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• W1964658450 abstract "For the more than 150 years that clinicians have been using nitrous oxide (N2O), researchers continue to struggle over the mechanisms for both its anaesthetic/analgesic action as well as its toxicity. Eger's exhaustive tome, ‘Nitrous oxide/N2O’, published in 1985 [1], provided an excellent summary of clinical and research issues as they stood at that time. Since then, investigators continue to penetrate the mysteries of this unique anaesthetic gas. Rather than recite the well-known pharmacokinetic and pharmacodynamic aspects of this drug (ably reported in a recent Editorial that countenanced its abandonment from future practice [2]), we will concentrate on the more recent advances in understanding the mechanistic aspects of the most commonly used anaesthetic gas. General anaesthetics are assumed to act at synaptic targets, particularly on fast, neurotransmitter-gated receptor channels and voltage-gated calcium channels, which form a superfamily. This superfamily contains ionotropic receptors for the neurotransmitters, such as gamma-aminobutyric acid (GABA), glycine, acetylcholine and 5-hydroxytryptamine. For example, various inhalational and intravenous general anaesthetics are known to potentiate the activity of GABA at inhibitory GABAa receptor channels or even to gate the channels in the absence of GABA. Until recently, excitatory ionotropic receptors for glutamate, and particularly NMDA (N-methyl-d-aspartate) receptors, were thought to be relatively insensitive to inhibition by inhalational anaesthetic agents even though NMDA receptors were known to play an important role in the central nervous system in learning, memory and sensitisation of pain processing pathways. Using cultured rat hippocampal neurones, Jevtovic-Todorovic et al. found that N2O significantly inhibited NMDA-activated currents, while it showed no effect on GABA-activated currents [3]. Franks et al. reported a similar finding for xenon [4]. NMDA antagonists, such as ketamine, produce profound psychotomimetic effects and have led to the suggestion that the underlying mechanism for the euphoric effects of N2O may be due to the inhibition of NMDA receptor-mediated neural substrates. NMDA receptors have also been implicated in acute neuronal death following anoxia, hypoglycaemia and head trauma. Consistent with this, Jevtovic-Todorovic et al. also demonstrated that N2O showed a protective effect against neurodegenerative changes caused by N-methyl-d,l aspartic acid, a racemic form of NMDA [3]. On the other hand, NMDA antagonists are known to cause neurotoxicity as well, depending on the circumstances. The same investigators also demonstrated that N2O indeed showed neurotoxic effects similar to those caused by MK-801, a NMDA antagonist [3]. These findings have raised concern on the usage of N2O, especially when it is used alone under hyperbaric conditions, or when used with another NMDA antagonist. Concerns of neurotoxicity may be lessened when N2O is co-administered with other general anaesthetics, because most of them exert at least some of their effects on GABAa receptor, which may act to mitigate the neurotoxicity of N2O. Certainly, further investigations are needed to clarify these issues. In addition to its inhibitory effects on NMDA receptors, stimulatory effects of N2O on dopaminergic neurones have been known for a while. In 1983, Hynes and Berkowitz first reported that haloperidol, a dopamine receptor antagonist, reduced N2O-induced locomotor activity in mice and suggested that dopamine may be involved in this effect [5]. Dorris and Truong later reported that N2O-induced locomotor activity was blocked either by depleting catecholamine stores or by blocking catecholamine synthesis [6]. Recent studies demonstrating region-dependent effects of N2O on dopamine and/or norepinephrine concentrations or turnover in the brain [7, 8] have provided further direct evidence for the involvement of dopamine and/or norepinephrine in transducing some of N2O's effects in the central nervous system. Although the underlying mechanisms are unclear, several studies have suggested that N2O releases opioid peptides in the central nervous system [9, 10]. In addition, there is much evidence suggesting that N2O produces similar physiological effects as opioids [11]. While anaesthetic mechanisms of N2O remain unclear, analgesic mechanisms of this gas are being rapidly clarified (it is more accurate to refer to its antinociceptive effect when studies are performed in animals that are unable to communicate the emotive experience of pain). Results from recent studies have led to the hypothesis that N2O-induced opioid peptide release in the peri-aqueductal grey area of the midbrain stimulates descending noradrenergic neuronal pathways, which modulate nociceptive processing through the release of norepinephrine acting at α2 adrenoceptors in the dorsal horn of the spinal cord. This hypothesis is based on the results pieced together from several laboratories. To wit, systemic administration of opiate receptor antagonists blocks the antinociceptive effect of N2O [12]. While, intrathecal opiate receptor antagonists are without effect [13], bilateral microinjection of opiate receptor antagonists into the ventrolateral periaqueductal grey area blocks the antinociceptive effect of N2O [14, 15]. Ablation of the peri-aqueductal grey area in the rat completely attenuated the antinociceptive effect of N2O [16]. We demonstrated that intrathecally but not supraspinally administered α2 adrenoceptor antagonists could block the antinociceptive action of N2O, thereby localizing the site of action to α2 adrenoceptors in the spinal cord [13]. Because transection of the spinal cord eliminated N2O's antinociceptive property, it appeared that spinal pathways were involved [17]. An involvement of descending inhibitory neurones in antinociceptive effect of N2O was first suggested by Komatsu et al. in 1981 [18]. Furthermore, N2O provoked release of norepinephrine at the level of the dorsal horn of the spinal cord and when this neurotransmitter was depleted, N2O was no longer able to produce antinociception [17]. There are three α2 adrenoceptor subtypes (α2A, α2B and α2C); each of the genes for these receptor subtypes have been cloned, thereby facilitating the creation of genetically modified reagents with dysfunctional (‘transgenic’) or deficient (‘knockout’) subtypes. Using a moderately selective pharmacological probe in rats, as well as the D79N transgenic mouse, which has a dysfunctional α2A adrenoceptor subtype, we showed that the α2A subtype was not responsible for the antinociceptive effect of N2O [19]. Thus, at least two different α2 adrenoceptor subtypes modulate nociception depending on whether the ligand is delivered exogenously or endogenously. Descending noradrenergic inhibitory neurones are not functional at birth and take at least 3 weeks to fully develop in rats [20]. In fact, rats do not exhibit sensitivity to the antinociceptive effects of N2O before 4 weeks of age [21]. While the sequential neurological development in rat and human central nervous systems are not totally comparable, it has been suggested that the central nervous system of a 3-week-old rat is equivalent to that of a human at the toddler stage [22]. If that is true, N2O might not be efficacious as an analgesic agent in early childhood. The antinociceptive effect of N2O diminishes over time during continuous administration in both animal [23] and humans [24], a biological phenomenon referred to as tolerance or desensitisation. Marked strain differences in the development of acute tolerance to N2O [25] and in the antinociceptive effect of N2O itself [26] has provided insight into the purported mechanisms for this pharmacodynamic alteration. For example, while the Fischer strain of rat shows strong antinociceptive effect by N2O and does not show acute tolerance, the Lewis strain of rat shows no antinociceptive effect to N2O at all [25]. It is worth noting that these two strains differ markedly in behavioural responses to other drugs (including morphine, alcohol and cocaine) and demonstrate marked differences in catecholamine and opiate peptide synthesis in various regions of the brain [27, 28]. The strain which is unresponsive to N2O has lower basal levels of opioid peptides and unlike the responsive strain, endogenous opiate peptide levels do not increase following morphine administration [28]. Earlier it had been suggested that acute depletion of opiate peptides in the central nervous system causes acute tolerance to N2O based on the finding that maintaining high levels of enkephalin with an enkephalinase inhibitor prevented the development of acute tolerance in rats [29]. Another aspect of N2O that has been more clearly understood from recent studies is its teratogenic effect that was first reported by Fink et al. in 1967 [30]. It has been well known that N2O oxidises vitamin B12, which cannot then function as a coenzyme for methionine synthase [31]. This enzyme catalyses the transmethylation from methyltetrahydrofolate and homocysteine to produce tetrahydrofolate and methionine. The expected results of its inhibition is decreased tetrahydrofolate, which may lead to impaired DNA synthesis, and decreased methionine, which may lead to impairment of ‘Carbon 1’ metabolic pathways including methylation reactions. For many years, impaired DNA synthesis had been proposed to account for both N2O's teratogenicity [32] and haematotoxicity [33]. However, recent studies have shown that N2O-induced teratogenicity is multifactorial and more complex mechanisms are involved [34]. For example, supplementation with folinic acid, which should restore DNA synthesis to normal, only partially prevented N2O-induced teratogenicity in in vivo studies, e.g. minor skeletal abnormalities [35, 36], whereas supplementation with methionine, but not with folinic acid, almost completely prevented N2O-induced teratogenicity (other than situs inversus – see below) [37]. These findings are not surprising because it is likely that the salvage pathway for thymidylate, which is known to exist in many mammalian tissues, may become more active in the embryo to compensate for the decreased de novo synthesis of thymidylate. On the other hand, methionine, via its activated form S-adenosylmethionine, is the principal substrate for methylation in many biochemical reactions that are known to play important roles in development. Sympathomimetic action of N2O, i.e. α1 adrenergic stimulation, has been shown to play a partial role on N2O-induced teratogenicity. In an in vivo study, phenoxybenzamine, an α1 adrenoceptor antagonist, has been shown to partially prevent N2O-induced teratogenicity, e.g. resorptions [38]. In in vitro studies, administration of α1 adrenoceptor agonists, e.g. phenylephrine, during the embryogenesis interferes with normal development of the left/right body axis, which leads to situs inversus. [39]. The critical developmental stage which results in situs inversus by α1 adrenergic stimulation was determined as so-called ‘early neural plate stage’, the very beginning of the neurulation process [40]. Interestingly, these findings have contributed to the identification of genes which determine left/right body axis by Levin et al. in 1995 [41], which has led to the discovery of many other such genes [42]. Most recently, Nonaka et al. discovered anticlockwise rotation of the cilia around the ‘node’ in mouse embryos and demonstrated that this directional movement of the cilia at the ‘early neural plate stage’ is critical in determining normal left/right body axis [43]. Since it is well known that α1 adrenergic stimulation decreases motility of cilia in the respiratory tract, the underlying mechanism of N2O-induced situs inversus may be explained by its inhibitory effect on cilial movement. Consistent with this theory, lidocaine, which is also known to inhibit cilial function, has been shown to cause situs inversus as well [44]. There may come a day when we no longer use N2O for clinical practice. Yet this will not detract from the many contributions which this unique anaesthetic gas has provided in our understanding of anaesthetic mechanisms and in the clinical practice of our speciality. Despite of its uncertain future this anaesthetic gas will certainly continue to be a useful probe in our pursuit of the holy grail of general anaesthesia –how do they work!" @default.
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• W1964658450 title "Recent advances in understanding the actions and toxicity of nitrous oxide" @default.
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