Effects Of Ketamine And Pentobarbital On Noradrenaline .
388Laboratory InvestigationsEffects of ketamine andpentobarbital on noradrenaline release from themedial prefrontal cortexin ratsTakeshi Kubota MD,Noriyuki Anzawa MD,Kazuyoshi Hirota MD,Hitoshi Yoshida MO,Tetsuya Kushikata MD,Akitomo Matsuki MDPurpose: To determine the effects of ketamine and pentobarbital on noradrenaline release from the medial prefrontal cortex.Methods: In 14 male Wistar rats, a microdialysis probe with a 2 mm long semipermeable membrane wasimplanted in the medial prefrontal cortex. The dialysis probe was perfused at a rate of I pl-min-' with an artificialcerebrospinal fluid solution. The rats were randomly allocated to two groups: ketamine (group K, n--7) and pentobarbital (group P, n 7). Each rat was subsequently given 0 (saline), I, 10 and 100 mg'kg-I ketamine ip in groupK, and 0 (saline), 0.5, 5 and 50 mgkg-' pentobarbital ip in group P. Sixty minutes elapsed between administration.Noradrenaline concentration was measured by HPLC with an electrochemical detector at 20 min intervals.(detection limit : 250 fg'20pl-', coefficient variation of the assay: 4.9%). The data in the 20-40 min after each doseof ketamine or pentobarbital ip were used for the statistical analysis.Results: Noradrenaline release after 100 mg.kg-' ketamine increased by 7.7 2.0 (SEM) pg-collectiont compared with 2.7 0.7, 3.3 1.0 and 4.2 0.8 pg.collection-' after saline, I and 10 mg'kg-' ketamine, repectively (P 0.05). Noradrenaline release did not change after pentobarbitalConclusion: This study suggests the ketamine and pentobarbital have different effects on noradrenergic neuronsin the medial prefrontal cortex. The stimulating effect of ketamine on noradrenaline release from the cortex mightcontribute to unique clinical features of ketamine anesthesia.Objeetif: D&erminer les effets de la k6tamine et du pentobarbital sur la lib&ation de noradr naline par le cortex m dial prefrontal.M(:thode : On a implant dans le cortex m dial prefrontal de 14 rats males Wistar une sonde pour microdialyse avec une membrane semi-permeable de 2 mm de long. La sonde a t irrigu& avec une solution de liquidec phalo-rachidien artificiel un d bit de I pl.min-'. Les rats ont t r partis au hasard en deux groupes : k tamine (groupe K, n 7) et pentobarbital (groupe P, n 7). On a ensuite administr chaque animal 0 (solutionsalve), I, I 0 et I O0 mg-kg-I de k&amine ip dans le groupe K, et 0 (solution sal&), O, 5, 5 et 50 mg-kg-I de pentobarbital ip dans le groupe R Soixante minutes s@paraient chaque injection. Les concentrations de noradr6nalineont t mesur es par CLHP avec un d tecteur lectrochimique des intervalles de 20 min (limite de d&ection :250 fg'20/Jl-', coefficient de variation du dosage : 4,9 %). Les donn&s obtenues pendant rintervalle de 20-40min apt& chaque dose de k tamine ou de pentobarbital ip ont & utilis&s aux fins de ranalyse statistique.R ttltats 9 La lib&ation de noradr naline apt& 100 mg'kg-' de k&amine a augment de 7,7 2,0 (erreur type)pg-collection comparativement 2,7 0,7 ; 3,3 1,0 et 4,2 0,8 pg.collection-' apt& la solution sal6e, Iet 10 mg'kg-' de k&amine, respectivement (P 0,05). La lib&ation de noradr naline n'a pas chang& apr s I'administration de pentobarbital.Conclusion : Cette &ude a montr que la k&amine et le pentobarbital ont des effets diff&ents sur les neuronesnoradr nergiques dans le cortex m dial prefrontal. I'effet stimulant de la k&amine sur la lib&ation de noradr&naline par le cortex peut jouer un r61e dans le tableau clinique de I'anesth&ie avec k tamine.From the Department of Anesthesiology, University of Hirosaki School of Medicine. 5 Zaifu-cho, Hirosaki 036-8216, JapanAddress correspondence to: Dr T Kubota, Phone: 81-172-39-5111; Fax: 81-172-39-5112.Supported in part by grant-in-aid for scientific research (No 09470323) from the Minister of Education, Science and Culture in Japan.Acceptedfor publication January 12, 2999CAN J ANESTH 1999 / 46: 4 / pp 388-392
Kubota et al.: CORTICALNORADRENALINERELEASENORADRENALINE is a major neurotransmitter in the noradrenergic projections ofthe central nervous system (CNS).Noradrenergic neurons in the CNS play animportant role in the regulation of many physiologicalvariables including sleep-awake cycle,1,2 stressresponse, s,4 cardiovascular system,s attention and learning6,7 and are also known to be an important target ingeneral anesthesia, s The activity of the locus coeruleus(one of the major brain noradrenergic projections) influences the minimum alveolar concentration (MAC) ofhalothane and cyclopropane. 9 Moreover, neurons of thelocus coeruleus are strongly activated during recoveryfrom halothane anesthesia, l We have also previouslyreported that noradrenaline release in the posteriorhypothalamus increased during recovery fromhalothane,ix sevoflttrane,11,12and isoflurane is anesthesia.These findings suggest that suppression and activation ofnoradrenergic neurotransmission may have an importantrole in producing and emergence from general anesthesia by inhalational anesthetics, respectively. However, ivanesthetics have not been studied in this regard.Ketamine is an unique anesthetic which interactswith N-methyl-D-aspartate receptors, opioid receptors,monoaminergic receptors, muscafinic receptors andvoltage-sensitive Ca2 channels. However, it does notinteract with GABA receptors, unlike other generalanesthetic agents such as pentobarbital. 14 The clinicalfeatures of ketamine anesthesia are described as "dissociative anesthesia", a peculiar state of unconsciousnessin which the patient is in a cataleptic state, "disconnected" from the surroundings and is able to undergosurgery in comfort and without recall, is Moreover, ketamine produces posthypnotic emergence reactions suchas prolonged hallucinations and delirium. 16 Althoughthe effect ofketamine on neurotransmission in the CNSis not fully elucidated, a recent study suggests that itsaction on neurotransmitter release is different from thatofpentobarbital, a depressant anesthetic. 17The medial prefrontal cortex is one of the mostimportant brain sites for the manifestation of emotional behaviour. Is Moreover, the cerebral cortex hasbeen recognized as a target site of general anesthetics. 19 Therefore, we have investigated the effects ofketamine and pentobarbital on noradrenaline releasefrom the medial prefrontal cortex using a microdialysis technique, which is now widely used for detectionof extracelluar neurotransmitter level in the CNS.389randomly allocated to two equal groups including ketamine and pentobarbital groups (group K and P,respectively). They were housed for at least a weekbefore the experiment. They were kept in a 12 hrlight-dark cycle environment, lights on 8:00 AM to8:00 PM at a temperature of 22-24 and with ahumidity of 40%. They had free access to food andwater except on the day of the experiment.PreparationRats were mounted on a stereotaxic frame under pentobarbital anesthesia (50 mg-kg-1 ip.). A stainless guidecannula was stereotaxically implanted unilaterally intothe medial prefrontal cortex with the following coordinates (A:3.3, L:0.4, V:2.0 mm) in relation to the bregma according to the atlas by Paxinos. 2 The cannula wasfixed to the skull with dental resin and stainless-steelscrews. After all experiments, the location of the probewas verified by histological examination. Forty eighthours were allowed for recovery from the influence ofthe guide cannula implantation and a probe (A-I-12-2,Eicom, Kyoto, Japan) with a 2 mm long semipermeablemembrane in its tip was inserted through the guide cannula. The dialysis probe was perfused at a rate of 1 .min -1 with an artificial cerebrospinal fluid solution(NaCI 128 mM; KCI 2.6 mM; CaCI2 1.3 raM; MgCI20.9 mM; NaHCO s 20 mM; Na2HPO 4 1.3 mM) containing i mM pargyline to prevent degradation ofnoradrenaline. For the experiment, each rat was placed in acustom-built plexiglass box in which it could movefreely. All experiments were conducted from 10:00 AMto 5:00 PM considering the circadianrhythm of noradrenaline release. 21Experimental protocolAfter the equilibration period, samples of dialysatewere collected every 20 min. Control samples weretaken before starting anesthesia and the stability ofbaseline noradrenaline release was verified. In group K,each rat was subsequently administered equal volumesof 0 (saline placebo), 1, 10 and 100 mg-kg-1 of ketanfme ip at 60 min intervals. In group P, each rat wassubsequently administered equal volumes of 0 (salineplacebo), 0.5, 5 and 50 kg-mg-l pentobarbital ip at 60min intervals. Therefore, there were three samples perinjection period subsequent to five control samples foreach rat for a total of 17 samples per rat.Measurement of noradrenaline releaseMaterials and methodsThis study was approved by the animal care committee of our institution. Fourteen male Wistar rats(Japan Clea, Kyoto, Japan) weighing 250-350 g wereThe noradrenaline content was measured by high-performance liquid chromatography (HPLC) equippedwith an electrochemical detector. The samples werepreserved and injected by autoinjector into ODS-C18
390reverse-phase column (2.1 x 150 mm CA-5ODS:Eicom, Kyoto, Japan) maintained at 25 The mobilephase was made from 0.1 M phosphate buffer (pH6.0) containing 50 mg.l-I EDTA2Na, 400 mg-I-I 1octanesulfonate and methanol 5%. The flow rate ofthe mobile phase was 220 #.min -1 and the oxidationpotential of the graphite electrode was set at 400mVagainst a Ag/AgC1 reference electrode (ECD-300,Eicom, Kyoto, Japan). The detection limit of the assaywas 250 fg.20 p1-1 and the coefficient variation of theassay was 4.9% (2 pg-20 lal-I standard solution, n 8).The detector response was linear beyond the range ofour measurements.StatisticsWe defined an anesthetic period as a time lacking inthe fighting reflex and, preliminarily, observed thatthe righting reflex was lost within five minutes andrecovered 45-60 min after 100 mg-kg-1 ketamine ip,and was lost within 10 min and recovered 85-120 minafter 50 mg-kg-1 pentobarbital ip. Therefore, dataobtained 20-40 min after each dose of ketamine orpentobarbital ip were used for analysis as this timelikely coincided with an anesthetic state in each groupafter the maximal dose of ketamine or pentobarbital.All values were expressed as mean SEM of actualdata. Statistical analysis was by two way repeated measures ANOVA followed by Bonferroni t test. A P 0.05 was considered significant.CANADIAN JOURNAL OF ANESTHESIANA release(pg.collection -110"t*w987 Group K- - l - - Group P6-543210IK0P0IK1P0.5IIK10K100P5P50FIGURE Effects ofketamine and pcntobarbital on noradrenalinerelease from the medial prefrontal cortex. All data are expressed asmean SEM. K 0 , 1, 10, 100: Dose of ketamine ip (mg.kgq); P 0,0.5, 5, 50: dose ofpentobarbital ip (mg.kg-1). *: P 0.05 vsKO ip,t: P 0.05 vsK1, :: P 0.05 vsKlO, w : P 0.05 vsP50.Re,stiltsNo anesthetic state was produced in rats after i and 10mg.kg-1 ketamine ip or after 0.5 and 5 mg.kg-1 pentobarbital ip. Basal noradrenaline release betweengroups K and P was not different: 2.3 0.6 and 2.6 0.6 pg-collection-1, respectively. Noradrenalinerelease, 20-40 min after saline placebo ip in groups Kand P were 2.7 0.7 and 2.6 0.6 pg.collection-I,respectively, and did not differ from the basal release.In group K, 100 mg.kg-1 ketamine ip increased noradrenaline release compared with 0, 1 and 10 mg.kg-Iketamine ip (Figure). On the contrary, no changes innoradrenaline release were observed in group P(Figure). There was a difference of noradrenalinerelease between 100 mg.kg-1 ketamine and 50mg-kg-I pentobarbital.DiscussionThe present study showed that noradrenaline releasefrom the medial prefrontal cortex was not changed bypentobarbital ip. Pan et al. demonstrated that therewas no difference in basal extracelluar concentrationsof noradrenaline in the medial prefrontal cortexbetween conscious rats and rats anesthetized withpentobarbital. 22 Our data coincides with their result.However, Mizuno et al. reported that noradrenalinerelease in the preoptic area decreased by 40-50% ofbasal release after 35 mg.kg-1 pentobarbital ip. 23 Thisdiscrepancy may be explained by differences in majornoradrenergic innervation between the cerebral cortexand the preoptic area. The major noradrenergic innervation of the cerebral cortex originates mainly fromthe locus coeruleus,24 while the preoptic area is innervated by not only the locus coeruleus but also theother cell groups in the medulla oblongata and pons. 2sIn contrast, a dose-dependent increase in noradrenaline release by ketamine was observed, and themean noradrenaline release after an anesthetic dose ofketamine (100 mg.kg-1 ip) was different from thoseafter subanesthetic doses of ketamine or after an anesthetic dose of pentobarbital. Although stress by ipinjection may cause increases in the CNS noradrenergic activities, 4 the injection stress in this study probably did not affect the outcome because we did not findany differences in the noradrenaline releases between
Kubota etal.:391C O R T I C A L N O R A D K E N A L I N E RELEASEthe basal and post- saline ip. Therefore, ketaminemight cause activation o f the noradrenergic system inthe locus coeruleus-cerebral cortex.The role of the noradrenergic system in anesthesia hasbeen the subject of much investigation. Roizen et al.reported that bilatereal destruction of the locus coeruleusdecreased halothane MAC from 1.13 to 0.78%, cyclopropane MAC from 20.5 to 16.1% and decreased noradrenaline content in the cerebral cortex by 80%.9 Birch etal. also reported that L-phenylisopropyladenosine (LPIA) treatment decreased central noradrenergic transmission and reduced the MAC of halothane by 49%. 2sSaunier et al. showed that noradrenergic neurons in thelocus coeruleus were strongly activated during recoveryfrom halothane anesthesia and donidine, an a2-adrenoceptor agonists, inhibited the activity o f the locuscoeruleus neurons during recovery from halothane anesthesia. De Sarro et al. revealed that microinfusion ofclonidine into the locus coeruleus produced behaviouralsedation and sleep in rat. 26 Moreover, dexmedetomidine,another a2-adrenoceptor agonist reduced dose requirements for halothane. 2z These reports suggest that inhibition of noradrenergic neuronal activity in the locuscoeruleus is involved in the mechanism of inhalationalanesthesia. However, in this study, ketamine and pentobarbital did not inhibit noradrenergic activity in the cerebral cortex which is mainly innervated by the locuscoeruleus. Therefore, inhibition of noradrenergic activityin the cerebral cortex may not be related to the mechanism o f ketamine and pentobarbital anesthesia.In the present study, we observed marked activationof noradrenaline neurons in the cerebral cortex by ketamine. The locus coeruleus receives multi-modal innervation from neurons containing excitatory amino acids,noradrenaline, 5-hydroxytryptamine and acetylcholine,and activation of these neurons greatly influences theexcitability o f the locus coeruleus. 2s As ketamine increases release o f acetylcholine17 and reduces 5-hydroxytryptamine synthesis and metabolism in the CNS, 29 it mightindirectly activate noradrenergic neurons in the locuscoeruleus via other neurotransmission systems. However,further studies are needed to clarify the mechanism.In conclusion, ketamine increased noradrenalinerelease from the medial prefrontal cortex whereas pentobarbital did not. The stirnulatory effects ofketamineon noradrenaline release from the medial prefrontalcortex might contribute to the unique clinical featureso f ketamine anesthesia.AcknowledgmentWe thank Associate Professor Yutaka Sakurai(National Defense Medical College, Japan) for hisvaluable direction about statistics.References1 Mohankumar V, Datta S, Chhina GS, Gandhi N, Singh B.Sleep-awake responses elicited from medial preoptic areaon application of norepinephrine and p henoxybenzaminein free moving rats. Brain Res 1984; 322: 322-5.2 Mallick BN, Alam MN. Different types of norepinephrinergic receptors are involved in preoptic area mediated independent modulation of sleep-wakefulness andbody temperature. Brain Res 1992; 591: 8-19.3 Yokoo H, Tanaka M, Yoshida M, Tsuda A, Tanaka T,Mizoguchi K. Direct evidence of conditioned fear-elicited enhancement ofnoradrenaline release in the rathypothalamus assessed by intracranial microdialysis.Brain Res 1990; 536: 305-8.4 Nakane H, Shimizu iV, Hori T. Stress-induced norepinephrine release in the rat prefrontal cortex measuredby microdialysis. Am J Physiol 1994; 267: R1559-66.5 Morilak DA, Fornal CA, Jacobs BL. Effects of physiological manipulations on locus coeruleus neuronalactivity in freely moving cats. II. Cardiovascular challenge. Brain Res 1987; 422: 24-31.6 Robbins T . Cortical noradrenaline, attention andarousal (Editorial). Psycho Med 1984; 14: 13-21.7 Sara SJ. Noradrenergic modulation of selective attention: its role in memory retrieval. Ann NY Acad Sci1985; 444: 178-93.8 Angel A. Central neuronal pathways and the process ofanaesthesia. Br J Anaesth 1993; 71: 148-63.9 Roizen MF, White PF, Eger EI II, Brownstein M. Effectsof ablation of serotonin or norepinephrine brain-stemareas on halothane and cyclopropane MACs in rats.Anesthesiology 1978; 49: 252-5.10 Saunier CF, Akaoka H, de La Chapelle B, et al.Activation of brain noradrenergic neurons duringrecovery from halothane anesthesia. Anesthesiology1993; 79: 1072-82.11 Chave S, Kushikata T, Ohkawa H, Ishiara H, Grimaud 1),Matsuki A. Effects of two volatile anesthetics (sevoflurane and halothane) on the hypothalamic noradrenalinerelease in rat brain. Brain Res 1996; 706: 293-6.12 Ohkawa Kushikata T, Satoh 7", Hirota K, IshiharaH, Matsuki A. Posterior hypothalamic noradrenalinerelease during emergence from sevoflurane anesthesiain rats. Anesth Analg 1995; 81: 1289-91.13 Kushikata T, Anzawa N, Yoshida I-I, Hirota K.Isoflurane anesthesia influences norepinephrinergicneuronal activity in the rat anterior and posterior hypothalamus. Journal of the Japanese Society forPharmacoanesthesiology 1997; 10: 3-8.14 Hirota K. Lambert DG. Ketamine: its mechanism(s) ofaction and unusual clinical use (Editorial). Br J Anaesth1996; 77; 441-4.15 Corssen G, Domino EF. Dissociative anesthesia: further
392pharmacologic studies and first clinical experience withthe phencyclidine derivative CI-581. Anesth Analg1966; 45: 2 9 4 0 .16 Sussman DR. A comparative evaluation ofketamineanesthesia in children and adults. Anesthesiology 1974;40: 459-64.17 Sato K, WuJ, Kikuchi T, Wang Y, Watanabe I,Okumura F. Differential effects of ketamine and pentobarbitone on acetylcholine release from the rat hippocampus and striatum. Br J Anaesth 1996; 77: 381--4.18 Korf J, Aghajanian GK, Roth RH. Increased turnoverofnorepinephrine in the rat cerebral cortex duringstress: r01e of the locus coeruleus. Neuropharmacology1973; 12: 933-8.19 Angel A, Gratton DA. The effect of anaesthetic agentson cerebral cortical responses in the rat. Br JPharmacol 1982; 76: 541-9.20 Paxinos G, Watson C. The Rat Brain in StereotaxicCoordinates, 2nd ed. San Diego: Academic Press,1986.21 ManshardtJ, Wurtman RJ. Daily rhythm in the noradrenaline content of rat hypothalamus. Nature 1968;217: 574-5.22 Pan WHT, LAI Y-J. Anesthetics decreased the microdialysis extraction fraction of norepinephrine but notdopamine in the medial prefrontal cortex. Synapse1995; 21: 85-92.23 Mizuno T, Ito E, Kimura F. Pentobarbital sodiuminhibits the release of noradrenaline in the medial preoptic area in the rat. Neurosci Lett 1994; 170: 111-3.24 Ungerstedt U. Stereotaxic mapping of the monoaminepathways in the rat brain. Acta Physiol Scand 1971;367(Suppl): 1-48.25 Birch BD, Louie GL, VickeryRG, Gaba DM, Maze M. Lphenylisopropyladenosine (L-PIA) diminishes halothaneanesthetic requirements and decreases noradrenergicneurotransmission in rats. Life Sci 1988; 42: 1355-60.26 De Sarro GB, Ascioti C, Froio F, Libri V, Nistico G.Evidenc
Les rats ont t r partis au hasard en deux groupes : k ta- mine (groupe K, n 7) et pentobarbital (groupe P, n 7). On a ensuite administr chaque animal 0 (solution salve), I, I 0 et I O0 mg-kg -I de k&amine ip dans le groupe K, et 0 (solution sal&), O, 5, 5 et 50 mg-kg -I de pen- tobarbital ip dans le groupe R Soixante minutes s@paraient .
Florida Spine Institute, 2250 Drew Street Clearwater, FL 33765 (USA) E-Mail ahanna@fsispine.com Single Case Effects of Intravenous Ketamine Infusions in a Neuropathic Pain . da Spine Institute and reported complete abolishment of her pain syndrome. For the first time, we report that ketamine infusions also dramatically improved a patient's .
(2.55 vs. 1.07) (Table 1). Patients receiving ketamine demonstrated a lower prev-alence of PTSD. Of those receiving ketamine, the prevalence of PTSD was 26.9% (32 of 119) versus 46.4% in those not receiving keta
Utilisation de la kétamine en anesthésie pédiatrique . Assistance Publique Hôpitaux de Paris. Pharmacologie de la kétamine petite molécule très liposoluble Teq 11 s métabolisme hépatique norkétamine, métabolite actif, contribue à l’analgésie . (très immature à la naissance)-homme (espèce précoce)
participants completed a detailed cognitive battery that covered general intelligence, verbal memory, visual memory, executive function, motor speed, and language. Participants in the primarily ketamine group predominantly used ketamine, whereas participants in the
(v) in transected frog cutaneous pectoris muscles. Since ketamine has a pKa of 7.5, the block of e.p.c. parameters was more effective at pH 5.3 (more ionized) than at pH 9.1. Recovery from e.p.c. block by ketamine, ditran, and phencyclidine (PCP) was asymmetrical in that v recovered more quickly than did Ip when the drugs were washed from the bath.
The RSDSA is also tackling the thorny issue on how individuals with CRPS are treated by Emergency Department (ED) staff when they go to obtain pain relief for an unbearable pain flare. The answer may be intravenous (IV) ketamine. ED staff are very familiar with ketamine, but not as a rescue agent for breakthrough neuropathic pain.
GBL (Gamma hydroxybutyrate) is an anaesthetic; GBL (Gamma butyrolactone) is closely related to GHB (pro-drug). GHB/GBL are water-like liquids, to be drunk with water or other soft drinks. Ketamine is a powder which is usually snorted, the effects usually last around 45-90 minutes. If injected or swallowed, effects can last for up to three hours.
An Introduction to Modal Logic 2009 Formosan Summer School on Logic, Language, and Computation 29 June-10 July, 2009 ; 9 9 B . : The Agenda Introduction Basic Modal Logic Normal Systems of Modal Logic Meta-theorems of Normal Systems Variants of Modal Logic Conclusion ; 9 9 B . ; Introduction Let me tell you the story ; 9 9 B . Introduction Historical overview .
