Central sensitization is a potential severe consequence of invasive surgical procedures. It results in postoperative and potentially chronic pain enhancement. It results in postoperative pain enhancement; clinically manifested as hyperalgesia and allodynia. N-methyl-D-aspartate (NMDA) receptor plays a crucial role in the mechanism of central sensitisation. Ketamine is most commonly used NMDA-antagonist in human and veterinary practice. However, the antinociceptive serum concentration of ketamine is not yet properly established in dogs. Six dogs were used in a crossover design, with one week washout period. Treatments consisted of: 1) 0.5 mg/kg ketamine followed by continuous rate infusion (CRI) of 30 μg/kg/min; 2) 0.5 mg/kg ketamine followed by CRI of 30 μg/kg/min and lidocaine (2 mg/kg followed by CRI of 100 μg/kg/min); and 3) 0.5 mg/kg ketamine followed by CRI of 50 μg/kg/min. The infusion was administered up to 120 min. Nociceptive thresholds and ketamine serum concentrations were measured before drug administration, and at 5, 10, 20, 40, 60, 90, 120, 140 and 160 min after the start of infusion.

Various nonpharmacological and pharmacological trials have been used for attenuating postoperative sore throat (POST) with no proven single modality. Ketamine has been used as a gargle or nebulization in the attenuation of POST by its action on peripheral N-methyl-D-aspartate receptors. Topical administration of clonidine elicits antinociception through α2-adrenoceptors without producing undesirable side effect.

Although recent studies provide insight into the molecular mechanisms of the effects of ketamine, the antidepressant mechanism of ketamine enantiomers and their metabolites is not fully understood. In view of the involvement of mechanisms other than the N-methyl-D-aspartate receptor in ketamine's action, we investigated the effects of (R)-ketamine, (S)-ketamine, (R)-norketamine [(R)-NK], (S)-NK, (2R,6R)-hydroxynorketamine [(2R,6R)-HNK], and (2S,6S)-HNK on monoaminergic neurotransmission in the prefrontal cortex of mice.

No abstract available

Differences in the pharmacological effects of (S)-ketamine and (R)-ketamine are at the focus of research. Clinical data and our rat studies confirmed the antidepressant effect of (S)- but not (R)-ketamine, with similar differences in quantitative electroencephalogram (EEG) and sleep effects. In contrast, studies mainly on mice showed some stronger, preferable effects of (R)-ketamine. EEG theta (5-9 Hz) rhythm originates from the hippocampus, and its power is associated with cognitive functions, attention, and decreased anxiety. To find a brain parameter that is not associated with the antidepressant effect of drugs and may confirm potent in vivo effects of (R)-ketamine in rats, theta EEG power-inducing effects of the two enantiomers were measured and compared for 23 h. EEG-equipped Wistar rats were treated with (R)-ketamine (7.5, 15, 30 mg/kg i.p.), (S)-ketamine (7.5 and 15 mg/kg i.p.), or vehicle at the beginning of the passive phase. Frontoparietal EEG, electromyogram, and motor activity were recorded. (R)-ketamine but not (S)-ketamine dose-dependently increased EEG theta power during wakefulness and rapid eye movement (REM) sleep for 23 h. These results suggest that (R)-ketamine has an effect on a hippocampal function that was not affected by (S)-ketamine and may be associated with neural plasticity and memory encoding.

Inflammation is an important biological process which contributes to risk for depression, in part as a result of the production of proinflammatory cytokines and of alterations in glutamatergic neurotransmission. Ketamine has anti-inflammatory properties which might contribute to its antidepressant effects. This study was designed to clarify mechanisms of action for ketamine and its active metabolites, (2R,6R;2S,6S)-hydroxynorketamine (HNK), which also appear to play a major role in ketamine's rapid antidepressant effects. An HMC3 human microglial cell line was used as a model system to test a possible role for ketamine in immune response regulation that might contribute to its antidepressant effects. Our results highlight the fact that ketamine and its two active metabolites can regulate the type I interferon pathway mediated, at least partially, through signal transducer and activation of transcription 3 (STAT3) which plays a major role in the immune response. Specifically, STAT3 downstream genes that were modulated by either ketamine or its active metabolites were enriched in the "response to type I interferon" pathway. Our data also suggest that STAT3 might play a role in ketamine's antidepressant effects, mediated, at least in part, through eukaryotic elongation factor 2 (EEF2), resulting in the augmentation of brain-derived neurotropic factor (BDNF) expression and promoting the synthesis of synaptic proteins postsynaptic density protein 95 (PSD95) and synapsin I (SYN1).

Ketamine (KET), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, is most frequently used as an anesthetic, analgesic, and sedative drug in pediatric clinical practices. However, the adverse effects of KET administration such as psychotic episodes limited the use of KET. The aim of the present study was to evaluate whether the addition of small doses of fentanyl (FENT) and dexmedetomidine would reduce the overall KET consumption without concession on the safety and efficacy of anesthesia and analgesia in rats. We compared the effects of KET (50 mg/kg) administration alone and KET (25 mg/kg) combined with FENT (0.005 mg/kg) and dexmedetomidine (0.05 mg/kg) (KFD) on the times of onset and duration of anesthesia and analgesia. Compared with the KET group, the KFD group provides similar onset time of anesthesia, but longer duration of anesthesia, and better analgesic effect. Unlike the KET group, the KFD group had a lower heart rate and higher respiratory rate. Meanwhile, KFD induced markedly changes in the electroencephalography (EEG) spectral power when compared with control and KET. Furthermore, combination of FENT and dexmedetomidine alleviated the liver toxicity of KET. These results indicated that, when compared with KET alone, the administration of KFD combination offered safer and more efficient anesthesia.

The abnormal expression of the dopamine D1 receptor (DRD1) may be associated with schizophrenia. MicroRNAs (miRNAs) can post-transcriptionally regulate DRD1 expression. Here, we established a ketamine-induced schizophrenia-like behavior mouse model and investigated the changes in miR-15a-3p, miR-15b-3p, miR-16-1-3p, and DRD1 in response to ketamine. Administration of high-dose ketamine for seven consecutive days to mice simulated the main symptoms of schizophrenia. The mice exhibited increasing excitability and autonomous activity and reduced learning and memory, including spatial memory. Moreover, ketamine decreased miR-15a-3p, miR-15b-3p, and miR-16-1-3p expression levels in the prefrontal cortex (PFC) and miR-16-1-3p expression in the hippocampus, whereas DRD1 expression increased in these brain regions. In HT22 mouse hippocampal neuronal cells, ketamine induced a dose-dependent increase of endogenous DRD1, which was partially attenuated by a combination of miR-15b-3p and miR-16-1-3p mimics. Indeed, the miR-15b-3p and miR-16-1-3p mimics could significantly inhibit endogenous DRD1expression. We identified +72 to +78 bp (TGCTGCT) of the DRD1 3'UTR as the core regulatory region recognized by the target miRNAs. In summary, we developed a ketamine-induced schizophrenia-like behavior mouse model and found that ketamine inhibited the levels of miR-15a-3p, miR-15b-3p, miR-16-1-3p and increased DRD1 expression in mice.

Handling of common marmoset (Callithrix jacchus) usually requires chemical restraint. Ketamine has been associated with muscle damage in primates, while common marmosets, compared to other primates, additionally display an exceptional high sensitivity to ketamine-associated side-effects. Notably, muscle twitching movements of limbs and hands, and a marked increase in salivation are observed. We investigated two alternative intramuscular (i.m.) immobilisation protocols against ketamine (50 mg/kg; protocol 1) in a double-blind randomised crossover study in ten healthy adult common marmosets for use as a safe reliable, short-term immobilisation and sedation. These protocols comprised: alphaxalone (12 mg/kg; protocol 2) and 25 mg/kg ketamine combined with 0.50 mg/kg medetomidine (reversal with 2.5 mg/kg atipamezole; protocol 3A). Following completion and unblinding, the project was extended with an additional protocol (3B), comprising 25 mg/kg ketamine combined with 0.05 mg/kg medetomidine (reversal with 0.25 mg/kg atipamezole, twice with 35 min interval).

Status asthmaticus is a common cause of morbidity and mortality. The addition of ketamine to the standard treatment regimen of severe asthma has shown to improve outcome and alleviate the need for mechanical ventilation. The purpose of this review is to determine the pulmonary effects of ketamine and to determine whether sufficient evidence exists to support its use for refractory status asthmaticus.

Depression is the third leading cause of disability in the world. Depressive symptoms may be reduced within several weeks after the start of conventional antidepressants, but treatment resistance concerns one-third of patients who fail to achieve recovery. Over the last 20 years, ketamine, an antagonist of the N-methyl-D-aspartate receptor, has been described to have antidepressant properties. A literature review was conducted through an exhaustive electronic search. It was restricted to Cochrane reviews, meta-analyses, and randomized controlled trials (RCTs) of ketamine for major depressive disorder and/or bipolar disorder. This review included two Cochrane reviews, 14 meta-analyses and 15 trials. Ketamine was studied versus placebo, versus other comparators and as an anesthetic adjuvant before electroconvulsive therapy. In 14 publications, ketamine provided a rapid antidepressant effect with a maximum efficacy reached at 24 hrs. Its effect lasted for 1-2 weeks after infusion, but a longer-term effect is little reported. Ketamine does not seem to improve depressive symptoms at the end of electroconvulsive sessions. Safety and tolerability profiles with ketamine at low single dose are generally good in depressed patients. However, there is a lack of data concerning ketamine with repeated administration at higher doses. The clinical use of ketamine is increasing. Intranasal (S)-ketamine has recently been approved for depression by the Food and Drug Administration. It could be a promising treatment in depressed patients with suicidal ideation. Collectively, the level of proof of efficacy remains low and more RCTs are needed to explore efficacy and safety issues of ketamine in depression.

Adenocarcinoma of the pancreas is one of the most aggressive cancer diseases affecting the human body. The oncogenic potential of this type of cancer is mainly characterized by its extreme growth rate triggered by the activation of signaling cascades. Modern oncological treatment strategies aim at efficiently modulating specific signaling and transcriptional pathways. Recently, anti-tumoral potential has been proven for several substances that are not primarily used in cancer treatment. In some tumor entities, for example, administration of glutamate antagonists inhibits cell proliferation, cell cycle arrest, and finally cell death. To attain endogenic proof of NMDA receptor type expression in the pancreatic cancer cell lines PaTu8988t and Panc-1 and to investigate the impact of ketamine, s-ketamine, and the NMDA receptor antagonist MK 801 on proliferation, apoptosis, and necrosis in pancreatic carcinoma.

Neuropathic pain is an intractable clinical problem. Intrathecal ketamine, a noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist, is reported to be useful for treating neuropathic pain in clinic by inhibiting the activity of spinal neurons. Nevertheless, emerging studies have disclosed that spinal astrocytes played a critical role in the initiation and maintenance of neuropathic pain. However, the present clinical therapeutics is still just concerning about neuronal participation. Therefore, the present study is to validate the coadministration effects of a neuronal noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine and astrocytic cytotoxin L-α-aminoadipate (LAA) on spinal nerve ligation (SNL)-induced neuropathic pain.

Background: Previous studies have examined the effects of long-term ketamine use on gray matter volume. But it is unclear whether chronic ketamine use alters cortical thickness and whether cortical thickness changes in chronic ketamine users are associated with cognitive deficits observed in chronic ketamine users. Methods: Here, 28 chronic ketamine users and 30 healthy controls (HCs) were recruited. Cortical morphometry based on Computational Anatomy Toolbox (CAT12) was used to measure cortical thickness. Cognitive performance was measured by MATRICS Consensus Cognitive Battery (MCCB). Two-sample t-test was used to assess differences in cortical thickness and cognitive performance between the two groups. Partial correlation analysis was used for assessing correlations between cortical thickness changes and clinical characteristics, cognitive performance in chronic ketamine users. Results: Chronic ketamine users exhibited significantly reduced cortical thickness in frontal, parietal, temporal, and occipital lobes compared to HC [false discovery rate (FDR) corrected at p < 0.05]. In chronic ketamine users, the average quantity (g) of ketamine use/day was negatively correlated with cortical thickness in the left superior frontal gyrus (SFG), right caudal middle frontal gyrus (MFG), and right paracentral lobule. The frequency of ketamine use (days per week) was negatively correlated with cortical thickness in the left isthmus cingulate cortex. Duration of ketamine use (month) was negatively correlated with cortical thickness in the left precentral gyrus. The chronic ketamine users showed significantly poorer cognitive performance on the working memory (P = 0.009), visual learning (P = 0.009), speed of processing (P < 0.000), and Matrics composite (P = 0.01). There was no correlation between scores of domains of MCCB and reduced cortical thickness. Conclusion: The present study observed reduced cortical thickness in multiple brain areas, especially in the prefrontal cortex (PFC) in chronic ketamine users. Dose, frequency, and duration of ketamine use was negatively correlated with cortical thickness of some brain areas. Our results suggest that chronic ketamine use may lead to a decrease of cortical thickness. But the present study did not observe any correlation between reduced cortical thickness and decreased cognitive performance in chronic ketamine users.

Ketamine has been reported to impair human cognitive function as a recreational drug of abuse. However, chronic effects of ketamine on central nervous system need to be further explored. We set out to establish chronic ketamine addiction models by giving mice a three or six month course of daily intraperitoneal injections of ketamine, then examined whether long-term ketamine administration induced cognition deficits and changed hippocampal post-synaptic protein expression in adult mice. Behavior tests results showed that mice exhibited dose- and time-dependent learning and memory deficits after long-term ketamine administration. Western blot results showed levels of GluA1, p-S845 and p-S831 proteins demonstrated significant decline with ketamine 60 mg/kg until six months administration paradigm. But levels of p-S845 and p-S831 proteins exhibited obvious increase with ketamine 60 mg/kg three months administration paradigm. NR1 protein levels significantly decrease with ketamine 60 mg/kg three and six months administration paradigm. Our results indicate that reduced expression levels and decreased phosphorylation levels of hippocampal post-synaptic membrane GluA1- containing AMPA receptors maybe involved in cognition impairment after long-term ketamine administration. These findings provide further evidence for the cognitive damage of chronic ketamine addiction as a recreational drug.

The aims of this study were to measure plasma levels of R- and S-ketamine and their major metabolites R- and S-norketamine following single intravenous bolus administration of racemic or S-ketamine in sevoflurane anaesthetised dogs and to calculate the relevant pharmacokinetic profiles. Six adult healthy beagle dogs were used in the study. An intravenous bolus of 4mg/kg racemic ketamine (RS-KET) or 2mg/kg S-ketamine (S-KET) was administered, with a three-weeks washout period between treatments. Venous blood samples were collected at fixed times until 900min and R- and S-ketamine as well as R- and S-norketamine plasma levels determined by liquid chromatography coupled with tandem mass spectrometry. Cardiovascular parameters were recorded during the anaesthesia until 240min. All dogs recovered well from anaesthesia. No statistical differences between groups were detected in any cardiovascular parameter. The pharmacokinetics of S-ketamine did not differ when injected intravenously alone or as part of the racemic mixture in dogs anaesthetised with sevoflurane. Following racemic ketamine, the area under the curve of R-norketamine was statistically higher than the one of S-norketamine.

Pancreatic ductal adenocarcinoma is one of the most aggressive malignancies in humans. The main reason for its unfavourable prognosis is the combination of rapid tumour growth, early-onset metastasis and currently still inadequate diagnostic and therapeutic options. Thus, only very few patients are eligible for radical resection of the primary tumour as the only curative treatment option available so far. In the perioperative period, tumour progression and metastasis are facilitated by the activation of key signalling pathways and the altered regulation of transcription factors. Various tumour entities have shown increased expression of the integrin-3 receptor subunit, which correlates with more rapid tumour progression and metastasis through advanced migration, invasion and proliferation. The influence of perioperative medication and postoperative pain management remains unclear. To investigate the effects of ketamine, s-ketamine and MK 801 on integrin beta-3-mediated cell migration in pancreatic cancer cells in vitro.

There is a robust empirical evidence base supporting the acute efficacy of electroconvulsive therapy (ECT) for severe and treatment resistant depression. However, a major limitation, probably contributing to its declining use, is that ECT is associated with impairment in cognition, notably in anterograde and retrograde memory and executive function. Preclinical and preliminary human data suggests that ketamine, used either as the sole anaesthetic agent or in addition to other anaesthetics, may reduce or prevent cognitive impairment following ECT. A putative hypothesis is that ketamine, through antagonising glutamate receptors, protects from excess excitatory neurotransmitter stimulation during ECT. The primary aim of the ketamine-ECT study is to investigate whether adjunctive ketamine can attenuate the cognitive impairment caused by ECT. Its secondary aim is to examine if ketamine increases the speed of clinical improvement with ECT.

Racemic ketamine consists of two enantiomers, namely (R)-ketamine and (S)-ketamine, with distinguishable pharmacological properties. Both enantiomers have been reported to show rapid antidepressant effects in rodents. Currently, the (S)-enantiomer has been approved for the treatment of major depression, whereas (R)-ketamine failed to show antidepressant effect in recent clinical studies. Major depressive disorder is frequently characterized by disinhibition of rapid eye movement (REM) sleep and disruption of non-REM (NREM) sleep. Racemic ketamine and most conventional antidepressants affect these parameters. However, it remains largely unknown which enantiomer is responsible for these effects.

Our previous studies find that subcutaneously administered (s.c.) subanesthetic ketamine promotes sustained cortical disinhibition and plasticity in adult mouse binocular visual cortex (bV1). We hypothesized that intranasal delivery (i.n.) of subanesthetic ketamine may have similar actions. To test this, we delivered ketamine (10 mg/kg, i.n.) to adult mice and then recorded excitatory pyramidal neurons or PV+ interneurons in L2/3 of bV1 slices. In pyramidal neurons the baseline IPSC amplitudes from mice treated with ketamine are significantly weaker than those in control mice. Acute bath application of neuregulin-1 (NRG1) to cortical slices increases these IPSC amplitudes in mice treated with ketamine but not in controls. In PV+ interneurons, the baseline EPSC amplitudes from mice treated with ketamine are significantly weaker than those in control mice. Acute bath application of NRG1 to cortical slices increases these EPSC amplitudes in mice treated with ketamine but not in controls. We also found that mice treated with ketamine exhibit increased pCREB staining in L2/3 of bV1. Together, our results show that a single intranasal delivery of ketamine reduces PV+ interneuron excitation and reduces pyramidal neuron inhibition and that these effects are acutely reversed by NRG1. These results are significant as they show that intranasal delivery of ketamine induces cortical disinhibition, which has implications for the treatment of psychiatric, neurologic, and ophthalmic disorders.