Effects of nitrous oxide and ketamine on electrophysiological and molecular responses in the prefrontal cortex of mice: A comparative study.

Nitrous oxide (N2O; laughing gas) has recently reported to produce rapid antidepressant effects, but little is known about the underlying mechanisms. We performed transcriptomics, in situ hybridization, and electrophysiological studies to examine the potential shared signatures induced by 1 h inhalation of 50% N2O and a single subanesthetic dose of ketamine (10 mg/kg, i.p.) in the medial prefrontal cortex (mPFC) in adult mice. Both treatments similarly affected the transcription of several negative regulators of mitogen-activated protein kinases (MAPKs), namely, dual specificity phosphatases (DUSPs). The effects were primarily located in the pyramidal cells. Notably, the overall effects of N2O on mRNA expression were much more prominent and widespread compared to ketamine. Ketamine caused an elevation of the spiking frequency of putative pyramidal neurons and increased gamma activity (30-100 Hz) of cortical local field potentials. However, N2O produced no such effects. Spiking amplitudes and spike-to-local field potential phase locking of putative pyramidal neurons and interneurons in this brain area showed no uniform changes across treatments. Our findings suggest that N2O and subanesthetic-dose ketamine target MAPK pathway in the mPFC but produce varying acute electrophysiological responses.

Practical Use of Self-Adjusted Nitrous Oxide During Transrectal Prostate Biopsy: A Double-Blind Randomized Controlled Trial.

PURPOSE: Transrectal prostate biopsy is a common ambulatory procedure that can result in pain and anxiety for some men. Low-dose, adjustable nitrous oxide is increasingly being used to improve experience of care for patients undergoing painful procedures. This study seeks to evaluate the efficacy and safety of low-dose (<45%) nitrous oxide, which has not been previously established for transrectal prostate biopsies. MATERIALS AND METHODS: A single-institution, prospective, double-blind, randomized, controlled trial was conducted on patients undergoing transrectal prostate biopsies. Patients were randomized to receive either self-adjusted nitrous oxide or oxygen, in addition to routine periprostatic bupivacaine block. Nitrous oxide at levels between 20% and 45% were adjusted to patients' desired effect. Patients completed a visual analog scale for anxiety, State Trait Anxiety Inventory, and a visual analog scale for pain immediately before and after biopsy. The blinded operating urologist evaluated ease of procedure. Periprocedural vitals and complications were assessed. Patients were allowed to drive home independently. RESULTS: A total of 133 patients received either nitrous oxide (66) or oxygen (67). There was no statistically significant difference in the primary anxiety end point of State Trait Anxiety Inventory or the visual analog scale for anxiety scores between the nitrous oxide and oxygen groups. However, patients in the nitrous oxide group reported significantly lower visual analog scale for pain scores compared to the oxygen group (P = .026). The operating urologists' rating of tolerance of the procedure was better in the nitrous oxide group (P = .03). There were no differences in biopsy performance time. Complications were similarly low between the 2 groups. CONCLUSIONS: Patient-adjusted nitrous oxide at levels of 20% to 45% is a safe adjunct during transrectal prostate biopsy. Although there was not an observed difference in the primary end point of anxiety, nitrous oxide was associated with lower patient-reported pain scores.

Safety and efficacy of a nitrous oxide procedural sedation programme in a paediatric emergency department: a decade of outcomes.

BACKGROUND: Nitrous oxide (N2O) has multiple benefits in paediatric procedural sedation (PPS), but use is restricted by its limited analgesic properties. Analgesic potency could be increased by combining N2O and intranasal fentanyl (INF). We assessed safety and efficacy data from 10 years (2011-2021) of our N2O PPS programme. METHODS: Prospectively collected data from a sedation registry at a paediatric emergency department (PED) were reviewed. Total procedures performed with N2O alone or with INF, success rate, sedation depth and adverse events were determined. Contributing factors for these outcomes were assessed via regression analysis and compared between different N2O concentrations, N2O in combination with INF, and for physician versus nurse administered sedation. A post hoc analysis on factors associated with vomiting was also performed. RESULTS: 831 N2O procedural sedations were performed, 358 (43.1%) involved a combination INF and N2O. Nurses managed sedation in 728 (87.6%) cases. Median sedation depth on the University of Michigan Sedation Scale was 1 (IQR 1-2). Sedation was successful in 809 (97.4%) cases. Combination INF/N2O demonstrated higher median sedation scores (2 vs 1, p<0.001) and increased vomiting (RR 1.8, 95% CI 1.3 to 2.5), with no difference in sedation success compared with N2O alone. No serious adverse events (SAEs) were reported (desaturation, apnoea, aspiration, bradycardia or hypotension) regardless of N2O concentration or use of INF. 137 (16.5%) minor adverse events occurred. Vomiting occurred in 113 (13.6%) cases and was associated with higher concentrations of N2O and INF use, but not associated with fasting status. There were no differences in adverse events (RR 0.98, 95% CI 0.97 to 1.04) or success rates (RR 0.93, 95% CI 0.56 to 1.7) between physician provided and nurse provided sedation. CONCLUSION: N2O can provide effective PED PPS. No SAEs were recorded. INF may be an effective PPS adjunct but remains limited by increased rates of vomiting.

Brain function changes reveal rapid antidepressant effects of nitrous oxide for treatment-resistant depression:Evidence from task-state EEG.

Nitrous oxide has rapid antidepressant effects in patients with treatment-resistant depression (TRD), but its underlying mechanisms of therapeutic actions are not well understood. Moreover, most of the current studies lack objective biological indicators to evaluate the changes of nitrous oxide-induced brain function for TRD. Therefore, this study assessed the effect of nitrous oxide on brain function for TRD based on event-related potential (ERP) components and functional connectivity networks (FCNs) methods. In this randomized, longitudinal, placebo-controlled trial, all TRD participants were divided into two groups to receive either a 1-hour inhalation of nitrous oxide or a placebo treatment, and they took part in the same task-state electroencephalogram (EEG) experiment before and after treatment. The experimental results showed that nitrous oxide improved depressive symptoms better than placebo in terms of 17-Hamilton Depression Rating Scale score (HAMD-17). Statistical analysis based on ERP components showed that nitrous oxide-induced significant differences in amplitude and latency of N1, P1, N2, P2. In addition, increased brain functional connectivity was found after nitrous oxide treatment. And the change of network metrics has a significant correlation with decreased depressive symptoms. These findings may suggest that nitrous oxide improves depression symptoms for TRD by modifying brain function.

Depression of Synaptic N-methyl-D-Aspartate Responses by Xenon and Nitrous Oxide.

In "synapse bouton preparation" of rat hippocampal CA3 neurons, we examined how Xe and N2O modulate N-methyl-D-aspartate (NMDA) receptor-mediated spontaneous and evoked excitatory post-synaptic currents (sEPSCNMDA and eEPSCNMDA). This preparation is a mechanically isolated single neuron attached with nerve endings (boutons) preserving normal physiologic function and promoting the exact evaluation of sEPSCNMDA and eEPSCNMDA responses without influence of extrasynaptic, glial, and other neuronal tonic currents. These sEPSCs and eEPSCs are elicited by spontaneous glutamate release from many homologous glutamatergic boutons and by focal paired-pulse electric stimulation of a single bouton, respectively. The s/eEPSCAMPA/KA and s/eEPSCNMDA were isolated pharmacologically by their specific antagonists. Thus, independent contributions of pre- and postsynaptic responses could also be quantified. All kinetic properties of s/eEPSCAMPA/KA and s/eEPSCNMDA were detected clearly. The s/eEPSCNMDA showed smaller amplitude and slower rise and 1/e decay time constant (τ Decay) than s/eEPSCAMPA/KA Xe (70%) and N2O (70%) significantly decreased the frequency and amplitude without altering the τ Decay of sEPSCNMDA They also decreased the amplitude but increased the Rf and PPR without altering the τ Decay of the eEPSCNMDA These data show clearly that "synapse bouton preparation" can be an accurate model for evaluating s/eEPSCNMDA Such inhibitory effects of gas anesthetics are primarily due to presynaptic mechanisms. Present results may explain partially the powerful analgesic effects of Xe and N2O. SIGNIFICANCE STATEMENT: We could record pharmacologically isolated NMDA receptor-mediated spontaneous and (action potential-evoked) excitatory postsynaptic currents (sEPSCNMDA and eEPSCNMDA) and clearly detect all kinetic parameters of sEPSCNMDA and eEPSCNMDA at synaptic levels by using "synapse bouton preparation" of rat hippocampal CA3 neurons. We found that Xe and N2O clearly suppressed both sEPSCNMDA and eEPSCNMDA. Different from previous studies, present results suggest that Xe and N2O predominantly inhibit the NMDA responses by presynaptic mechanisms.

Nitrous Oxide, a Rapid Antidepressant, Has Ketamine-like Effects on Excitatory Transmission in the Adult Hippocampus.

BACKGROUND: Nitrous oxide (N2O) is a noncompetitive inhibitor of NMDA receptors that appears to have ketamine-like rapid antidepressant effects in patients with treatment-resistant major depression. In preclinical studies, ketamine enhances glutamate-mediated synaptic transmission in the hippocampus and prefrontal cortex. In this study, we examined the effects of N2O on glutamate transmission in the hippocampus and compared its effects to those of ketamine. METHODS: Glutamate-mediated synaptic transmission was studied in the CA1 region of hippocampal slices from adult albino rats using standard extracellular recording methods. Effects of N2O and ketamine at subanesthetic concentrations were evaluated by acute administration. RESULTS: Akin to 1 µM ketamine, 30% N2O administered for 15-20 minutes resulted in persistent enhancement of synaptic responses mediated by both AMPA receptors and NMDA receptors. Synaptic enhancement by both N2O and ketamine was blocked by co-administration of a competitive NMDA receptor antagonist at saturating concentration, but only ketamine was blocked by an AMPA receptor antagonist. Synaptic enhancement by both agents involved TrkB (tropomyosin receptor kinase B), mTOR (mechanistic target of rapamycin), and NOS (nitric oxide synthase) with some differences between N2O and ketamine. N2O potentiation occluded enhancement by ketamine, and in vivo N2O exposure occluded further potentiation by both N2O and ketamine. CONCLUSIONS: These results indicate that N2O has ketamine-like effects on hippocampal synaptic function at a subanesthetic, but therapeutically relevant concentration. These 2 rapid antidepressants have similar, but not identical mechanisms that result in persisting synaptic enhancement, possibly contributing to psychotropic actions.

SCH 23390 inhibits the acquisition of nitrous oxide-induced conditioned place preference and the changes in ERK phosphorylation expression in nucleus accumbens of mice.

Nitrous oxide (N2O) has a long history of abuse, but its abuse mechanism has not been clear yet. This research aimed at the possibility of mesolimbic dopaminergic system (MLDS) involved in the rewarding effect of N2O. In this work, the rewarding behavior of N2O in mice was evaluated using a typical gas-administered conditioned place preference (CPP) procedure. SCH 23390, a Dopamine D1 receptor (D1R) antagonist, and Haloperidol, a Dopamine D2 receptor (D2R) antagonist were administered during CPP to evaluate the role of dopamine receptors in the N2O-induced CPP. The accompanying changes in phosphorylation of extracellular signal-regulated kinase (ERK) in MLDS related brain regions, including the ventral tegmental area (VTA), caudate putamen (CPu), prefrontal cortex (PFC), and nucleus accumbens (NAc) were measured to assess the neural plasticity changes in the CPP mice by Western blot analysis. Results revealed that 60% N2O induced CPP in the gas-administered mice and promoted the ERK phosphorylation (p-ERK) in the NAc and CPu during the test session of the CPP test. Pretreatment of SCH 23390 (0.5 mg/kg) inhibited the acquisition of N2O-induced CPP and the enhanced p-ERK in NAc. It suggested that Dopamine D1 receptor may play an important role in the acquisition of N2O-induced CPP and the accompanied ERK activation in the NAc, which provide insight into the molecular mechanism in the rewarding properties of nitrous oxide.

Procedural analgesia with nitrous oxide at home for epidermolysis bullosa: A case report.

RATIONALE: Epidermolysis bullosa (EB) is an inherited disease characterized by fragile skin with painful blistering, which requires lifelong skin and wound care. This case report describes the use of inhaled nitrous oxide (N2O) for procedural pain control at home during wound care in a young man with severe dystrophic EB. To our knowledge, only 1 case was reported by Ingelmo et al in 2017 regarding the use of N2O at home in a 4-year-old-child. To date, no such attempt has been made in adult patients. PATIENT CONCERNS: Our patient was a 28-year-old man. Frequent blisters appear spontaneously, and are often preceded by erythema and itching. Patient required daily treatment daily consisting of lancing blisters with a needle and emptying them by compression. DIAGNOSES: Severe recessive dystrophic EB diagnosed at the time of delivery. INTERVENTIONS: Procedural pain control was managed by the auto-administration of an inhaled N2O and air gas mixture. OUTCOMES: Conscious sedation with N2O leads to beneficial effects, such as reduction in dressing duration, acute procedural pain, local antibiotic needing, medication memory, anxiety, anticipatory pain, and fatigue after the dressing session. LESSONS: N2O analgesia is safe and effective, resulting in a significant reduction in procedural pain and an improvement in the quality of life of patients and their caregivers.

Activation of NLR family, domain of pyrin containing 3 inflammasome by nitrous oxide through thioredoxin-interacting protein to induce nerve cell injury.

Nitrous Oxide (N2O) has been shown to be neurotoxic, but its specific mechanism is still unclear. The purpose of this work is to probe into the impact of N2O on nerve cell injury through regulating thioredoxin-interacting protein (TXNIP)/the NOD-like receptor domain of pyrin containing 3 (NLRP3) pathway. The results indicated that, N2O exposure elevated TXNIP/NLRP3 expression in vivo and in vitro, led to declined learning and memory capabilities in mice, reduced apoptosis rate in hippocampal neuron and Nissl bodies, elevated inflammatory factors TNF-α, IL-1ß and IL-6 levels, as well as cleaved caspase-3 and Bax expressions, and reduced Bcl-2 expression. Overexpressing TXNIP or NLRP3 further aggravated these injuries, but knocking down TXNIP or NLRP3 improved them. CO-IP indicated that TXNIP and NLRP3 can be combined, with interaction relationship. All in all, the results manifested that N2O is available to promote nerve cell inflammation and apoptosis through activating the TXNIP/NLRP3 pathway that can be used as a potential target for N2O-induced nerve damage in the future.

The international ENIGMA-II substudy on postoperative cognitive disorders (ISEP).

There is a large controversy as to whether nitrous oxide (N2O) added to the anaesthetic gas mixture is harmful or harmless for postoperative cognitive function recovery. We performed a nested study in the ENIGMA-II trial and compared postoperative neurocognitive recovery of patients randomly receiving N2O (70%) or Air (70%) in 30% O2 during anesthesia. We included adults having non cardiac surgery. We compared recovery scores for episodic memory, decision making/processing speed and executive functions measured with the computerised Cambridge Neuropsychological Test Automated Battery (CANTAB). Assessments were performed at baseline, seven and ninety days. At first interim analysis, following recruitment of 140 participants, the trial was suspended. We found that the mean (95%CI) changes of scores for episodic memory were in the Pocock futility boundaries. Decision making/processing speed did not differ either between groups (P > 0.182). But for executive functions at seven days, the mean number (95% CI) of problems successfully solved and the number of correct box choices made was higher in the N2O group, P = 0.029. N2O with the limitations of an interim analysis appears to have no harmful effect on cognitive functions (memory/processing speed). It may improve the early recovery process of executive functions. This preliminary finding warrants further investigations.

Rapid-acting antidepressants and the regulation of TrkB neurotrophic signalling-Insights from ketamine, nitrous oxide, seizures and anaesthesia.

Increased glutamatergic neurotransmission and synaptic plasticity in the prefrontal cortex have been associated with the rapid antidepressant effects of ketamine. Activation of BDNF (brain-derived neurotrophic factor) receptor TrkB is considered a key molecular event for antidepressant-induced functional and structural synaptic plasticity. Several mechanisms have been proposed to underlie ketamine's effects on TrkB, but much remains unclear. Notably, preliminary studies suggest that besides ketamine, nitrous oxide (N2 O) can rapidly alleviate depressive symptoms. We have shown nitrous oxide to evoke TrkB signalling preferentially after the acute pharmacological effects have dissipated (ie after receptor disengagement), when slow delta frequency electroencephalogram (EEG) activity is up-regulated. Our findings also demonstrate that various anaesthetics and sedatives activate TrkB signalling, further highlighting the complex mechanisms underlying TrkB activation. We hypothesize that rapid-acting antidepressants share the ability to regulate TrkB signalling during homeostatically evoked slow-wave activity and that this mechanism is important for sustained antidepressant effects. Our observations urge the examination of rapid and sustained antidepressant effects beyond conventional receptor pharmacology by focusing on brain physiology and temporally distributed signalling patterns spanning both wake and sleep. Potential implications of this approach for the improvement of current therapies and discovery of novel antidepressants are discussed.

Combination of nitrous oxide and the modified inflation-deflation method for identifying the intersegmental plane in segmentectomy: A randomized controlled trial.

BACKGROUND: During thoracoscopic segmentectomy, accurately and rapidly identifying the intersegmental plane (ISP) is of great importance. This study aimed to investigate the effect and safety of a nitrous oxide (N2 O)/oxygen (O2 ) inspired mixture on the appearance time of the ISP (TISP ) via the modified inflation-deflation method. METHODS: A total of 65 participants who underwent segmentectomy were randomized into three groups: 75% N2 O (n = 24), 50% N2 O (n = 23) or 0% N2 O (n = 18). The 75% N2 O group received a gas mixture of N2 O/O2 (Fio2 = 0.25), the 50% N2 O group received N2 O/O2 (Fio2 = 0.5), and the 0% N2 O group received 100% oxygen during lung expansion. The appearance time of satisfactory and ideal planes was recorded. Furthermore, arterial blood gas at breathing room air, one-lung ventilation (OLV) before lung expansion, 5 and 15 min after lung expansion were also recorded. RESULTS: TISP was significantly shorter in the 75% N2 O group (320.2 ± 65.9 s) compared with that of the 50% N2 O group (552.4 ± 88.9 s, p < 0.001) and the 0% N2 O group (968.3 ± 85.5 s, p < 0.001), while the 50% N2 O group was shorter than that of the 0% N2 O group (p < 0.001). Arterial oxygenation was significantly improved in the 0% N2 O group only after lung expansion, before which there were no differences in mean PaO2 values among groups. CONCLUSIONS: The use of N2 O in the inspired gas mixture during lung expansion is an applicable strategy to rapidly identify the ISP via the modified inflation-deflation method without any adverse effect on OLV related arterial oxygenation during segmentectomy.

Rewarding Subjective Effects of the NMDAR Antagonist Nitrous Oxide (Laughing Gas) Are Moderated by Impulsivity and Depressive Symptoms in Healthy Volunteers.

BACKGROUND: Nitrous oxide (N2O) is an anesthetic gas with both therapeutic and abuse potential. Because N2O is an NMDA receptor (NMDAR) antagonist, its effects are expected to resemble those of the prototypical NMDAR antagonist, ketamine. In this study, we examined the subjective rewarding effects of N2O using measures previously employed in studies of ketamine. We also tested for moderation of these effects by bipolar phenotype, depressive symptoms, and impulsivity. METHODS: Healthy volunteers were randomly assigned to either 50% N2O (n = 40) or medical air (n = 40). Self-reported rewarding (liking and wanting), and alcohol-like effects were assessed pre-, peri- and post inhalation. RESULTS: Effect sizes for the various rewarding/alcohol-like effects of N2O were generally similar to those reported in studies of moderate-dose ketamine. Impulsivity moderated the subjective reinforcing (liking) effects of inhaled gas, while depressive symptoms moderated motivational (wanting [more]) effects. However, depression and impulsivity had opposite directional influences, such that higher impulsivity was associated with higher N2O liking, and higher depression, with lower N2O wanting. CONCLUSION: To the extent that static (versus longitudinal) subjective rewarding effects are a reliable indicator of future problematic drug use, our findings suggests that impulsivity and depression may predispose and protect, respectively, against N2O abuse. Future studies should examine if these moderators are relevant for other NMDAR antagonists, including ketamine, and novel ketamine-like therapeutic and recreational drugs. Similarities between moderate-dose N2O and moderate-dose ketamine in the intensity of certain subjective effects suggest that N2O may, at least to some extent, serve as substitute for ketamine as a safe and easily implemented experimental tool for probing reward-related NMDAR function and dysfunction in humans.

Stunning of pigs with different gas mixtures: Behavioural and physiological reactions.

The present study used thirty-one pigs to investigate induction of unconsciousness and behavioural reactions in different gas mixtures: 80% CO2/air, 90 s; 40% CO2/30% O2/air, 180 s; 70% N2O/30% CO2, 90 s. All pigs lost consciousness. All presented respiratory difficulties and most pigs involuntary muscle contractions, often before loss of standing posture. Between mixtures, average latencies of certain behaviours and delays between behaviours differed. Following immersion, blood pH was lower than normal. The low pH induced by the CO2/O2/air mixture was physiologically associated with hyperoxemia. Relationships between blood gases, different behavioural and heart rate responses are discussed. In conclusion, all mixtures caused discomfort due to respiratory difficulties and the addition of O2 or N2O to the CO2 mixture did not present an advantage.

In vivo comparison of dl-sotalol-induced electrocardiographic responses among halothane anesthesia, isoflurane anesthesia with nitrous oxide, and conscious state.

We compared dl-sotalol-induced electrocardiographic responses in intact dogs using a repeated-measures design among 1% halothane anesthesia, 1.5% isoflurane anesthesia with nitrous oxide (N2O), and conscious state to clarify influences of the anesthetics (n = 4). Basal PR interval was longer in halothane than either in isoflurane with N2O or in conscious state, reflecting sympathetic nerve suppression for the atrioventricular node by halothane. Both anesthetics exhibited longer basal QRS width than conscious state, suggesting their ventricular INa inhibition. Also, both anesthetics showed longer basal QT interval, QTcF and Tpeak-Tend than conscious state, indicating their ventricular IKr inhibition. Meanwhile, dl-sotalol prolonged PR interval similarly in isoflurane with N2O and in conscious state, which was less great in halothane, suggesting further sympathetic nerve suppression for the atrioventricular node might be limited in halothane. dl-Sotalol prolonged QT interval and QTcF >3 times greater in either of the anesthetics than in conscious state; moreover, dl-sotalol prolonged Tpeak-Tend similarly in both anesthetics, but hardly altered it in conscious state; indicating isoflurane with N2O as well as halothane may have reduced the repolarization reserve to increase the sensitivity of ventricle toward IKr suppression. Thus, isoflurane with nitrous oxide could be useful for in vivo IKr assay like halothane.

Differential expression of clade I and II N2O reductase genes in denitrifying Thauera linaloolentis 47LolT under different nitrogen conditions.

Nitrous oxide (N2O) is a potent greenhouse gas and its reduction to dinitrogen gas by the N2O reductase (encoded by the nosZ gene) is the only known biological N2O sink. Within the nosZ phylogeny there are two major clades (I and II), which seem to have different ecological niches. However, physiological differences of nosZI and nosZII expression that may impact emissions of N2O are not well understood. Here, we evaluated the differential expression of nosZI and nosZII, both present in Thauera linaloolentis strain 47LolT, in response to N2O concentration and the presence of the competing electron acceptor nitrate (NO3-). Different N2O levels had a negligible effect on the expression of both nosZ clades. Interestingly, nosZII expression was strongly upregulated in the absence of NO3-, while nosZI expression remained constant across the conditions tested. Thus, NO3- possibly inhibited nosZII expression, which suggests that N2O mitigation mediated by nosZII can be restricted due to the presence of NO3- in the environment. This is the first study demonstrating differential expression of nosZI and nosZII genes under the same physiological conditions and their implications for N2O emission under varying environmental conditions in terms of NO3- availability.

Inhalation Sedation During the COVID-19 Outbreak: An Expert Opinion.

BACKGROUND: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the pathogen that causes coronavirus disease-2019 (COVID-19), is thought to be transmitted via droplets and aerosols, and was detected in saliva of infected individuals. These droplets from the upper airway may infect the inhalation sedation mask and tubing. The authors determined the adequate measures needed to prevent the transmission of COVID-19 by nitrous-oxide (N2O) system during inhalation sedation in dentistry and provided evidence on mask and tubing sterilization. Additional measures to protect patients and healthcare workers from COVID-19 that may be transmitted by the inhalation sedation system are discussed. The authors recommend minimal use of a N2O system during inhalation sedation in dentistry. In case of need, the practitioners should have more than one scavenger kit and nasal masks for each N2O/O2 mixer. Biologic barriers should be mounted between the scavenger's tubing and the central evacuation system. Strict cleansing and sterilization should be performed for all parts of the N2O system. The use a disposable scavenger system and nasal mask should be considered as a viable option.

Effects of nitrous oxide on glycinergic transmission in rat spinal neurons.

We investigated the effects of nitrous oxide (N2O) on glycinergic inhibitory whole-cell and synaptic responses using a "synapse bouton preparation," dissociated mechanically from rat spinal sacral dorsal commissural nucleus (SDCN) neurons. This technique can evaluate pure single- or multi-synaptic responses from native functional nerve endings and enable us to accurately quantify how N2O influences pre- and postsynaptic transmission. We found that 70 % N2O enhanced exogenous glycine-induced whole-cell currents (IGly) at glycine concentrations lower than 3 × 10-5 M, but did not affect IGly at glycine concentrations higher than 10-4 M. N2O did not affect the amplitude and 1/e decay-time of both spontaneous and miniature glycinergic inhibitory postsynaptic currents recorded in the absence and presence of tetrodotoxin (sIPSCs and mIPSCs, respectively). The decrease in frequency induced by N2O was observed in sIPSCs but not in mIPSCs, which was recorded in the presence of both tetrodotoxin and Cd2+, which block voltage-gated Na+ and Ca2+ channels, respectively. N2O also decreased the amplitude and increased the failure rate and paired-pulse ratio of action potential-evoked glycinergic inhibitory postsynaptic currents. N2O slightly decreased the Ba2+ currents mediated by voltage-gated Ca2+ channels in SDCN neurons. We found that N2O suppresses glycinergic responses at synaptic levels with presynaptic effect having much more predominant role. The difference between glycinergic whole-cell and synaptic responses suggests that extrasynaptic responses seriously modulate whole-cell currents. Our results strongly suggest that these responses may thus in part explain analgesic effects of N2O via marked glutamatergic inhibition by glycinergic responses in the spinal cord.