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The in vivo effect of inhibitors of fatty acid amide hydrolase (FAAH) upon oedema volume and FAAH activity was evaluated in the carrageenan induced hind paw inflammation model in the mouse. Oedema was measured at two time points, 2 and 4 h, after intraplantar injection of carrageenan to anaesthetised mice. Intraperitoneal (i.p.) injections of the FAAH inhibitor URB597 (0.1, 0.3, 1 and 3 mg kg−1) 30 min prior to carrageenan administration, dose‐dependently reduced oedema formation. At the 4 h time point, the ED50 for URB597 was ∼0.3 mg kg−1. Indomethacin (5 mg kg−1 i.p.) completely prevented the oedema response to carrageenan. The antioedema effects of indomethacin and URB597 were blocked by 3 mg kg−1 i.p. of the CB2 receptor antagonist SR144528. The effect of URB597 was not affected by pretreatment with the peroxisome proliferator‐activated receptor γ antagonist bisphenol A diglycidyl ether (30 mg kg−1 i.p.) or the TRPV1 antagonist capsazepine (10 mg kg−1 i.p.), when oedema was assessed 4 h after carrageenan administration. The CB1 receptor antagonists AM251 (3 mg kg−1 i.p.) and rimonabant (0.5 mg kg−1 i.p.) gave inconsistent effects upon the antioedema effect of URB597. FAAH measurements were conducted ex vivo in the paws, spinal cords and brains of the mice. The activities of FAAH in the paws and spinal cords of the inflamed vehicle‐treated mice were significantly lower than the corresponding activities in the noninflamed mice. PMSF treatment almost completely inhibited the FAAH activity in all three tissues, as did the highest dose of URB597 (3 mg kg−1) in spinal cord samples, whereas no obvious changes were seen ex vivo for the other treatments. In conclusion, the results show that in mice, treatment with indomethacin and URB597 produce SR144528‐sensitive anti‐inflammatory effects in the carrageenan model of acute inflammation. British Journal of Pharmacology (2005) 146, 467–476. doi:10.1038/sj.bjp.0706348

Although preclinical studies suggest that GHB has low likelihood for abuse, case reports indicate that GHB is abused. This study evaluated the relative abuse liability of GHB in 14 volunteers with histories of drug abuse. Psychomotor, subjective, and cognitive effects of a broad range of GHB doses (2-18 g/70 kg), up to a dose that produced severe behavioral impairment in each participant, were compared to placebo and two abused sedative/hypnotic drugs, triazolam (0.5 and 1 mg/70 kg) and pentobarbital (200 and 400 mg/70 kg), under double-blind, double-dummy conditions at a residential research facility. In general, GHB produced effects similar to triazolam and pentobarbital, although GHB was not identified as a benzodiazepine or barbiturate by participants that correctly identified triazolam and pentobarbital as such. On most measures of likelihood of abuse (eg ratings of liking, reinforcing effects), effects of pentobarbital were significantly greater than those of triazolam, with GHB being intermediate. GHB produced significantly greater negative subjective effects, including nausea, than the other drugs. Memory impairment after GHB was less than that after triazolam and pentobarbital. Within participants, the dose-effect function for sedation was steeper for GHB than for triazolam and pentobarbital. Also, at higher doses, GHB was associated with greater sedation and more variability across participants in sedation. Taken together, these data suggest that the profile of effects of GHB only partially overlaps with that of triazolam and pentobarbital. Although the likelihood for GHB to be abused is intermediate to triazolam and pentobarbital, the possibility of accidental overdose (ie greater sedation than intended) with GHB appears to be greater.

Neurosteroids that positively modulate GABAA receptors are among a growing list of rapidly acting antidepressants, including ketamine and psychedelics. To develop increasingly specific treatments with fewer side effects, we explored the possibility of EEG signatures in mice, which could serve as a cross-species screening tool. There are few studies of the impact of non-sedative doses of rapid antidepressants on EEG in either rodents or humans. Here we hypothesize that EEG features may separate a rapid antidepressant neurosteroid, allopregnanolone, from other GABAA positive modulators, pentobarbital and diazepam. Further, we compared the actions GABA modulators with those of ketamine, an NMDA antagonist and prototype rapid antidepressant. We examined EEG spectra during active exploration at two cortical locations and examined cross-regional and cross-frequency interactions. We found that at comparable doses, the effects of allopregnanolone, despite purported selectivity for certain GABAAR subtypes, was indistinguishable from pentobarbital during active waking exploration. The actions of diazepam had recognizable common features with allopregnanolone and pentobarbital but was also distinct, consistent with subunit selectivity of benzodiazepines. Finally, ketamine exhibited no distinguishing overlap with allopregnanolone in the parameters examined. Our results suggest that rapid antidepressants with different molecular substrates may remain separated at the level of large-scale ensemble activity, but the studies leave open the possibility of commonalities in more discrete circuits and/or in the context of a dysfunctional brain.

Rodents are widely used for animal research in Egypt. Pentobarbital is the most common anesthetic agent; however overdoses may affect the experimental outcomes and limit the use of tissues. To investigate the effects of sodium pentobarbital overdoses during exsanguination, three groups (6 rats/group) of male and female rats were injected i.p. with 50, 100 and 150 mg/kg of sodium pentobarbital, then carotid exsanguination was performed immediately after loss of consciousness. Hypoxia-inducible factor 1-alpha (Hif1a) and tumor necrosis factor-alpha (Tnfa) mRNA expressions in liver and kidney organs were evaluated. As well as, serum aminotransferase activities (AST&ALT), glucose, urea, creatinine, malondialdehyde (MDA), reduced glutathione (GSH) and catalase (CAT) levels were determined. The histological alterations in liver, kidney and spleen were studied. It was found that Hif1a and Tnfa were significantly overexpressed in the studied organs and serum AST, glucose, creatinine and urea levels were significantly increased after sodium pentobarbital overdoses (100 and 150 mg/kg) compared to 50 mg/kg dose. Similarly, significant increase in MDA and GSH levels of liver, kidney and spleen were noticed. Results showed gender difference where Hif1a and Tnfa levels were significantly overexpressed at high dose of sodium pentobarbital of liver and kidney organs in female more than male rats. Since euthanasia protocol may influence the physiological variables and affect genes’ expression, it is recommended to avoid sodium pentobarbital overdose during euthanasia as it may interfere with the biochemical, molecular and histological measurements.

Background The Canadian Council on Animal Care and American Veterinary Medical Association classify intraperitoneal (IP) pentobarbital as an acceptable euthanasia method in rats. However, national guidelines do not exist for a recommended dose or volume and IP euthanasia has been described as unreliable, with misinjections leading to variable success in ensuring a timely death. The aims of this study were to assess and improve efficacy and consistency of IP euthanasia. In a randomized, blinded study, 51 adult female Sprague-Dawley rats (170–495 g) received one of four treatments: low-dose low-volume (LL) IP pentobarbital ( n = 13, 200 mg/kg pentobarbital), low-dose high-volume (LH) IP pentobarbital ( n = 14, 200 mg/kg diluted 1:3 with phosphate buffered saline), high-dose high-volume (HH, n = 14, 800 mg/kg pentobarbital), or saline. Times to loss of righting reflex (LORR) and cessation of heartbeat (CHB) were recorded. To identify misinjections, necropsy examinations were performed on all rats. Video recordings of LL and HH groups were analyzed for pain-associated behaviors. Between-group comparisons were performed with 1-way ANOVA and Games-Howell post hoc tests. Variability in CHB was assessed by calculating the coefficient of variation (CV). Results The fastest euthanasia method (CHB) was HH (283.7 ± 38.0 s), compared with LL (485.8 ± 140.7 s, p = 0.002) and LH (347.7 ± 72.0 s, p = 0.039). Values for CV were: HH, 13.4%; LH, 20.7%; LL, 29.0%. LORR time was longest in LL (139.5 ± 29.6 s), compared with HH (111.6 ± 19.7 s, p = 0.046) and LH (104.2 ± 19.3 s, p = 0.01). Misinjections occurred in 17.0% (7/41) of euthanasia attempts. Pain-associated behavior incidence ranged from 36% (4/11, LL) to 46% (5/11, HH). Conclusions These data illustrate refinement of the IP pentobarbital euthanasia technique. Both dose and volume contribute to speed of death, with a dose of 800 mg/kg (HH) being the most effective method. An increase in volume alone does not significantly reduce variability. The proportion of misinjections was similar to that of previous studies.

Electrophysiology (ERG) is widely used for retinal function assessment, but the effects of different anesthetics on ERG recordings, particularly in degenerated retinas, remain unclear. This study investigated the effects of different anesthetic drugs on ERG in wild-type (WT), Kv8.2 knockout (KO), and rd10 mice. Anesthetic drugs, avertin (300 mg/kg) and pentobarbital sodium (50 mg/kg) were administered intraperitoneally, isoflurane was given at 5% for induction and 1.5% for maintenance. Full-field flash electroretinography (ff-ERG) was recorded, including scotopic and photopic responses. Specifically, the amplitudes of a-wave, b-wave, oscillatory potentials (OPs), photopic negative response (PhNR), and c-wave were analyzed, respectively. Additionally, fundus imaging and optical coherence tomography (OCT) were performed to analyze retinal morphology. The three anesthetics had no obvious effect on retinal morphology. Pentobarbital sodium decreased scotopic OPs, increased scotopic and photopic b-wave amplitudes and decreased photopic a-wave amplitude in all groups of mice. Isoflurane resulted in larger scotopic OPs and photopic a-wave amplitudes in all groups, with a larger scotopic a-wave amplitude in KO mice. The PhNR amplitude was greater in WT mice anesthetized with avertin. The ERG amplitudes in mice showed significant differences among the three anesthetic conditions. Pentobarbital sodium markedly suppressed retinal OPs, suggesting it may not be suitable for assessing inner retinal function, particularly amacrine cells. Isoflurane enabled excellent recordings of various types of ERG, making it suitable for nearly all ERG recordings. Avertin might serve as a suitable alternative in the absence of isoflurane.

Scale-free statistics of coordinated neuronal activity, suggesting a universal operating mechanism across spatio-temporal scales, have been proposed as a necessary condition of healthy resting-state brain activity. Recent studies have focused on anesthetic agents to induce distinct neural states in which consciousness is altered to understand the importance of critical dynamics. However, variation in experimental techniques, species, and anesthetics, have made comparisons across studies difficult. Here we conduct a survey of several common anesthetics (isoflurane, pentobarbital, ketamine) at multiple dosages, using calcium wide-field optical imaging of the mouse cortex. We show that while low-dose anesthesia largely preserves scale-free statistics, surgical plane anesthesia induces multiple dynamical modes, most of which do not maintain critical avalanche dynamics. Our findings indicate multiple pathways away from default critical dynamics associated with quiet wakefulness, not only reflecting differences between these common anesthetics but also showing significant variations in individual responses. This is suggestive of a non-trivial relationship between criticality and the underlying state of the subject. The significance of deviations from scale-free (SF) neural activity for consciousness is unclear. Using anesthetics, the authors show multiple paths from SF activity, indicating a complex relationship between non-SF activity and the participant’s state.

In modern societies, insomnia stands out as a widespread health concern. Gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, can exert hypnotic effects. However, despite various clinical trials conducted, scientific evidence regarding the impact of ingested GABA on sleep remains unclear. Therefore, in this study, we investigated the sedative effects of fermented rice germ (RG30) extract with a high GABA concentration through electroencephalography (EEG) analysis in a pentobarbital-induced sleep animal model. The exploration into the neural basis of these positive effects involved evaluating orexin, GABA A receptor, and serotonin (5-HT) immunoreactivity in the brain using immunohistochemical methods. Furthermore, we conducted a binding assay for GABA A receptors and 5-HT 2C receptors, as these are considered pivotal targets in the mechanism of action for sleep aids. In the binding assay, RG30 displayed binding affinity to the GABA A receptor (IC50 value of 5.911 µg/mL) and 5-HT 2C receptor (IC50 value of 56.89 µg/mL). Administration of RG30 increased NREM sleep time and reduced wake time in a pentobarbital-induced sleep model. Low-dose RG30 (RG30_L; 40 mg/kg) induced significant alterations in EEG-defined sleep architecture, whereas high-dose RG30 (RG30_H; 90 mg/kg) predominantly modulated orexin expression in the lateral hypothalamus and GABA A receptor levels in the ventrolateral preoptic nucleus. No significant changes were observed in 5-HT expression within the dorsal raphe nucleus. In conclusion, RG30 increased NREM sleep and significantly improved sleep behavior due to its action on the GABA A receptors. The collective findings suggest that RG30 could be considered as a novel sleep-enhancing agent in pharmaceutical and food industries.

Sleep disturbances are an increasing health concern, and limitations associated with long-term use of conventional hypnotics have prompted interest in alternative approaches that support sleep health. Growing evidence suggests that the gut–brain axis contributes to sleep regulation; however, the effects of probiotics on objective sleep parameters and their underlying mechanisms remain incompletely understood and may vary across probiotic strains. The present study investigated the sleep – modulating effects of a selected probiotic strain, Limosilactobacillus reuteri LM1063 (LM1063), using murine models. Sleep latency and duration were assessed using a pentobarbital-induced sleep test, and sleep architecture was evaluated by electroencephalogram (EEG) recordings, including rapid eye movement (REM) and non-rapid eye movement (NREM) sleep. To explore potential mechanisms, neurochemical analyses focusing on key neurotransmitters, including gamma-aminobutyric acid (GABA) and serotonin, were conducted. Administration of LM1063 significantly shortened sleep latency and prolonged sleep duration in mice. EEG analysis revealed shifts in overall sleep architecture toward a sleep-favorable state without disruption of normal sleep organization. These sleep-related changes were accompanied by modulation of GABAergic and serotonergic neurochemical pathways. In conclusion, LM1063 exerts strain-specific sleep-modulating effects through neurochemical mechanisms associated with the gut–brain axis. By integrating behavioral sleep assessment, electrophysiological analysis, and neurochemical profiling, this study provides mechanistic insight supporting the potential translational application of microbiome-targeted approaches for promoting sleep health.

This study investigated the effects of lemon verbena extract (LVE) on sleep regulation using both a pentobarbital-induced sleep model and an EEG-based sleep assessment model in mice. To elucidate its potential mechanisms, mice were randomly assigned to five groups: control, positive control (diazepam, 2 mg/kg b.w.), and three LVE-treated groups receiving 40, 80, or 160 mg/kg b.w. via oral administration. In the pentobarbital-induced sleep model, mice underwent a two-week oral administration of LVE, followed by intraperitoneal pentobarbital injections. The results demonstrated that LVE significantly shortened sleep latency and prolonged sleep duration compared to the control group. Notably, adenosine A1 receptor expression, both at the mRNA and protein levels, was markedly upregulated in the brains of LVE-treated mice. Furthermore, LVE's administration led to a significant increase in the mRNA expression of gamma-aminobutyric acid type A (GABA ) receptor subunits (α2 and β2) in brain tissue. In the electroencephalography (EEG)/electromyogram (EMG)-based sleep model, mice underwent surgical implantation of EEG and EMG electrodes, followed by one week of LVE administration. Quantitative EEG analysis revealed that LVE treatment reduced wakefulness while significantly enhancing REM and NREM sleep's duration, indicating its potential sleep-promoting effects. These findings suggest that LVE may serve as a promising natural sleep aid, improving both the quality and duration of sleep through the modulation of adenosine and GABAergic signaling pathways.