate antagonist, on the impairments induced by ketamine on RT. Thirty six healthy subjects (3 groups of 12) performed a two-choice RT task in which the foreperiod was manipulated. All subjects performed the task under perfusion of ketamine (intravenous bolus of 0.12 mg followed by a perfusion of 0.5 mg/kg over 60 mn) or placebo (saline). Depending on the group, an oral dose of topiramate (50 mg) or placebo (lactose) was administered 2 h before ketamine infusion (randomised, double-blind, double-dummy, parallel-group design). At the dose studied, topiramate exerted no detectable effect on RT. The results relative to ketamine corroborate previous findings and suggest that this molecule affects motor preparation through the blockade of NMDA receptors.     

Ketamine enhances the efficacy to and delays the development of tolerance to electroacupuncture-induced antinociception in rats

Our previous studies have shown that 100 Hz electroacupuncture (EA) produced antinociception through the release of endogenous opioids (mainly dynorphin) and the activated kappa-opioid receptors in normal rats. Acupuncture is an effective treatment in relieving pain, but it develops tolerance after repeated administration. It has been reported that N-methyl-D-aspartate (NMDA) receptor antagonists could increase the antinociceptive effects induced by morphine and delay the development of tolerance to morphine but nothing has yet been described to reduce EA tolerance. Here we test whether ketamine, a non-competitive NMDA receptor antagonist, would enhance 100 Hz EA antinociception as well as prevent or delay the development of chronic tolerance to 100 Hz EA in normal rats. The results are as follows: (1) ketamine injected intraperitoneally (i.p.) 15 min prior to EA enhanced the antinociceptive effects of 100 Hz EA at a dose of 5.0 mg/kg, but not 0.2 or 1.0 mg/kg. However, ketamine at either dose did not affect the basal nociceptive threshold (represented by tail-flick latency). (2) Ketamine at a dose of 5.0 mg/kg delayed the development of chronic tolerance to 100 Hz EA antinociception. We conclude that ketamine can enhance antinociception of 100 Hz EA and delay the tolerance to 100 Hz EA in rats. These results suggest that the development of 100 Hz EA tolerance to antinociception was mediated, at least in part, through peripheral NMDA receptors, which may be useful in improving the therapeutic effects of EA in the treatment of pain when EA tolerance occurs.     

Ketamine affects memory consolidation: differential effects in T-maze and passive avoidance paradigms in mice

The effects of ketamine, an N-methyl-D-aspartate (NMDA) antagonist, on memory in animals have been limited to the sub-anesthetic dose given prior to training in previous studies. We evaluated the effects of post-training anesthetic doses of ketamine to selectively manipulate memory consolidation, and the effect of pre-retention sub-anesthetic doses of ketamine on memory retrieval in passive avoidance and T-maze tasks in mice. Repeated post-training anesthetic doses of ketamine impaired the consolidation of memory in the T-maze but not in passive avoidance paradigms. This impairment was not permanent but diminished 1-2 days after ketamine withdrawal. Sub-anesthetic post-training doses of ketamine (5 mg/kg) had no effect on memory consolidation, and larger doses (10, 20 and 50 mg/kg) did not influence the retrieval of memory in the T-maze. The data suggest that repeated anesthetic doses of ketamine block NMDA receptors and affect memory consolidation. Moreover, NMDA mechanisms antagonized by ketamine appear to be selectively involved in spatial (T-maze) memory mechanisms but may not be necessary for non-spatial (passive avoidance) memory consolidation.     

NMDA receptor antagonists extend the sensitive period for imprinting

Filial imprinting in the domestic chick occurs during a sensitive period of development. The exact timing of this period can vary according to the methods used to measure imprinting. Using our imprinting paradigm, we have shown that normal, dark-reared chicks lose the ability to imprint after the second day post-hatching. Further, we reported that chicks treated 10 h after hatching with a mixture of the noncompetitive NMDA receptor antagonist ketamine (55 mg/kg) and the alpha(2)-adrenergic receptor agonist xylazine (6 mg/kg) were able to imprint on day 8 after hatching, whereas controls treated with saline did not imprint. We now show that the effect of the ketamine-xylazine mixture can be mimicked by treating chicks with ketamine alone or with another noncompetitive NMDA receptor antagonist, MK-801 (5 mg/kg). Treating chicks with a single dose of ketamine (55 mg/kg) or with a single dose of xylazine (6 mg/kg) failed to produce the effect on the sensitive period. However, prolonging the action of ketamine by treating chicks with two doses of ketamine (at 10 and 12 h after hatching) did allow imprinting on day 8. In contrast, prolonging the action of xylazine had no effect on the sensitive period for imprinting. Chicks treated with MK-801 were also able to imprint on day 8. Thus, we have evidence that the NMDA receptor system is involved in the mechanisms that control the sensitive period for imprinting.     

Ketamine-related expression of glutamatergic postsynaptic density genes: Possible implications in psychosis

Systemic administration of ketamine, a non-competitive antagonist of the N-methyl-d-aspartate receptor (NMDA-R), produces a condition of NMDA-R hypofunction, which is considered one of the putative molecular mechanisms involved in psychosis. In this study, we evaluated the effect of ketamine on glutamatergic markers of the postsynaptic density (PSD), a pivotal site for dopamine–glutamate interaction. We assessed gene expression of Homer1a, α and βCaMKII, and dopamine transporter (DAT) by two different doses of ketamine. These genes were chosen because of their impact on signal transduction and dopamine–glutamate interplay in postsynaptic density. Moreover, Homer1a is modulated by antipsychotics and represents a candidate gene for schizophrenia. Male Sprague–Dawley rats were injected with saline, 12 mg/kg ketamine or 50 mg/kg ketamine, and sacrificed 90 minutes after injections. In situ hybridization histochemistry was used to quantitate the rate of gene expression in rat forebrain. Homer1a was induced by 50 mg/kg ketamine in ventral striatum and by both 50 and 12 mg/kg ketamine in nucleus accumbens, whereas gene expression was not affected in dorsal striatum. αCaMKII was increased by 12 mg/kg ketamine against saline in almost all subregions assessed. βCaMKII was not affected by ketamine. DAT was increased by both doses of ketamine in the ventro-tegmental area and substantia nigra pars compacta. We suggest that these changes may represent molecular adaptations to the perturbation in glutamatergic transmission induced by ketamine blockade of NMDA receptors and may be implicated in molecular alterations occurring in schizophrenia.     

天门冬氨酸盐及氯氨酮对反复缺氧小鼠海马中NOS表达的影响(英文)

兴奋性氨基酸、ＮＭ ＤＡ 受体和一氧化氮合酶／一氧化氮系统参与了缺氧性脑损伤的形成,急性重复缺氧则能通过缺氧预适应显著提高小鼠对缺氧的耐受性。本研究旨在观察外源离子型ＮＭ ＤＡ 受体激动剂天门冬氨酸和抑制剂氯氨酮对小鼠缺氧预适应的形成以及形成过程中ＮＯＳ在小鼠海马脑区表达的影响。取昆明小鼠随机分为天冬氨酸、氯氨酸和正常对照三组,分别腹腔注射天门冬氨酸（３ ｇ／ｋｇ）、氯氨酮（１００ ｍ ｇ／ｋｇ）和生理盐水（３ ｍ ｌ／ｋｇ）;分别造成各组动物急性重复缺氧１ 次和４ 次同时测定各组缺氧耐受时间,并采用ＮＡＤＰＨ ｄ 组织化学技术观察各组动物脑内ＮＯＳ的表达。结果表明：天冬氨酸和氯氨酮分别显著地缩短和延长了小鼠的标准耐受时间。缺氧１ 次后,各组动物脑内ＮＯＳ的表达增强,而４ 次缺氧后,由于缺氧预适应的形成ＮＯＳ的表达未继续增加而保持不变。三组动物在缺氧４ 次后脑内ＮＯＳ的表达依次为天门冬氨酸组＞ 正常对照组＞ 氯氨酮组。上述结果提示：ＮＯＳ的抑制可能有益于缺氧耐受,并可能是预适应的机制之一。离子型ＮＭＤＡ 受体的激活和抑制分别不利于和有利于缺氧预适应的形成,这也可能是因为受体的激活和抑制分别促进和抑制了ＮＯＳ在海马的表达。     

Gene expression profiling in the developing rat brain exposed to ketamine

Ketamine, a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, is associated with accelerated neuronal apoptosis in the developing rodent brain. In this study, postnatal day (PND) 7 rats were treated with 20 mg/kg ketamine or saline in six successive doses (s.c.) at 2-h intervals. Brain frontal cortical areas were collected 6 h after the last dose and RNA isolated and hybridized to Illumina Rat Ref-12 Expression BeadChips containing 22,226 probes. Many of the differentially expressed genes were associated with cell death or differentiation and receptor activity. Ingenuity Pathway Analysis software identified perturbations in NMDA-type glutamate, GABA and dopamine receptor signaling. Quantitative polymerase chain reaction (Q-PCR) confirmed that NMDA receptor subunits were significantly up-regulated. Up-regulation of NMDA receptor mRNA signaling was further confirmed by in situ hybridization. These observations support our working hypothesis that prolonged ketamine exposure produces up-regulation of NMDA receptors and subsequent over-stimulation of the glutamatergic system by endogenous glutamate, triggering enhanced apoptosis in developing neurons.     

Effects of ketamine and N-methyl-D-aspartate on glutamate and dopamine release in the rat prefrontal cortex: modulation by a group II selective metabotropic glutamate receptor agonist LY379268

Previous studies have shown that the metabotropic glutamate receptor (mGluR)2/3 agonist LY354740 attenuated glutamate release in medial prefrontal cortex (mPFC) induced by the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist phencyclidine. In the present study we examined the effects of the more potent mGluR2/3 selective agonist LY379268 on ketamine-evoked glutamate and dopamine (DA) release in mPFC of male rats. Subjects were implanted with a unilateral microdialysis probe in the mPFC and were tested 12-24 h after implantation. Ketamine (18 mg/kg, s.c.) evoked a significant release of glutamate and DA, although the glutamate response was slower in onset compared with DA. Pretreatment with either systemic (3 mg/kg s.c.) or local (1 microM, in the probe) LY379268 blocked ketamine-evoked glutamate, but not DA, release. When applied directly to the mPFC via the dialysis probe, ketamine (1 mM in the probe) had no effect on glutamate release but did significantly enhance the release of DA. Application of NMDA (500 microM in the probe), on the other hand, decreased DA while increasing glutamate release. The effect of NMDA on evoking glutamate release was blocked by systemic but not local administration of LY379268. These findings indicate that systemic ketamine increases both glutamate and DA release in mPFC and that the effect on glutamate can be blocked by stimulating mPFC group II mGluR receptors. Local ketamine, on the other hand, does not increase glutamate but does increase DA release. This suggests that ketamine acts outside of the mPFC to enhance glutamate, but within the mPFC to enhance DA release. The origin of the ketamine effect on mPFC glutamate is currently not known.     

Differential role of N-methyl-d-aspartate receptor subunits 2A and 2B in mediating phencyclidine-induced perinatal neuronal apoptosis and behavioral deficits

The mechanism underlying phencyclidine (PCP)-induced apoptosis in perinatal rats and the development of schizophrenia-like behaviors is incompletely understood. We used antagonists for N-methyl-d-aspartate (NMDA) receptor subunit NR2A- and NR2B-containing NMDA receptor to test the hypothesis that the behavioral and apoptotic effects of PCP are mediated by blockade of NR1/NR2A-containing receptors, rather than NR1/NR2B-containing receptors. Sprague-Dawley rats were treated on PN7, PN9, and PN11 with PCP (10 mg/kg), PEAQX (NR2A-preferring antagonist; 10, 20, or 40 mg/kg), or ifenprodil (selective NR2B antagonist; 1, 5, or 10 mg/kg) and sacrificed for measurement of caspase-3 activity (an index of apoptosis) or allowed to age and tested for locomotor sensitization to PCP challenge on PN28-PN35. PCP or PEAQX on PN7, PN9, and PN11 markedly elevated caspase-3 activity in the cortex; ifenprodil showed no effect. Striatal apoptosis was evident only after subchronic treatment with a high dose of PEAQX (20 mg/kg). Animals treated with PCP or PEAQX on PN7, PN9, and PN11 showed a sensitized locomotor response to PCP challenge on PN28-PN35. Ifenprodil treatment had no effect on either measure. Therefore, PCP blockade of cortical NR1/NR2A, rather than NR1/NR2B, appears to be responsible for PCP-induced apoptosis and the development of long-lasting behavioral deficits.     

N-methyl-D-aspartate antagonists and working memory performance: comparison with the effects of scopolamine, propranolol, diazepam, and phenylisopropyladenosine.

The effects of the competitive N-methyl-D-aspartate (NMDA) antagonists CPP (5 & 10 mg/kg) and NPC 12626 (25 & 40 mg/kg) and the noncompetitive NMDA antagonists phencyclidine (1, 3, & 6.25 mg/kg) and MK 801 (0.1 & 0.2 mg/kg) on performance of rats on a nonspatial delayed matching-to-sample working memory task were evaluated. At the highest dose, each NMDA antagonist reduced choice accuracy at all retention intervals. In contrast, the reference anticholinergic agent scopolamine selectively reduced accuracy at long retention intervals, suggesting that scopolamine but not the NMDA antagonists directly interfered with time-dependent working memory retention. Propranolol, diazepam, and phenylisopropyladenosine had little or no effect on choice accuracy, suggesting that noradrenergic, gamma-aminobutyric acid-diazepam, and adenosine receptors may be relatively unimportant for working memory performance as assessed in this task. The NMDA antagonists also differed from scopolamine in that doses of NMDA antagonists that reduced response accuracy also reduced response probability, altered bias (competitive antagonists only), and increased intertrial interval responding (noncompetitive antagonists only). It was concluded that NMDA antagonists disrupt cognitive functions including, but not limited to, those required for accurate working memory performance.     

Contribution of peripheral N-methyl-D-aspartate receptors to c-fos expression in the trigeminal spinal nucleus following acute masseteric inflammation

In this study, we examined the contribution of N-methyl-D-aspartate (NMDA) receptors on c-fos expression in the trigeminal brainstem nuclei following acute muscle inflammation. Mustard oil (MO; 20%, 30 microL) injected into the masseter muscle induced extensive peripheral edema and Fos-like immunoreactivity (Fos-LI) in several trigeminal brainstem areas including the subnucleus caudalis of the trigeminal spinal nucleus (Vc), the ventral and dorsal regions of the Vc/subnucleus interpolaris transition zone, and the paratrigeminal nucleus. In order to assess the effect of antagonizing NMDA receptors on MO-induced Fos-LI, rats were pre-treated with two different doses of i.v. MK-801 (0.3 mg/kg, 3 mg/kg), a non-competitive NMDA receptor antagonist, 30 min prior to MO injection. Additional groups of rats received MK-801 (0.3 mg/kg) directly in the masseter muscle or in the biceps muscle 5 min prior to MO injection. A higher dose of i.v. MK-801 (3 mg/kg) and MK-801 given locally into the masseter muscle (0.3 mg/kg) produced a significant reduction in total number of MO-induced Fos-LI. Further analyses revealed that pre-treatment with MK-801 (3 mg/kg i.v.) significantly reduced the Fos-LI all throughout the Vc. Only at the caudal Vc, there was a dose-dependent reduction of MO induced Fos-LI. Pre-treatment with masseteric MK-801 also significantly reduced the Fos-LI in the caudal Vc, with the effect greater than that produced by the same dose of MK-801 given intravenously. These results suggest that peripheral NMDA receptors contribute to nociceptive processing from craniofacial muscles.     

Determination of amino acid levels in the rat striatum,after administration of ethanol alone and associated with ketamine,a glutamatergic antagonist

The main goal of this study was to determine the amino acids (glutamate, aspartate, glutamine and tyrosine) levels in the rat striatum, after ethanol administration alone and/or associated with ketamine. In protocol 1 (Et + ketamine-1), ethanol was administered to male Wistar rats until the 7th day, and at the next day the group received only ketamine (25 mg/kg, i.p.) up to the 14th day. In protocol 2 (Et + ketamine-2), ethanol was also administered up to the 7th day, and was associated with ketamine from the 8th up to the 14th day. In other groups, animals were treated daily with ethanol (4 g/kg, p.o.), for 7 or 14 days or ketamine daily for 7 days. Controls were administered with distilled water for 7 days. Results showed that, in protocol 1, aspartate (ASP) levels increased after ketamine administration, as compared to the controls. This effect was inhibited in the group Et + ketamine-1. Ethanol (7 days) increased glutamate (GLU) levels, as compared to control, and this effect did not differ significantly from that observed in the ketamine group. When ketamine was administered after the ethanol withdrawal (protocol 1), no alterations in those amino acid concentrations were seen, as compared to the control and ketamine groups. A tendency for increasing GLU levels was observed, after administration of ethanol (14 days) or ketamine alone or associated (protocol 2), when compared to control values. In protocol 2, TYR levels decreased as related to controls and to the 14-day ethanol-treated group. We can assume that ketamine presents only an antagonist effect, in animals pretreated with ethanol, followed by ketamine administered from the 8th day on. This is due to the fact that NMDA receptors are already sensitized, leading to a decrease in these receptors functions and consequently to ASP and GLU releases.     

致死剂量N-甲基-D-天冬氨酸中毒模型小鼠对丙泊酚的反应

背景：丙泊酚具有较好的抗惊厥作用,但其作用机制尚不清楚。 目的:观察丙泊酚对致死剂量N-甲基-D-天冬氨酸中毒模型小鼠的行为学及存活率的影响。 方法：建立N-甲基-D-天冬氨酸致死模型昆明小鼠,给药前10 min,腹腔注射丙泊酚12.5,25,50,75,100 mg/kg,观察中毒小鼠的行为学改变及存活率,阳性对照组在造模前腹腔注射非特异性的N-甲基-D-天冬氨酸受体拮抗剂地佐环平   2 mg/kg,为排除丙泊酚溶剂脂肪乳可能的作用,设定了脂肪乳组,在造模前腹腔注射等容积的脂肪乳作为对照。 结果与结论：腹腔注射N-甲基-D-天冬氨酸175 mg/kg可导致小鼠全身惊厥发生并且很快死亡,而提前给予丙泊酚12.5,25,50,75,100 mg/kg后,可见其可剂量依赖性的对抗小鼠惊厥的发生,并降低小鼠的死亡率,地佐环平(2 mg/kg)可完全预防惊厥发生,而脂肪乳不能抑制惊厥的发生,对致死剂量N-甲基-D-天冬氨酸中毒模型小鼠无保护作用。提示丙泊酚的抗惊厥作用可能与N-甲基-D-天冬氨酸受体有关。     

Effects of ionotropic glutamate receptor channel blockers on the development of pentylenetetrazol kindling in mice

Experiments on mice were performed to study the ability of monocationic and dicationic adamantane and phenylcyclohexyl derivatives to prevent the development of kindling induced by i.p. administration of pentylenetetrazol (Corasol, 35 mg/kg). The monocationic phenylcyclohexyl derivative IEM-1921 effectively slowed the development of kindling, this being seen over a wide range of doses (0.0001–0.1 μmol/kg). A monocationic adamantane derivative (memantine), also a selective non-competitive blocker of NMDA receptors, produced a similar effect at doses 100 times higher. The anticonvulsive activity of the dicationic phenylcyclohexyl derivative IEM-1925, which could block both types of glutamate receptors, differed from the activity of the monocationic derivative by having a more complex dose-response relationship. Thus, the development of kindling was suppressed by essentially the same doses as needed for the monocation IEM-1921 (0.001 μmol/kg). However, on reducing the dose by a factor of 10 (0.0001 μmol/kg), IEM-1925 facilitated the development of kindling. This difference in the prophylactic activities of selective NMDA receptor blockers and substances able to block both NMDA and AMPA receptors provides evidence that the mechanism of kindling involves both types of ionotropic glutamate receptor and the effects of compounds depend not only on the ratio of the contributions of these receptors, but also on the kinetic characteristics of the blocking action. __________ Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 91, No. 11, pp. 1241–1251, November, 2005.     

Role of ventral hippocampal NMDA receptors in anxiolytic-like effect of morphine

The possible role of ventral hippocampal N-methyl-d-aspartate (NMDA) receptors on morphine-induced anxiolytic-like behavior in an elevated plus maze (EPM) task was investigated in the present study. Adult male mice (7 per group) with cannulas aimed at the ventral hippocampus (VH) received NMDA or a competitive NMDA receptor antagonist D-AP5 with or without morphine and 30 min later were subjected to an EPM task. Intraperitoneal injection (i.p.) of morphine (3-9 mg/kg) increased the percentage of open arm time (%OAT) and open arm entries (%OAE), which suggested an anxiolytic-like effect. Intra-VH microinjection of NMDA (0.5-1 μg/mouse) with an ineffective dose of morphine (3 mg/kg, i.p.) significantly increased %OAT and %OAE. However, microinjections of the same doses of NMDA into the VH in the absence of morphine had no effect on %OAT and %OAE. Intra-VH microinjection of D-AP5 (0.5-2 μg/mouse) decreased the anxiolytic-like effect of morphine, while intra-VH microinjection of the same doses of D-AP5 alone increased %OAT and %OAE, which indicated an anxiolytic response. Furthermore, intra-VH microinjection of D-AP5 reversed the effect of NMDA response to the administration of a lower morphine dose as seen in the EPM task. It should be noted that intra-VH microinjection of D-AP5 plus NMDA, 5 min before morphine increased locomotor activity, while other treatments had no effect on this parameter. The results suggest that VH-NMDA receptors participate in the mediation of morphine-induced anxiolytic-like behavior.     

Neural circuits underlying ketamine-induced oculomotor behavior in the rat: 2-deoxyglucose studies

 Time-related changes in oculomotor function and of metabolic activity patterns in selected brain networks, as assessed by the quantitative 2-deoxyglucose technique, were investigated in Long-Evans rats following intraperitoneal administration of a ketamine anesthetic dose. During ketamine-induced anesthesia a nystagmic-like behavior was present, characterized by unidirectional slow ocular drifts with superimposed paroxystic bursts of quick (saccadic-like) eye movements; all quick movements were executed in the horizontal direction, were strictly confined to an ocular hemifield of vision, and were followed by a backward (centripetal) drift. A metabolic hyperactivity was found in the dorsomedial shoulder region of the frontal cortex, corresponding to the rat saccadic cortical generator area, whereas functional activity levels were decreased in cerebellum and in several brainstem regions, including portions of the reticular formation and medial vestibular nuclei, putatively indicated as the locus of the oculomotor neural integrator. Starting 2 h after drug injection, a gradual recovery of oculomotor function occurred, with the disappearance of slow ocular drifts. However, an almost uninterrupted sequence of individual saccades was still present. Significant metabolic increases were found at this time in the cingulate and frontal cortex, basal ganglia, superior colliculus, paramedian reticular formation and oculomotor nuclei, the cerebellar vermis and paraflocculus. In medial vestibular nuclei, metabolic levels were undistinguishable from controls. These results suggest different concentration-dependent actions of ketamine on cortical and subcortical circuits involved in saccade generation and gaze holding. These effects are likely to be related at least in part to antagonism of N-methyl-d-aspartate receptor-mediated functions. Received: 25 March 1998 / Accepted: 7 July 1998     

Synergistic interaction between mazindol, an anorectic drug, and swim-stress on analgesic responses in the formalin test in mice

The present study examined the interaction between mazindol (MZ), an anorectic drug extensively used in Brazil and opioid/non-opioid endogenous analgesic systems activated by swim-stress. Further, the role of opioid, dopamine and N-methyl-D-aspartate (NMDA) receptors in mediating the analgesic effect was evaluated. The stress-induced analgesia of a 3-min swimming at 32 degrees C (opioid/non-opioid) and 20 degrees C (non-opioid) were assessed using the formalin test. Male Swiss mice were intraperitoneally injected with naloxone (1.0 mg/kg), sulpiride (3.0 mg/kg), MK-801 (0.075 mg/kg) or saline/vehicle 15 min prior, and with MZ (0.5 mg/kg) or saline/vehicle 5 min prior to swimming. The dose of MZ (0.5 mg/kg) did not cause analgesic effect, however, the association of MZ and swim-stress at both temperatures displayed synergistic interaction on analgesia that was blocked by sulpiride and MK-801 but not by naloxone. The present results suggest that MZ and swim-stress acted synergistically on analgesic responses, involving mainly the non-opioid component and possibly mediated by dopamine D2 receptors and NMDA receptors.     

Large dose ketamine inhibits lipopolysaccharide-induced acute lung injury in rats

Background: Sepsis is associated with the highest risk of progression to acute lung injury or the acute respiratory distress syndrome. Ketamine has been advocated for anesthesia in endotoxemic and other severely ill patients because it is a cardiovascular stimulant. Our study was designed to investigate the effect of ketamine on the endotoxin-induced acute lung injury in vivo.Materials and methods: Adult male Wistar rats were randomly divided into 6 groups: saline controls; rats challenged with endotoxin (5 mg/kg) and treated with saline; challenged with endotoxin (5 mg/kg) and treated with ketamine (0.5 mg/kg); challenged with endotoxin (5 mg/kg) and treated with ketamine (5 mg/kg); challenged with endotoxin (5 mg/kg) and treated with ketamine (50 mg/kg); saline injected and treated with ketamine (50 mg/kg). TNF-, IL-6 and NF-kappa B were investigated in the tissues of the lung after 2 h. Myeloperoxidase (MPO) activity and wet/dry weight ratio were investigated 6 h later.Results: We demonstrated that intravenous administration of endotoxin could provoke significant lung injury, which was characterized by increase of MPO activity and wet/dry weight ratio, TNF- and IL-6 expression and NF-kappa B activation. Ketamine (5, 50 mg/kg) inhibited endotoxin-induced NF-kappa B activation. Ketamine only at a dose of 50 mg/kg inhibited TNF- and IL-6 production, and decreased MPO activity and wet/dry weight ratio after endotoxin challenge.Conclusions: Ketamine, only at a supra-anesthetic dosage, could inhibit endotoxin-induced pulmonary inflammation in vivo.Received 27 August 2004; returned for revision 11 November 2004; accepted by A. Falus 15 November 2004     

Participation of NMDA-glutamatergic receptors in hippocampal neuronal damage caused by adult-onset hypothyroidism

We analyzed the participation of N-methyl-d-aspartate (NMDA) receptors in the neuronal damage caused by adult-onset hypothyroidism. Wistar rats were randomly assigned into four groups. The euthyroid group received tap water. The hypothyroid group received methimazole (60 mg/kg) in their drinking water to induce hypothyroidism. Two more groups of rats received the antithyroid treatment and were injected daily with the NMDA antagonist ketamine (15 mg/kg, sc) or MK-801 (0.5 mg/kg, ip). Treatments were administered during 4 weeks. At the end of the respective treatments rats were deeply anaesthetized and perfused intracardially with 0.9% NaCl followed by 4% paraformaldehyde. The brains were removed from the skull, and coronal brain sections (7 μm thick) were obtained. Neurons were counted in the CA1, CA2, CA3, and CA4 hippocampal regions differentiating between normal and atrophic cells by an experimenter blind to the treatment. The percentage of neuronal damage found in the MMI group was significantly greater in the hippocampal regions compared to the euthyroid group. In contrast, both NMDA antagonists were able to prevent the neuronal damage secondary to hypothyroidism in all hippocampal regions. Our results suggest that the neuronal damage caused in the hippocampus of adult-onset hypothyroid rats requires activation of NMDA channels.