Action Of Ketamine Research Articles

A behavioral and molecular analysis of ketamine in zebrafish

Ketamine exerts powerful anesthetic, psychotic, and antidepressant effects in both healthy volunteers and clinically depressed patients. Although ketamine targets particular glutamate receptors, there is a dearth of evidence for additional, alternative molecular substrates for the behavioral actions of this N-methyl-D-aspartate (NMDA) receptor antagonist drug. Here, we provide behavioral and molecular evidence for the actions of ketamine using a new vertebrate model for psychiatric disorders: the zebrafish. Subanesthetic doses of ketamine produced a variety of abnormal behaviors in zebrafish that were qualitatively analogous to those previously measured in humans and rodents treated with drugs that produce transient psychosis. In addition, we revealed that the transcription factor Phox2b is a molecular substrate for the actions of ketamine, particularly during periods of hypoxic stress. Finally, we also show that SIRT1, a histone deacetylase widely recognized for its link to cell survival is also affected by hypoxia crises. These results establish a relevant assay system in which the effects of psychotomimetic drugs can rapidly be assessed, and provide a plausible and novel neuronal mechanism through which ketamine affects critical sensory circuits that monitor breathing behavior.

HIGHLIGHTS FROM THE LITERATURE

HIGHLIGHTS FROM THE LITERATURE

Cracking the moody brain: The rewards of self starvation

Understanding how the complex molecular mechanisms of the brain can be blighted, and what their role is in neurological disorders, can be an intricate task. The basis of mood alterations and how humans react to a damaged or altered brain circuit can provide clues for new therapies to target the root of these neurological glitches. In 'Bedside to Bench', Daniel Weinberger and Caroline Zink discuss how people with anorexia nervosa showed a connection between self starvation and motivational value—an opposite perspective to the traditional idea linking the absence of joy to the symptoms of this disorder and a new paradigm for developing the appropriate treatments. In 'Bench to Bedside', Dennis Charney and James Murrough peruse how the antidepressant action of ketamine in rats—a neurotrophic effect—can explain the rapid reduction in depression observed in the clinic with this drug. The receptors and signaling cascades involved may be used to develop therapies that may further enhance this rapid beneficial effect.

MTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists

The rapid antidepressant response after ketamine administration in treatment-resistant depressed patients suggests a possible new approach for treating mood disorders compared to the weeks or months required for standard medications. However, the mechanisms underlying this action of ketamine [a glutamate N-methyl-D-aspartic acid (NMDA) receptor antagonist] have not been identified. We observed that ketamine rapidly activated the mammalian target of rapamycin (mTOR) pathway, leading to increased synaptic signaling proteins and increased number and function of new spine synapses in the prefrontal cortex of rats. Moreover, blockade of mTOR signaling completely blocked ketamine induction of synaptogenesis and behavioral responses in models of depression. Our results demonstrate that these effects of ketamine are opposite to the synaptic deficits that result from exposure to stress and could contribute to the fast antidepressant actions of ketamine.

Effect of ketamine on high-voltage-activated calcium currents in rat hippocampal neurons

To investigate the effect of ketamine on the high-voltage-activated calcium currents (ICa(HVA)) in rat hippocampal neurons. Neurons were cultured from Wistar rat hippocampus. ICa(HVA) was recorded using whole-cell patch clamp technique. After application with ketamine at different concentrations (10, 30, 100, 300, and 1000 μmol/L), the effect of ketamine on ICa(HVA) was evaluated. ICa(HVA) was inhibited by ketamine in a concentration-dependent manner. Ketamine at 10 μmol/L showed no effect on ICa(HVA). Four concentrations of ketamine (30, 100, 300,and 1000 μmol/L) reduced the peak ICa(HVA) currents by (17.5 ∓ 4.5)%, (25.5 ∓ 6.9)%, (38.5 ∓ 4.1)%, and (42.3 ∓ 4.6)% respectively,with a mean half maximal inhibitory concentration of 68.2 μmol/L and Hill coefficient of 0.47. The maximal activation membrane potential was shifted to (5.3 ∓ 0.8) from (5.4 ∓ 0.9). The half maximal activation membrane potential of inactivation curve was shifted from(-26.7 ∓ 3.9) mV to(-32.8 ∓ 4.2) mV. Ketamine can remarkably inhibit calcium currents in the central neurons,which may explain at least partly the action of ketamine on central nervous system.

Vascular effects of ketamine in isolated rabbit aortic Smooth muscle

The precise mechanism by which ketamine induces relaxation of vascular smooth muscle is not clear. The goal of this study was to further characterize the vascular actions of ketamine in rabbit aortic smooth muscles. Ring segments (2mm) of rabbit aortae were suspended in 20ml organ baths containing physiological salt solution (PSS) and isometric contractions were recorded at 37 degrees C and pH 7.4. The medium was bubbled with O(2) 95 % and CO(2) 5 % mixture and rings were given an initial load of 2g. An equilibration period of 90 minutes was allowed. Three protocols were examined: (a) Effect of ketamine on baseline tension (b) relaxation-responses to ketamine following precontractions induced by 10(-7)M phenylephrine or high K(+) (40mM) PSS and (c) influence of presence or absence of endothelium on the relaxation response to ketamine. Ketamine produced relaxation of contractile responses induced by both phenylephrine and high K(+). The respective maximum relaxation responses induced by ketamine following precontractions by phenylephrine and high-K(+) were 76.8 +/- 2.3 and 71.2 +/- 8.0 (p > 0.05). Ach-induced relaxation was observed only in rings with intact endothelium whereas ketamine-induced relaxation was observed in intact as well as endothelium-denuded rings; this suggests that ketamine-induced relaxation of rabbit aortic smooth muscle is independent of vascular endothelium.

Efficacy of stellate ganglion block with an adjuvant ketamine for peripheral vascular disease of the upper limbs

Stellate ganglion block (STGB) is commonly indicated in painful conditions like reflex sympathetic dystrophy, malignancies of head and neck, Reynaud’s disease and vascular insufficiency of the upper limbs. The sympathetic blockade helps to relieve pain and ischaemia. Diagnostic STGB is usually performed with local anaesthetics followed by therapeutic blockade with steroids, neurolytic agents or radiofrequency ablation of ganglion. There is increasing popularity and evidence for the use of adjuvants like opioid, clonidine and N Methyl d Aspartate (NMDA) receptor antagonist – ketamine – for the regional and neuroaxial blocks. The action of ketamine with sympatholytic block is through blockade of peripherally located NMDA receptors that are the target in the management of neuropathic pain, with the added benefit of counteracting the “wind-up” phenomena of chronic pain. We studied ketamine as an adjuvant to the local anaesthetic for STGB in 20 cases of peripheral vascular disease of upper limbs during the last 5 years at our institution. STGB was given for 2 days with 2 ml of 2% lignocaine + 8 ml of 0.25% bupivacaine, followed by block with the addition of 0.5 mg/kg of ketamine for three consecutive days. There was significant pain relief of longer duration with significant rise in hand temperature. We also observed complete healing of the gangrenous fingers in 17/19 patients.

The vasodilatory effect of ketamine is independent of the N-methyl-D-aspartate receptor: lack of functional N-methyl-D-aspartate receptors in rat mesenteric artery smooth muscle

Ketamine, which is a general anaesthetic that induces a dissociative anaesthesia, acts by blocking the N-methyl-D-aspartate receptor (NMDAr) in the brain. Although ketamine elevates blood pressure under the clinical setting, the in-vitro effect of ketamine is vasodilatory. However, it is not clear yet whether the vasodilation by ketamine involves functions of the NMDAr. Therefore, we examined whether the NMDAr is functional in vascular smooth muscle and whether the vasodilatory effect of ketamine is associated with the NMDAr. We measured isometric tension of endothelium-denuded arterial rings from rat mesentery. The relaxing effects of ketamine, after rings were precontracted with noradrenaline (10 mumol l) or high KCl (70 mmol l), were examined. The effects of DL-2-amino-5-phosphonopentanoic acid (AP-5), a competitive NMDAr blocker that is structurally distinct from ketamine, were also examined. The relaxing effects of ketamine in the presence of AP-5 were compared with those in the absence of AP-5. The effects of NMDAr agonists N-methyl-D-aspartate and glutamate were analysed in order to examine the existence of a functional NMDAr. Both S(+)-ketamine and racemic(+/-)-ketamine, with similar potencies and efficacies and in a concentration-dependent manner, relaxed the precontracted arterial rings. However, AP-5 neither relaxed the arteries nor affected the vasodilatory actions of ketamine. N-methyl-D-aspartate and glutamate (0.01-1 mmol l) had negligible effects on isometric tension under the resting or precontracted condition. These results suggest that the NMDAr is not functional in vascular smooth muscle, and the vasodilatory action of ketamine is independent of the NMDAr in the rat mesenteric artery.

Mg2+Imparts NMDA Receptor Subtype Selectivity to the Alzheimer's Drug Memantine

N-methyl-D-aspartate receptors (NMDARs) mediate interneuronal communication and are broadly involved in nervous system physiology and pathology (Dingledine et al., 1999). Memantine, a drug that blocks the ion channel formed by NMDARs, is a widely prescribed treatment of Alzheimer's disease (Schmitt, 2005; Lipton, 2006; Parsons et al., 2007). Research on memantine's mechanism of action has focused on the NMDAR subtypes most highly expressed in adult cerebral cortex, NR1/2A and NR1/2B receptors (Cull-Candy and Leszkiewicz, 2004), and has largely ignored interactions with extracellular Mg(2+) (Mg(2+)(o)). Mg(2+)(o) is an endogenous NMDAR channel blocker that binds near memantine's binding site (Kashiwagi et al., 2002; Chen and Lipton, 2005). We report that a physiological concentration (1 mM) of Mg(2+)(o) decreased memantine inhibition of NR1/2A and NR1/2B receptors nearly 20-fold at a membrane voltage near rest. In contrast, memantine inhibition of the other principal NMDAR subtypes, NR1/2C and NR1/2D receptors, was decreased only approximately 3-fold. As a result, therapeutic memantine concentrations should have negligible effects on NR1/2A or NR1/2B receptor activity but pronounced effects on NR1/2C and NR1/2D receptors. Quantitative modeling showed that the voltage dependence of memantine inhibition also is altered by 1 mM Mg(2+)(o). We report similar results with the NMDAR channel blocker ketamine, a drug used to model schizophrenia (Krystal et al., 2003). These results suggest that currently hypothesized mechanisms of memantine and ketamine action should be reconsidered and that NR1/2C and/or NR1/2D receptors play a more important role in cortical physiology and pathology than previously appreciated.

HCN1 Channel Subunits Are a Molecular Substrate for Hypnotic Actions of Ketamine

Ketamine has important anesthetic, analgesic, and psychotropic actions. It is widely believed that NMDA receptor inhibition accounts for ketamine actions, but there remains a dearth of behavioral evidence to support this hypothesis. Here, we present an alternative, behaviorally relevant molecular substrate for anesthetic effects of ketamine: the HCN1 pacemaker channels that underlie a neuronal hyperpolarization-activated cationic current (I(h)). Ketamine caused subunit-specific inhibition of recombinant HCN1-containing channels and neuronal I(h) at clinically relevant concentrations; the channels were more potently inhibited by S-(+)-ketamine than racemic ketamine, consistent with anesthetic actions of the compounds. In cortical pyramidal neurons from wild-type, but not HCN1 knock-out mice, ketamine induced membrane hyperpolarization and enhanced dendritosomatic synaptic coupling; both effects are known to promote cortical synchronization and support slow cortical rhythms, like those accompanying anesthetic-induced hypnosis. Accordingly, we found that the potency for ketamine to provoke a loss-of-righting reflex, a behavioral correlate of hypnosis, was strongly reduced in HCN1 knock-out mice. In addition, hypnotic sensitivity to two other intravenous anesthetics in HCN1 knock-out mice matched effects on HCN1 channels; propofol selectively inhibited HCN1 channels and propofol sensitivity was diminished in HCN1 knock-out mice, whereas etomidate had no effect on HCN1 channels and hypnotic sensitivity to etomidate was unaffected by HCN1 gene deletion. These data advance HCN1 channels as a novel molecular target for ketamine, provide a plausible neuronal mechanism for enhanced cortical synchronization during anesthetic-induced hypnosis and suggest that HCN1 channels might contribute to other unexplained actions of ketamine.

Ketamine, But Not Phencyclidine, Selectively Modulates Cerebellar GABAAReceptors Containing α6 and δ Subunits

Phencyclidine (PCP) and ketamine are dissociative anesthetics capable of inducing analgesia, psychomimetic behavior, and a catatonic state of unconsciousness. Despite broad similarities, there are notable differences between the clinical actions of ketamine and PCP. Ketamine has a lower incidence of adverse effects and generally produces greater CNS depression than PCP. Both noncompetitively inhibit NMDA receptors, yet there is little evidence that these drugs affect GABA(A) receptors, the primary target of most anesthetics. alpha6beta2/3delta receptors are subtypes of the GABA(A) receptor family and are abundantly expressed in granular neurons within the adult cerebellum. Here, using an oocyte expression system, we show that at anesthetically relevant concentrations, ketamine, but not PCP, modulates alpha6beta2delta and alpha6beta3delta receptors. Additionally, at higher concentrations, ketamine directly activates these GABA(A) receptors. Comparatively, dizocilpine (MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate]), a potent noncompetitive antagonist of NMDA receptors that is structurally unrelated to PCP, did not produce any effect on alpha6beta2delta receptors. Of the recombinant GABA(A) receptor subtypes examined (alpha1beta2, alpha1beta2gamma2, alpha1beta2delta, alpha4beta2gamma2, alpha4beta2delta, alpha6beta2gamma2, alpha6beta2delta, and alpha6beta3delta), the actions of ketamine were unique to alpha6beta2delta and alpha6beta3delta receptors. In dissociated granule neurons and cerebellar slice recordings, ketamine potentiated the GABAergic conductance arising from alpha6-containing GABA(A) receptors, whereas PCP showed no effect. Furthermore, ketamine potentiation was absent in cerebellar granule neurons from transgenic functionally null alpha6(-/-) and delta(-/-)mice. These findings suggest that the higher CNS depressant level achieved by ketamine may be the result of its selective actions on alpha6beta2/3delta receptors.

Glutamate and the Neural Basis of the Subjective Effects of Ketamine

Ketamine evokes psychosislike symptoms, and its primary action is to impair N-methyl-D-aspartate glutamate receptor neurotransmission, but it also induces secondary increases in glutamate release. To identify the sites of action of ketamine in inducing symptoms and to determine the role of increased glutamate release using the glutamate release inhibitor lamotrigine. Two experiments with different participants were performed using a double-blind, placebo-controlled, randomized, crossover, counterbalanced-order design. In the first experiment, the effect of intravenous ketamine hydrochloride on regional blood oxygenation level-dependent (BOLD) signal and correlated symptoms was compared with intravenous saline placebo. In the second experiment, pretreatment with lamotrigine was compared with placebo to identify which effects of ketamine are mediated by increased glutamate release. Wellcome Trust Clinical Research Facility, Manchester, England. Thirty-three healthy, right-handed men were recruited by advertisements. In experiment 1, participants were given intravenous ketamine (1-minute bolus of 0.26 mg/kg, followed by a maintenance infusion of 0.25 mg/kg/h for the remainder of the session) or placebo (0.9% saline solution). In experiment 2, participants were pretreated with 300 mg of lamotrigine or placebo and then were given the same doses of ketamine as in experiment 1. Regional BOLD signal changes during ketamine or placebo infusion and Brief Psychiatric Rating Scale and Clinician-Administered Dissociative States Scale scores. Ketamine induced a rapid, focal, and unexpected decrease in ventromedial frontal cortex, including orbitofrontal cortex and subgenual cingulate, which strongly predicted its dissociative effects and increased activity in mid-posterior cingulate, thalamus, and temporal cortical regions (r = 0.90). Activations correlated with Brief Psychiatric Rating Scale psychosis scores. Lamotrigine pretreatment prevented many of the BOLD signal changes and the symptoms. These 2 changes may underpin 2 fundamental processes of psychosis: abnormal perceptual experiences and impaired cognitive-emotional evaluation of their significance. The results are compatible with the theory that the neural and subjective effects of ketamine involve increased glutamate release.

AMPA Receptors: A Target for Novel Antidepressants?

arate et al. (1) have reported that ketamine, an N-methylD-aspartate (NMDA) antagonist, produces a rapid, robust, and sustained antidepressant action in treatment-resistant atients following a single infusion. The results of this doublelind, placebo-controlled, crossover trial are congruent with hose of an earlier pilot study that reported a rapid reduction in amilton Depression Rating Scale scores of depressed patients ollowing a single ketamine infusion (2). These clinical reports re consistent with a well-developed preclinical literature demnstrating that NMDA antagonists are antidepressant in animal odels with high predictive validity for clinically effective agents nd that chronic treatment with biogenic amine-based antideressants affects glutamate function (3,4). The dramatic effects of etamine in depressed patients have rekindled interest in the use f NMDA antagonists as antidepressants, despite the highly ndesirable side effects associated with this class of compounds, articularly the high to moderate affinity channel blockers such s ketamine, phencyclidine, and dizocilpine. The accompanying article by Maeng et al. (5) adds a new twist o the unfolding saga of NMDA antagonists as antidepressants. hus, among the many cellular actions produced by NMDA ntagonists is an increase in glutamate release (6) resulting from lockade of NMDA receptors located on either presynaptic sites r interneurons. In turn, ketamine-induced increases in synaptic oncentrations of glutamate can activate alpha-amino-3-hydroxy-methyl-4-isoxazole propionic acid (AMPA) receptors (6), a amily of ionotropic glutamate receptors mediating fast excitatory ransmission in the central nervous system (4). Maeng et al. (5) ypothesized that the antidepressant actions of ketamine and ther NMDA antagonists might be effected through this mechaism and have now demonstrated that the antidepressant-like ffects of NMDA antagonists, manifested as a reduction in mmobility in behavioral despair procedures, can be antagonized y the prototypic AMPA receptor antagonist NBQX. These data re particularly compelling because NBQX blocked not only the ntidepressant-like effects of ketamine and dizocilpine (which resumably act at the same locus on NMDA receptors) but also he effect of a subunit selective NMDA antagonist (Ro 25-6981) cting at a distinct locus. The implication of these findings is that ctivation of AMPA receptors is a final common pathway for the ntidepressant-like effects of NMDA antagonists acting at multile, allosteric drug recognition sites on this family of ligand-gated on channels (3). If the reported antidepressant actions of etamine (and, in animal models, other NMDA antagonists) are he result of this downstream signaling event, it may be possible o circumvent the limiting side effects associated with NMDA eceptor blockade through agents that directly target AMPA eceptor activation. This commentary focuses on evaluating the potential for eveloping antidepressants that act through AMPA receptor ctivation. AMPA receptors, like other families of ligand-gated on channels, contain allosteric recognition sites that, when ccupied by the appropriate ligands, can bidirectionally (i.e.,

Activities of the Antipsychotic Drugs Haloperidol and Risperidone on Behavioural Effects Induced by Ketamine in Mice

This study presents the actions of risperidone (Risp) and haloperidol (Hal) on the behavioral effects elicited by ketamine (Ket) on open-field (OF), rota rod (RR) and tail suspension (TS) tests in mice. Male Swiss albino mice (25–30g) were used. Antipsychotics were administered alone (Risp: 0.1 or 0.2 mg/kg, ip; Hal: 0.1 and 0.2 mg/kg, ip) or thirty minutes before Ket (10 mg/Kg, ip). Ket increased (Ket: 63.3 ± 4.2) the locomotor activity compared to control, while neuroleptics decreased it (25.5 ± 4.2). Pretreatment with neuroleptics, in both doses, blocked hyperlocomotion caused by Ket. In RR, Ket decreased (Ket: 15 ± 4.1) the permanence time of the animals compared to control (Control: 59 ± 0.6), but this effect was not observed when neuroleptics were administered alone. Pretreatment with neuroleptics reverted the effect of Ket only in the RR. While Ket (17.3 ± 5.6) decreased the time of immobility in the tail suspension test compared to the control (80.2 ± 10.2), the pretreatment with neuroleptics reverted this mobility. The action of neuroleptics in this model made possible the blockade of the effects caused by acute administration of Ket. Thus, the mechanism of action of ketamine may involve the dopaminergic system.

A combination of ketamine and diazepam synergistically controls refractory status epilepticus induced by cholinergic stimulation

New treatments are needed for status epilepticus (SE) that is refractory to drugs modulating GABA(A) receptors, and NMDA receptor antagonists are candidate drugs. Clinically available NMDA receptor antagonist ketamine was tested for effectiveness in terminating prolonged SE induced by a combination of lithium and pilocarpine. Animals were treated 10 min after first grade 5 behavioral seizure (Racine scoring scale) by intraperitoneal administration of ketamine, diazepam, or saline. Seizure termination was determined by electroencephalogram (EEG) recordings from the hippocampus and the cortex. Animals treated with normal saline or either 20 mg/kg diazepam, or 50 mg/kg ketamine continued in SE for the next 300 min. However, combined treatment with diazepam and ketamine rapidly terminated prolonged cholinergic stimulation-induced SE. Detailed study of dose response relationships demonstrated that diazepam enhanced efficacy and potency of ketamine in terminating SE. This study demonstrated synergistic action of diazepam and ketamine in terminating SE. It suggests that a ketamine-diazepam combination might be a clinically useful therapeutic option for the treatment of refractory SE.

Acute administration of ketamine induces antidepressant-like effects in the forced swimming test and increases BDNF levels in the rat hippocampus

Ketamine is a non-competitive antagonist to the phencyclidine site of N-methyl- d-aspartate (NMDA) receptor. Clinical findings point to a rapid onset of action for ketamine on the treatment of major depression. Considering that classic antidepressants may take long-lasting time to exhibit their main therapeutic effects, the present study aims to compare the behavioral effects and the BDNF hippocampus levels of acute administration of ketamine and imipramine in rats. To this aim, rats were acutely treated with ketamine (5, 10 and 15 mg/kg) and imipramine (10, 20 and 30 mg/kg) and animal behavioral was assessed in the forced swimming and open-field tests. Afterwards, BDNF protein hippocampal levels were assessed in imipramine- and ketamine-treated rats by ELISA-sandwich assay. We observed that ketamine at the doses of 10 and 15 mg/kg, and imipramine at 20 and 30 mg/kg reduced immobility time compared to saline group, without affecting locomotor activity. Interesting enough, acute administration of ketamine at the higher dose, but not imipramine, increased BDNF protein levels in the rat hippocampus. In conclusion, our findings suggest that the increase of hippocampal BDNF protein levels induced by ketamine might be necessary to produce a rapid onset of antidepressant action.

Ketamine for pain relief in acute pancreatitis

Summary Patients with acute pancreatitis are often admitted to critical care unit and present with a spectrum of multiorgan problems. The commonest presenting symptom of acute pancreatitis is upper abdominal pain. The pain can be very severe and refractory to the treatment with conventional analgesics. The pain not only adds to the patient's distress but may also have adverse effects on the cardio-respiratory systems, which can be affected by acute pancreatitis itself. The pain in acute pancreatits is usually controlled by conventional analgesics, morphine/pethidine PCA or epidural analgesia. But at times all these measures of pain control fail and additional methods of pain relief become necessary. We encountered a patient with acute pancreatits with severe abdominal pain in whom conventional methods of pain relief failed to provide adequate analgesia. The patient had respiratory impairment secondary to upper abdominal pain and improved pain relief avoided the possible need for invasive ventilation. We used an intravenous ketamine infusion to supplement the analgesic regimen with a significant improvement in pain relief without any adverse psycho mimetic effects. The probable mechanisms of action of ketamine in improving pain relief are discussed. On search of the literature, the use of ketamine for pain relief in acute pancreatitis has never been reported.

Using the BOLD MR signal to differentiate the stereoisomers of ketamine in the rat

Rationale: Ketamine is a chiral molecule that is reported to model aspects of schizophrenia. Objectives: To investigate the stereospecificity of the isomers of ketamine using pharmacological magnetic resonance imaging (phMRI) in order to further understand ketamine's pharmacodynamic actions. Method: Responses to 25 mg kg −1 S(+) isomer, R(−) isomer and racemic ketamine in independent groups of Sprague–Dawley rats were investigated using a prepulse inhibition paradigm, locomotor observations, MRI and 2-deoxyglucose techniques. Results: Racemic ketamine and the S(+) isomer were both capable of disrupting sensorimotor gating as measured using prepulse inhibition and produced a longer period of hyperlocomotion comparative to the R(−) isomer. In contrast, large alterations in the BOLD MR signal were observed with R(−) isomer, whereas S(+) isomer and racemate precipitated more localized BOLD signal changes predominantly in cortical, hippocampal and hindbrain regions. Glucose utilization rates in conscious animals are in agreement with previously published data and verify the BOLD responses in the racemic group. However, no significant changes in glucose utilization were observed in the anesthetized cohort. Conclusions: Ketamine and its isomers have stereospecific effects on sensorimotor gating and locomotion that correlate with the enantiomer's affinity for the NMDA receptor. It would appear that anesthesia, as required for preclinical MRI procedures, may interact with and potentially attenuate the drug's response. Although analysis of the main effect of isomers in comparison to each other or the racemate offers an alternative analysis method that should be less susceptible to anesthetic interactions, only the R(−) isomer comparative to the racemate offers significant differences of interest.

Genetic background differences between FVB and C57BL/6 mice affect hypnotic susceptibility to pentobarbital, ketamine and nitrous oxide, but not isoflurane

Pharmacogenomics has allowed us to identify the mechanisms underlying much of the inherited variability in drug response. There have been several reports of strain-dependent anesthetic actions in rodents, indicating that significant genetic differences exist in the hypnotic and antinociceptive effects of various anesthetics. Loss of righting reflex was used to compare the hypnotic action of pentobarbital, ketamine, nitrous oxide and isoflurane between two genetically different populations of mice, C57BL/6 with black hair and Friends virus B (FVB) with white hair. C57BL/6 mice were more susceptible than FVB mice to the hypnotic effects of ketamine, pentobarbital and nitrous oxide. However, the sensitivity to isoflurane did not differ between C57BL/6 and FVB mice. Genetic background affects the hypnotic susceptibility to some anesthetic agents in mice. Our results indicate that there may be a different genetic basis for the operation of hypnosis between isoflurane and other anesthetics, such as pentobarbital, ketamine and nitrous oxide.

La kétamine dans la douleur aiguë : de la pharmacologie à la clinique

Ketamine is a well-known general anesthetic in use for a long time. The role of NMDA receptor in the processing of nociceptive input has led to renewed clinical interest in N-methyl-D-aspartate (NMDA) receptor antagonists such as ketamine. Animal studies on ketamine and opioid tolerance have shown promising results. Recent data in animal experiments as in clinical trials have clearly reported that pain modulation is related to an equilibrium between antinociceptive and pronociceptive systems. Therefore, the apparent pain level could not only be a consequence of a nociceptive input increase but could also result from a pain sensitization process. We evaluate the clinical literature and discuss the efficacy of low-dose ketamine in the management of acute pain when administered alone or in conjunction with other analgesic agents as morphine. Low-dose of ketamine is a peroperative intravenous bolus (0.1 to 0.5 mg/kg) followed by a constant infusion rate (1 to 2 mcg/kg per min) for 24 to 72 hours. Those ketamine doses improved postoperative pain management by reducing hyperalgesia due to both surgical trauma and high peroperative opioid doses. This antihyperalgesic action of ketamine also limited the postoperative morphine tolerance leading to a decrease in analgesic consumption and an increase in the analgesia quality. Adverse effects were not increased with small dose ketamine. The evidence suggests that low-dose ketamine is a safe and useful in postoperative pain management when used as an adjunct to local anesthetics, opioids, or other analgesic agents.