Rifampicin has a Profound Effect on the Pharmacokinetics of Oral S‐Ketamine and Less on Intravenous S‐Ketamine

Low‐dose ketamine is currently used in several acute and chronic pain conditions as an analgesic. Ketamine undergoes extensive metabolism and is thus susceptible to drug–drug interactions. We examined the effect rifampicin, a well‐known inducer of many cytochrome P450 (CYP) enzymes and transporters, on the pharmacokinetics of intravenous and oral S‐ketamine in healthy volunteers. Eleven healthy volunteers were administered in randomized order 600 mg rifampicin or placebo orally for 6 days in a four‐session paired cross‐over study. On day 6, S‐ketamine was administered intravenously (0.1 mg/kg) in the first part of the study and orally (0.3 mg/kg) in the second part. Plasma concentrations of ketamine and norketamine were measured up to 24 hr and behavioural and analgesic effects up to 12 hr. Rifampicin treatment decreased the mean area under the plasma ketamine concentration–time curve extrapolated to infinity (AUC _0–∞) of intravenous and oral S‐ketamine by 14% (p = 0.005) and 86% (p < 0.001), respectively. Rifampicin decreased greatly the peak plasma concentration of oral S‐ketamine by 81% (p < 0.001), but shortened only moderately the elimination half‐life of intravenous and oral S‐ketamine. Rifampicin decreased the ratio of norketamine AUC _0–∞ to ketamine AUC _0–∞ after intravenous S‐ketamine by 66%, (p < 0.001) but increased the ratio by 147% (p < 0.001) after the oral administration of S‐ketamine. Rifampicin profoundly reduces the plasma concentrations of ketamine and norketamine after oral administration of S‐ketamine, by inducing mainly its first‐pass metabolism.     

Sex-dependent changes in ketamine-induced locomotor activity and ketamine pharmacokinetics in preweanling,adolescent, and adult rats

Although ketamine has long been known to increase locomotor activity, only recently was it realized that this behavioral effect varies according to both sex and age. The purpose of the present study was threefold: first, to measure the locomotor activating effects of ketamine in male and female rats across early ontogeny and into adulthood; second, to assess ketamine and norketamine pharmacokinetics in the dorsal striatum and hippocampus of the same age groups; and, third, to use curvilinear regression to determine the relationship between locomotor activity and dorsal striatal concentrations of ketamine and norketamine. A high dose of ketamine (80 mg/kg, i.p.) was administered in order to examine the complete cycle of locomotor responsiveness across a 280-min testing session. In separate groups of rats, the dorsal striata and hippocampi were removed at 10 time points (0–360 min) after ketamine administration and samples were assayed for ketamine, norketamine, and dopamine using HPLC. In female rats, ketamine produced high levels of locomotor activity that varied only slightly among age groups. Male preweanling rats responded like females, but adolescent and adult male rats exhibited lesser amounts of ketamine-induced locomotor activity. Ketamine and norketamine pharmacokinetics, especially peak values and area under the curve, generally mirrored age- and sex-dependent differences in locomotor activity. Among male rats and younger female rats, dorsal striatal ketamine and norketamine levels accounted for a large proportion of the variance in locomotor activity. In adult female rats, however, an additional factor, perhaps involving other ketamine and norketamine metabolites, was influencing locomotor activity.     

The effects of acute and repeated administration of ketamine on attentional performance in the five-choice serial reaction time task in rats

Ketamine, the non-competitive antagonist of the N-methyl-d-aspartate receptors, is used in clinical and preclinical studies to produce schizophrenia-like cognitive impairments. However, the impact of ketamine on attentional functions remains poorly characterised. In the present study, we further examine the effects of ketamine on attentional processes assessed in the five-choice serial reaction time task (5-CSRTT) in rats. The applied schedules of ketamine administration have been previously demonstrated to evoke frontal-dependent set-shifting impairments. Rats were trained to reach a stable baseline performance. Afterwards, animals received a single injection of ketamine (0, 3 and 10 mg/kg, IP) 45 min before the 5-CSRTT session (experiment 1). In experiment 2, ketamine (0 and 30 mg/kg, IP) was administered after the daily test session for 10 consecutive days. The rats׳ performance was assessed at 22 h following ketamine administration and for 4 days after the last dose. Acute and repeated administration of ketamine disrupted rats׳ performance on the 5-CSRTT. Reduced speed of responding and an increased number of omissions were noted in the absence of reduced food motivation. The within-session pattern of responding differed between rats treated acutely and repeatedly with ketamine. Specifically, repeated drug administration evoked an increase in omissions toward the end of the session, and this effect was not secondary to the reduced motivation. Ketamine affected performance during the withdrawal period only when testing with variable inter-trial intervals. The repeated administration of ketamine can impair rats׳ ability to sustain attention over the course of session, suggesting some utility for modelling attentional disturbances.     

Interactions of (2S,6S;2R,6R)‐Hydroxynorketamine,a Secondary Metabolite of (R,S)‐Ketamine,with Morphine

Ketamine and its primary metabolite norketamine attenuate morphine tolerance by antagonising N‐methyl‐d ‐aspartate (NMDA) receptors. Ketamine is extensively metabolized to several other metabolites. The major secondary metabolite (2S,6S;2R,6R)‐hydroxynorketamine (6‐hydroxynorketamine) is not an NMDA antagonist. However, it may modulate nociception through negative allosteric modulation of α7 nicotinic acetylcholine receptors. We studied whether 6‐hydroxynorketamine could affect nociception or the effects of morphine in acute or chronic administration settings. Male Sprague Dawley rats received subcutaneous 6‐hydroxynorketamine or ketamine alone or in combination with morphine, as a cotreatment during induction of morphine tolerance, and after the development of tolerance induced by subcutaneous minipumps administering 9.6 mg morphine daily. Tail flick, hot plate, paw pressure and rotarod tests were used. Brain and serum drug concentrations were quantified with high‐performance liquid chromatography–tandem mass spectrometry. Ketamine (10 mg/kg), but not 6‐hydroxynorketamine (10 and 30 mg/kg), enhanced antinociception and decreased rotarod performance following acute administration either alone or combined with morphine. Ketamine efficiently attenuated morphine tolerance. Acutely administered 6‐hydroxynorketamine increased the brain concentration of morphine (by 60%), and brain and serum concentrations of 6‐hydroxynorketamine were doubled by morphine pre‐treatment. This pharmacokinetic interaction did not, however, lead to altered morphine tolerance. Co‐administration of 6‐hydroxynorketamine 20 mg/kg twice daily did not influence development of morphine tolerance. Even though morphine and 6‐hydroxynorketamine brain concentrations were increased after co‐administration, the pharmacokinetic interaction had no effect on acute morphine nociception or tolerance. These results indicate that 6‐hydroxynorketamine does not have antinociceptive properties or attenuate opioid tolerance in a similar way as ketamine.     

Chronic Administration of Ketamine Elicits Antidepressant‐Like Effects in Rats without Affecting Hippocampal Brain‐Derived Neurotrophic Factor Protein Levels

Abstract: A growing body of evidence has pointed to the blockade of the N‐methyl‐d ‐aspartate (NMDA) receptor signaling as a potential therapeutic target for the treatment of major depression. The present study was aimed to evaluate behavioural and molecular effects of the chronic treatment with ketamine and imipramine in rats. To this aim, rats were 14 days treated once a day with ketamine (5, 10 and 15 mg/kg) and imipramine (10, 20 and 30 mg/kg) and then subjected to the forced swimming and open‐field tests. Ketamine and imipramine, at the all doses tested, reduced immobility time, and increased both climbing and swimming time of rats compared to the saline group, without affecting spontaneous locomotor activity. Brain‐derived neurotrophic factor (BDNF) hippocampal levels were assessed in imipramine‐ and ketamine‐treated rats by ELISA sandwich assay. Chronic administration of both drugs, ketamine and imipramine, did not modify BDNF protein levels in the rat hippocampus. In conclusion, our findings demonstrate for the first time that chronic administration of acute inactive doses of ketamine (5 mg/kg) becomes active after chronic treatment, while no signs of tolerance to the behavioural effects of ketamine were observed after chronic administration of acute active doses (10 and 15 mg/kg). Finally, these findings further support the hypothesis that NMDA receptor could be a new pharmacological target for the treatment of mood disorders.     

氯胺酮在豚鼠毛发中的分布与代谢

目的:建立毛发中氯胺酮及其代谢物去甲氯胺酮的分析方法并研究氯胺酮在豚鼠毛发中的分布与代谢。方法:实验豚鼠随机分为灌胃(ig)组、腹腔注射(ip)组和空白组,氯胺酮给药方式为单次给药或连续给药。氯胺酮染毒豚鼠毛发样品经处理后采用气-质联用全扫描定性,内标工作曲线法气相色谱定量分析。结果:豚鼠给药后可在其毛发中检出氯胺酮及去甲氯胺酮,单次给药组在豚鼠末次给药后d3毛发内含量最高,检测时限超过10 d,多次给药组检出的药物浓度随给药次数的增加而上升,停药5 d后仍可检出。结论:连续给药后氯胺酮和去甲氯胺酮可在豚鼠毛发内形成蓄积。氯胺酮滥用可采用毛发检测分析,并根据毛发内氯胺酮的分布及代谢判断吸毒嫌疑人有无药物滥用史。     

Plasma concentration profiles of ketamine and norketamine after administration of various ketamine preparations to healthy Japanese volunteers

Ketamine is known to provide analgesic effects without an anesthetic when administered in a low dose. We previously reported that a tablet containing ketamine had analgesic effects in patients with neuropathic pain. In the present study, we compared the plasma concentration profiles of the enantiomers of ketamine and its active metabolite, norketamine, up to 8 h after the administration of 20 mg of ketamine by injection, after the administration of two tablets containing 25 mg of ketamine, after the administration of two sublingual tablets containing 25 mg of ketamine, after the insertion of a suppository containing 50 mg of ketamine, and after the application of a nasal spray containing 25 mg of ketamine to three healthy volunteers. The plasma concentration of ketamine biexponentially declined after the administration by injection; the value of T(1/2beta) for ketamine was approximately 120 min. The bioavailability of the tablet was estimated to be approximately 20%; the area under the plasma concentration-time curve, (AUC)(0-->8 h), of norketamine was approximately 500 ng h/ml in both enantiomers. The bioavailabilities of the sublingual tablet and the suppository were estimated to both be approximately 30%; the AUC(0-->8 h) of norketamine was 280-460 ng h/ml in both enantiomers. The plasma concentration profiles of the sublingual tablet and the suppository were almost similar to that of the tablet. The bioavailability of the nasal spray was estimated to be approximately 45%, which was the highest value among the preparations tested, and the AUC(0-->6 h) of norketamine was low (approximately 100 ng h/ml) in both enantiomers. These pharmacokinetic findings suggested that all of the ketamine preparations tested in this study may be useful for the alleviation of neuropathic pain. We propose that the type of ketamine preparation should be selected in accordance with the patient's disease condition and the required dosage amount of ketamine.     

Ketamine for the Acute Management of Excited Delirium and Agitation in the Prehospital Setting

Traditional first‐line therapy in the prehospital setting for the acutely agitated patient includes an antipsychotic in combination with a benzodiazepine. Recently, interest has grown regarding the use of ketamine in the prehospital setting as an attempt to overcome the limitations of the traditional medications and provide a more safe and effective therapy. This review provides an overview of the pharmacology of ketamine, evaluates the literature regarding ketamine use for prehospital agitation, and proposes an algorithm that may be used within the prehospital setting. A literature review was conducted to identify articles utilizing ketamine in the prehospital setting. The review was limited to English‐language articles identified in Embase (1988–June 2017) and the U.S. National Library of Medicine (1970–June 2017). References of all pertinent articles were also reviewed. Ten articles were identified including 418 patients receiving ketamine for agitation. The most commonly utilized route for administration was intramuscular (IM), with five of the seven IM administration studies using a ketamine dose of 5 mg/kg. Ketamine administered in this fashion was efficacious to achieve proper sedation during transport and did not require repeat dosing. Three studies applied a ketamine protocol to outline dosing and the management of ketamine adverse events. The most common adverse events identified were respiratory‐related events and hypersalivation. Ketamine has a role for agitation management in the prehospital setting; however, emergency personnel education and ketamine protocols should be utilized to aid in safe and effective pharmacotherapy and provide guidance on the management of adverse events. Future prospective comparative studies, with protocolized standard ketamine regimens, are needed to further delineate the role of ketamine in agitation management and identify accurate adverse event incidence rates.     

The duration of ketamine detection in hair after treatment cessation: Case study and review of the literature in forensic and clinical casework

The disappearance of drug from hair does not occur immediately after abstinence because dormant hair may contribute to the positivity of freshly grown hair. The aim of this study was to assess ketamine disappearance from hair after treatment cessation and to review the literature data. A 22-year-old female received three intravenous doses of ketamine (171 mg) for major depression treatment. Seventeen weeks later, a 26 cm lock of hair was sampled, and ketamine was determined by liquid chromatography tandem mass spectrometry (LC–MS/MS) on seven segments: A (proximal, 0–2 cm), B (2–4 cm), C (4–6 cm, period of ketamine therapy), and D to G (4 × 5 cm). Ketamine concentration was 58 pg/mg in Segment C and remained detectable over 4 months after treatment cessation at 67 pg/mg in Segment B and 2 pg/mg in Segment A, representing a 97% drop from the initial concentration. Ketamine elimination half-life in hair was estimated at 0.88 month, implying that indetectable concentration should be expected 7 months after cessation. Axial diffusion was excluded as ketamine was not detected in Segments D–G. Given the low ketamine concentrations, norketamine was not detected. While no data on ketamine disappearance from hair have been published to date, previous studies have shown that discontinuation resulted in negative hair results after 3 months for heroin, 3–4 months for cocaine and tramadol, 6 months for amphetamine and methamphetamine, and 6–7 months for THC-COOH. This study provides useful findings for ketamine hair concentration interpretation, which should be validated by more consistent and comprehensive investigations.     

Comparison of the Intramuscular,Intranasal or Sublingual Routes of Midazolam Administration for the Control of Soman‐Induced Seizures*

Abstract: This study evaluated the anticonvulsant effectiveness of midazolam to stop seizures elicited by the nerve agent soman when midazolam was administered by different routes (intramuscular, intranasal or sublingual) at one of two different times after the onset of seizure activity. Guinea pigs previously prepared with cortical electrodes to record brain electroencephalographic activity were pre‐treated with pyridostigmine (0.026 mg/kg, intramuscularly) 30 min. before challenge with a seizure‐inducing dose of the nerve agent soman (56 µg/kg, subcutaneously), and 1 min. later, they were administered 2.0 mg/kg atropine sulfate admixed with 25.0 mg/kg 2‐PAM Cl (intramuscularly). Groups of animals were administered differing doses of midazolam by the intramuscular, intranasal or sublingual route at either the onset of seizure activity or 40 min. after the onset of seizure activity that was detected in the electroencephalographic record. When given immediately after seizure onset, the anticonvulsant ED₅₀ of intramuscular midazolam was significantly lower than that of intranasal midazolam, which in turn was significantly lower than sublingual midazolam at that time. At the 40‐min. treatment delay, the anticonvulsant ED₅₀s of intramuscular or intranasal midazolam did not differ and both were significantly lower than the sublingual route. Higher doses of midazolam were required to stop seizures at the 40‐min. treatment delay time compared to immediate treatment. The speed of seizure control for intramuscular or intranasal midazolam was the same while sublingual midazolam acted significantly slower. Midazolam was effective in treating soman‐induced seizures when given by all three routes, but with differences in potency and speed of action.     

Caloric restriction increases the sensitivity to the hyperphagic effect of nociceptin/orphanin FQ limiting its ability to reduce binge eating in female rats

Rationale

Several studies have documented impairments in memory processes as a result of ketamine administration; however, few studies have compared the profile of cognitive effects of ketamine to other drugs.

Objectives

The aim of this study was to compare the cognitive effects of ketamine with those of triazolam in healthy volunteers.

Methods

Doses of ketamine (0.2, 0.4 mg/kg intramuscular (i.m.)), triazolam (0.2, 0.4 mg/70 kg p.o.), and double-dummy placebos were administered to 20 volunteers under repeated measures, counterbalanced, double-blind conditions. Peak physiological, psychomotor, subjective, and cognitive effects were examined.

Results

Ketamine impaired balance when balance was assessed early in the task order, whereas triazolam impaired psychomotor coordination and divided attention irrespective of task order. Triazolam also tended to produce greater effects on working memory and episodic memory tasks than ketamine at doses that produced lower subjective effects and higher estimates of performance.

Conclusions

Ketamine produces less cognitive impairment than triazolam at doses that produced greater subjective effects. Thus ketamine does not produce the underestimation of cognitive impairment typically seen with triazolam.     

Synthesis of carbon‐14 labeled ketamine and norketamine

Ketamine is a well‐known general anesthetic that inhibits cerebral NMDA receptors. Norketamine is a major circulating metabolite of this drug. A nasal spray formulation of esketamine, the S enantiomer of ketamine, is under development for the management of treatment‐resistant depression. To assess the pharmacokinetic properties, C‐14 labeled ketamine and norketamine were prepared separately from commercially available [¹⁴C]CuCN through a five‐step sequence with the C‐14 label at the quaternary carbon of the cyclohexyl ring. Chiral resolution of [¹⁴C]ketamine and chiral column separation of [¹⁴C]norketamine resolved/separated the (S)‐enantiomers from (R)‐enantiomers.     

Comparison of relative distribution of ketamine and norketamine in decomposed skeletal tissues following single and repeated exposures

Bone was analyzed for ketamine and norketamine to examine whether different patterns of drug exposure could be discriminated. Rats received (intraperitoneally) one 75 mg/kg dose (Acute-1 and Acute-2 groups), three 25-mg/kg doses 1 hour apart (Repeated group), or nine single daily ketamine doses of 75 mg/kg followed by a 24-h washout period (Chronic group). Following euthanasia, all animals decomposed to skeleton outdoors. Ground samples of recovered bone underwent methanolic extraction and analysis by gas chromatography-mass spectrometry after solid-phase extraction. Drug levels (mass normalized response ratios) were compared across bone types and exposure pattern. Bone type significantly influenced drug level for the Acute-1 and Repeated dose groups, and the drug/metabolite level ratio (DMLR) for the Acute-1 group. Mean ketamine and norketamine level and DMLR varied by up to 8-fold, 7-fold and 3-fold, respectively, in the Acute-1 group, and by up to 24-fold, 5-fold and 10-fold, respectively, in the Repeated group. Drug level and DMLR differed significantly between the Acute-1 and Repeated groups for most bone types. In the Chronic group, only 1/16 and 4/16 samples were positive for ketamine and norketamine, respectively. All Acute-2 samples were positive for ketamine and norketamine. The Acute-2 and Chronic groups differed significantly in ketamine and norketamine levels, and DMLR.     

Urine concentrations of ketamine and norketamine following illegal consumption

Ketamine, an anesthetic agent primarily used in veterinary medicine and pediatrics, continues to gain in popularity in the drug abuse scene or 'Rave Wave' of all-night dance clubs. The Division of Forensic Toxicology Laboratory (Office of the Armed Forces Medical Examiner) at the Armed Forces Institute of Pathology, as the primary analytical laboratory for criminal investigative agencies in the Department of Defense (DOD), has seen requests for ketamine analysis rise from 1 in 1997 to 116 in 2000. This increasing abuse has led the DOD Urine Drug Testing Laboratories to consider adding ketamine screening to their random urinalysis program. However, before ketamine testing can be implemented as standard policy, concentrations of ketamine and metabolites in urine need to be evaluated after actual drug use. There is very little information regarding the pharmacokinetics of ketamine, especially concentrations of the drug or its two major metabolites, norketamine and dehydronorketamine, that can be expected in urine. In fact, dehydronorketamine has been believed to be an analytical artifact caused by the high temperatures of gas chromatography. In this paper, we attempt to resolve this issue with the development of a liquid chromatography-mass spectrometry (LC-MS) method. The urine concentrations of ketamine, norketamine and dehydronorketamine (presumptive) detected in 33 "positive" cases received in our laboratory since 1998 are reported. Quantitations were accomplished with LC-MS. Ketamine concentrations ranged from 6 to 7744 ng/mL. Norketamine concentrations ranged from 7 to 7986 ng/mL and dehydronorketamine (presumptive) concentrations ranged from 37 to 23,239 ng/mL.     

Ketamine attenuates sepsis-induced acute lung injury via regulation of HMGB1-RAGE pathways

High mobility group box protein 1 (HMGB1) and receptor for the advanced glycation end product (RAGE) play important roles in the development of sepsis-induced acute lung injury (ALI). Ketamine is considered to confer protective effects on ALI during sepsis. In this study, we investigated the effects of ketamine on HMGB1-RAGE activation in a rat model of sepsis-induced ALI. ALI was induced in wild type (WT) and RAGE deficient (RAGE^−/−) rats by cecal ligation and puncture (CLP) or HMGB1 to mimic sepsis-induced ALI. Rats were randomly divided to six groups: sham-operation + normal saline (NS, 10 mL/kg), sham-operation + ketamine (10 mg/kg), CLP/HMGB1 + NS (10 mL/kg), CLP/HMGB1 + ketamine (5 mg/kg), CLP/HMGB1 + ketamine (7.5 mg/kg), and CLP/HMGB1 + ketamine (10 mg/kg) groups. NS and ketamine were administered at 3 and 12 h after CLP/HMGB1 via intraperitoneal injection. Pathological changes of lung, inflammatory cell counts, expression of HMGB1and RAGE, and concentrations of various inflammatory mediators in bronchoalveolar lavage fluids (BALF) and lung tissue were then assessed. Nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPK) signaling pathways in the lung were also evaluated. CLP/HMGB1 increased the wet to dry weight ratio and myeloperoxidase activity in lung, the number of total cells, neutrophils, and macrophages in the BALF, and inflammatory mediators in the BALF and lung tissues. Moreover, expression of HMGB1and RAGE in lung tissues was increased after CLP. Ketamine inhibited all the above effects. It also inhibited the activation of IκB-α, NF-κB p65, and MAPK. Ketamine protects rats against HMGB1-RAGE activation in a rat model of sepsis-induced ALI. These effects may partially result from reductions in NF-κB and MAPK.     

Ketamine inhibits serotonin synthesis and metabolism in vivo

Ketamine (160 mg/kg, i.p.) was found to reduce the accumulation of 5-hydroxytryptophan (5-HTP) in whole brain following inhibition of L-aromatic amino acid decarboxylase with 50 mg/kg of 3-hydroxybenzylhydrazine (NSD-1015). Smaller doses of ketamine did not affect whole brain 5-HTP accumulation. However in regional studies, 80 mg/kg of ketamine significantly reduced 5-HTP accumulation in the spinal cord and the midbrain-thalamus. A dose of 160 mg/kg ketamine also reduced 5-HTP accumulation in the spinal cord and midbrain-thalamus and in the medulla-pons, striatum and cortex as well. No significant changes in 5-HTP accumulation were observed in the hypothalamus or hippocampus. Ketamine (160 mg/kg) also reduced whole brain 5-hydroxyindoleacetic acid (5-HIAA) levels and slightly elevated whole brain 5-hydroxytryptamine (5-HT) levels. Smaller doses did not affect either 5-HIAA or 5-HT levels. Ketamine did not affect whole brain tryptophan levels nor did it inhibit [3H]tryptophan uptake or conversion to [3H]5-HT in vitro. These data demonstrate that ketamine reduced both 5-HT synthesis and metabolism in vivo. Since ketamine did not affect brain tryptophan levels nor did it inhibit 5-HT in vitro, the reduction of 5-HT turnover following ketamine administration appears to be a neuronal, adaptive phenomenon possibly occurring in response to a blockade of 5-HT uptake by ketamine.     

毛发颜色和给药剂量对氯胺酮在豚鼠毛发中分布与代谢的影响

目的:研究给药剂量及毛发颜色对豚鼠毛发中氯胺酮分布与代谢的影响。方法:豚鼠分高、中、低给药剂量3组或黑、棕、白色3组,单次和连续腹腔注射(ip)盐酸氯胺酮,给药后不同时间采集豚鼠毛发,毛发样品处理后采用气相色谱/质谱联用(GC/MS)全扫描定性,气相色谱(GC)定量分析毛发中的氯胺酮及其代谢物。结果:给药剂量与毛发内氯胺酮及去甲氯胺酮的检出量之间相关系数r值平均为0.91和0.84,3种毛发颜色中氯胺酮及去甲氯胺酮含量顺序为黑色>棕色>白色(P<0.05)。结论:给药剂量与毛发内氯胺酮及去甲氯胺酮的检出量之间有相关性,不同毛发颜色中氯胺酮及去甲氯胺酮检出量不同。氯胺酮滥用案件中可根据毛发内药物检出量推断滥用剂量,实际应用中应考虑毛发颜色对分析结果的影响。     

Opioid mechanisms of some behavioral effects of ketamine

The effect of naloxone on the duration of sleep and on analgesia produced by ketamine, and on the development of tolerance and cross-tolerance with morphine to ketamine analgesic effects were investigated in mice. Ketamine produced a dose-dependent analgesia. Naloxone (4 mg/kg) significantly inhibited the analgesic effects of ketamine (40 mg/kg), but (given in a dose of 2 mg/kg) did not affect the duration of ketamine sleep. Chronic administration of ketamine (160 mg/kg twice daily for 7 days) resulted in a gradual shortening of ketamine sleep and in the development of tolerance to the analgesic action of ketamine. There also developed cross-tolerance between analgesic effects of morphine and ketamine. Ketamine (20 mg/kg) significantly inhibited symptoms of morphine abstinence produced in morphine-pelleted mice by naloxone administration or by pellet removal. The results suggest that at least some elements of the mechanism of action of ketamine and morphine may be common and related to the endogenous opioid system.     

Activation of metabotropic glutamate (mGlu)2 receptors suppresses histamine release in limbic brain regions following acute ketamine challenge

In the present study we demonstrated that ketamine, an NMDA antagonist and possible psychotomimetic, increases extracellular histamine (HA) in the rat brain. We then examined the ability of the group II mGlu receptor agonist LY379268 to modulate the ketamine evoked increases in HA release in three limbic brain regions. Ketamine (25 mg/kg) increased HA in the medial prefrontal cortex (mPFC), ventral hippocampus (vHipp) and the nucleus accumbens (NAc) shell. LY379268 administered alone was without effect on basal HA efflux in the mPFC or vHipp but modestly decreased HA efflux in the NAc shell. Administration of LY379268 (3 and 10 mg/kg) prior to ketamine significantly attenuated the HA response in the mPFC, vHipp and the NAc shell. The inhibitory effects of LY379268 in the mPFC were mimicked by the systemic administration of the mGlu2 receptor positive allosteric modulator CBiPES (60 mg/kg). Finally, local perfusion experiments revealed that the effects of LY379268 on ketamine evoked HA efflux appear to be mediated by mGlu2 receptors outside the PFC as the intra-mPFC perfusion of LY379268 (100 μM or 300 μM) failed to attenuate ketamine evoked increases in HA efflux. Together, these novel observations reveal an effect of ketamine on histaminergic transmission in limbic brain areas and provide further insight into the possible antipsychotic mechanism of action of mGlu2/3 receptor agonists.