The effects of nitrous oxide on a glutamate-gated ion channel and their reversal by high pressure; a single channel analysis

Macdonald, A. G.; Ramsey, R. L.

doi:10.1016/0005-2736(95)00029-3

Cited by 12 publications

(5 citation statements)

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“…Although a lack of effect of N 2 O on GABA A receptors has been reported previously (Little and Thomas, 1986), a recent paper using isolated hippocampal neurons and a local perfusion system similar to that used here found potentiation of responses to exogenously applied muscimol (Dzoljic and Duiijn, 1998). Similarly, a study of invertebrate glutamate receptors reported blockade by N 2 O (Macdonald and Ramsey, 1995). Our present results combined with our previous results (Jevtovic-Todorovic et al, 1998) suggest that several postsynaptic effects may contribute to the anesthetic/analgesic effects of N 2 O.…”

Section: Discussionmentioning

confidence: 88%

Effect of Nitrous Oxide on Excitatory and Inhibitory Synaptic Transmission in Hippocampal Cultures

Mennerick¹,

et al. 1998

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Nitrous oxide (N 2 O; laughing gas) has been a widely used anesthetic/analgesic since the 19th century, although its cellular mechanism of action is not understood. Here we characterize the effects of N 2 O on excitatory and inhibitory synaptic transmission in microcultures of rat hippocampal neurons, a preparation in which anesthetic effects on monosynaptic communication can be examined in a setting free of polysynaptic network variables. Eighty percent N 2 O occludes peak NMDA receptor-mediated (NMDAR) excitatory autaptic currents (EACs) with no effect on the NMDAR EAC decay time course. N 2 O also mildly depresses AMPA receptor-mediated (AMPAR) EACs. We find that N 2 O inhibits both NMDA and non-NMDA receptor-mediated responses to exogenous agonist. The postsynaptic blockade of NMDA receptors exhibits slight apparent voltage dependence, whereas the blockade of AMPA receptors is not voltage dependent. Although the degree of ketamine and Mg 2ϩ blockade of NMDA-induced responses is dependent on permeant ion concentration, the degree of N 2 O blockade is not. We also observe a slight and variable prolongation of GABA A receptor-mediated (GABAR) postsynaptic currents likely caused by previously reported effects of N 2 O on GABA A receptors. Despite the effects of N 2 O on both NMDA and non-NMDA ionotropic receptors, glial glutamate transporter currents and metabotropic glutamate receptor-mediated synaptic depression are not affected. Paired-pulse depression, the frequency of spontaneous miniature excitatory synaptic currents, and high-voltage-activated calcium currents are not affected by N 2 O. Our results suggest that the effects of N 2 O on synaptic transmission are confined to postsynaptic targets. Key words: NMDA receptor; glutamate; nitrous oxide; GABA; postsynaptic; presynapticDespite much attention, cellular mechanisms underlying general anesthesia remain elusive. Many anesthetics share the ability to potentiate exogenously or synaptically generated GABA A receptor-mediated (GABAR) currents (Franks and Lieb, 1994). Halothane, isofluorane, barbiturates, neurosteroids, and propofol are examples of known anesthetic GABA A modulators. Some anesthetics like halothane inhibit high-voltage -activated calcium currents (Herrington et al., 1991;Miao et al., 1995), suggesting the possibility that presynaptic effects contribute to some of the anesthetic actions of these agents. Inhibitors of NMDA glutamate receptors, like ketamine, phencyclidine, and M K-801, have anesthetic properties, with ketamine enjoying widespread clinical use in pediatric populations.Nitrous oxide (N 2 O) has been used as an inhalation anesthetic for over a century and as a recreational drug of abuse since at least the 18th century; yet the mechanism(s) of the effects of nitrous oxide on signaling in the C NS is not understood. N 2 O is widely used clinically because of its good analgesic properties; however, it is a relatively weak anesthetic, requiring high volume percent and hyperbaric conditions to achieve the minimal alveolar concentration...

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Section: Discussionmentioning

confidence: 88%

Effect of Nitrous Oxide on Excitatory and Inhibitory Synaptic Transmission in Hippocampal Cultures

Mennerick¹,

et al. 1998

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“…It was notable that some papers whose titles suggested they were investigating ‘pressure reversal of anaesthesia’ in fact did not employ any anaesthetic agents in the experimental protocol 34 ; these were clearly excluded from further consideration. Several other papers (e.g., Macdonald and Ramsay, 35 and summarised by Halsey 33 ) studied pressure effects in artificial lipid or membrane systems, without any biological end‐points: these were also not used in our analysis.…”

Section: Resultsmentioning

confidence: 99%

“…Macdonald and Ramsay examined the effect on open probability of the quisqualate‐sensitive glutamate‐gated channel of locust muscle (qGlu‐R) by N 2 O at just two ambient pressures (Figure 6). 35 The effect of pressure on N 2 O anaesthesia was biphasic; hence neither ‘reversal’ nor ‘enhancement’. The study was complicated by N 2 O, itself having a MAC >100 and so required administration at pressure.…”

Section: Resultsmentioning

confidence: 99%

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General anaesthetics as ‘awakening agents’? Re‐appraising the evidence for suggested ‘pressure reversal’ of anaesthesia

George

Pandit

2021

Clin Exp Pharma Physio

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Increasing ambient pressure has been suggested to reverse general anaesthesia and provides support for the ‘lipid theory’. Anaesthetic dissolution into cell membranes is said to cause their expansion to a critical volume. This triggers a sequence of events as basis of a unitary theory of anaesthestic mechanism. Pressure is argued to restore membrane volume to below critical level, reversing this process. We wished to review the original literature to assess internal consistency within and across papers, and to consider if alternative interpretations were possible. A literature search yielded 31 relevant ‘pressure reversal’ papers for narrative review, and 8 papers that allowed us to re‐plot original data more consistently as ‘dose‐response’ curves for the anaesthetics examined. Original studies were heterogenous for end‐points, pressure ranges, species, and agents. Pressure effects were inconsistent, with narcosis at certain pressures and excitation at others, influenced by carrier gas (e.g., nitrogen vs helium). Pressure reversal (a right‐ or downward‐shift on the re‐plotted dose‐response curves) was evident, but only in some species and at certain pressures and anaesthetic concentrations. However, even more striking was a novel ‘awakening’ effect of anaesthetics: i.e., anaesthetics reversed the narcotic effect of pressure, but this was limited to certain pressures at generally low anaesthetic concentrations. Contrary to the established view, ‘pressure reversal’ is not a universal phenomenon. The awakening effect of anaesthetics – described here for the first time ‐ has equal evidence to support it, within the same literature, and is something that cannot be fully explained. Pressure cannot meaningfully be used to gain insight into anaesthetic mechanisms because of its heterogenous, non‐specific and unpredictable effects on biological systems.

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“…As the lipid-based hypotheses fell out of favor, several studies attempted to explain pressure reversal in terms of protein targets, hypothesizing that pressure changed the binding dynamics of general anesthetics at key receptors. 47,62,63 However, a method like pressure reversal has too many nonspecific effects to be an effective probe for anesthetic mechanisms. While ultimately unsuccessful as a reversal method, hyperbaric pressure demonstrated that careful behavioral assessment of reversal is important since putative reversal agents can reverse the sedative effects of a drug without reversing its cognitive or physiologic effects.…”

Section: Assessment Methodsmentioning

confidence: 99%

Time to Wake Up! The Ongoing Search for General Anesthetic Reversal Agents

Cylinder,

van Zundert,

Solt

et al. 2024

Anesthesiology

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How general anesthetics work remains a topic of ongoing study. A parallel field of research has sought to identify methods to reverse general anesthesia. Reversal agents could shorten patients’ recovery time and potentially reduce the risk of postoperative complications. An incomplete understanding of the mechanisms of general anesthesia has hampered the pursuit for reversal agents. Nevertheless, the search for reversal agents has furthered understanding of the mechanisms underlying general anesthesia. The study of potential reversal agents has highlighted the importance of rigorous criteria to assess recovery from general anesthesia in animal models, and has helped identify key arousal systems (e.g., cholinergic, dopaminergic, and orexinergic systems) relevant to emergence from general anesthesia. Furthermore, the effects of reversal agents have been found to be inconsistent across different general anesthetics, revealing differences in mechanisms among these drugs. The presynapse and glia probably also contribute to general anesthesia recovery alongside postsynaptic receptors. The next stage in the search for reversal agents will have to consider alternate mechanisms encompassing the tripartite synapse.

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The effects of nitrous oxide on a glutamate-gated ion channel and their reversal by high pressure; a single channel analysis

Cited by 12 publications

References 14 publications

Effect of Nitrous Oxide on Excitatory and Inhibitory Synaptic Transmission in Hippocampal Cultures

Effect of Nitrous Oxide on Excitatory and Inhibitory Synaptic Transmission in Hippocampal Cultures

General anaesthetics as ‘awakening agents’? Re‐appraising the evidence for suggested ‘pressure reversal’ of anaesthesia

Time to Wake Up! The Ongoing Search for General Anesthetic Reversal Agents

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