Advances in understanding the actions of nitrous oxide.

Nitrous oxide (N(2)O) has been used for well over 150 years in clinical dentistry for its analgesic and anxiolytic properties. This small and simple inorganic chemical molecule has indisputable effects of analgesia, anxiolysis, and anesthesia that are of great clinical interest. Recent studies have helped to clarify the analgesic mechanisms of N(2)O, but the mechanisms involved in its anxiolytic and anesthetic actions remain less clear. Findings to date indicate that the analgesic effect of N(2)O is opioid in nature, and, like morphine, may involve a myriad of neuromodulators in the spinal cord. The anxiolytic effect of N(2)O, on the other hand, resembles that of benzodiazepines and may be initiated at selected subunits of the gamma-aminobutyric acid type A (GABA(A)) receptor. Similarly, the anesthetic effect of N(2)O may involve actions at GABA(A) receptors and possibly at N-methyl-D-aspartate receptors as well. This article reviews the latest information on the proposed modes of action for these clinical effects of N(2)O

Nitrous oxide anxiolytic effect in mice in the elevated plus maze: Mediation by benzodiazepine receptors

In earlier research, we have hypothesized that exposure to nitrous oxide (N2O) produces an anxiolytic effect that is mediated by benzodiazepine (BZ) receptors. The present research was conducted to characterize pharmacologically the behavioral effects of N2O in comparison with a BZ standard, chlordiazepoxide (CP), in the mouse elevated plus maze. Exposure to increasing levels of N2O produced a concentration-related increase in the percent of total entries into and the percent of total time spent on the open arms, a pattern of response similar to that induced by CP. These effects of N2O and CP were both antagonized by pretreatment with the BZ receptor blocker flumazenil (FLU). In another experiment, mice made tolerant to CP also exhibited a cross-tolerance to N2O. These results support the hypothesis that the anxiolytic effect of N2O is mediated by BZ receptors. © 1994 Springer-Verlag

A study of the role of serotonin in the anxiolytic effect of nitrous oxide in rodents

Rationale: In earlier studies, we have shown that nitrous oxide (N2O)-induced behavioral effects in rats and mice are mediated by benzodiazepine receptors. Objectives: This two-part study was conducted in order to investigate the possible role of serotonin (5-HT) in the behavioral effects of N2O by clarifying its effects on regional brain concentrations of 5-HT and assessing the influence of 5-HT antagonist and reuptake inhibiting drugs on the anxiolytic-like behavioral effect of N2O. Methods: In experiment A, male, 150-200 g Sprague-Dawley rats were killed following a 15-min exposure to room air or 70% N2O. The frontal cortex, hippocampus, corpus striatum and hypothalamus were dissected out and analyzed by HPLC with electrochemical detection for content of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA); dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) were also measured. In experiment B, male 18-22 g NIH Swiss mice were pretreated with the 5-HT2 antagonist cinanserin, the 5-HT3 antagonist LY-278,584, the 5-HT reuptake inhibitor fluoxetine or saline and tested in the light/dark exploration test under 70% N2O 30 min after pretreatment. Results: In experiment A, N2O produced differential effects on 5-HT neurons in distinct brain areas. There was increased 5-HT turnover in the hypothalamus, decreased turnover in the frontal cortex but no changes in either hippocampus or corpus striatum. By comparison, dopamine turnover in these brain regions was unaltered by N2O exposure. In experiment B, pretreatment with neither cinanserin, LY-278,584 nor fluoxetine had any appreciable effect on the N2O-induced increase in time spent in the light compartment. Only cinanserin significantly reduced the N2O-induced increase in transitions. Conclusions: While neurochemical results suggest an effect of N2O on brain 5-HT function, there was no effect of 5-HT2 or 5-HT3 antagonists or 5-HT reuptake inhibitor on N2O-induced anxiolytic-like behavior. © 2006 Elsevier Inc. All rights reserved

Nitrous oxide-antinociception is mediated by opioid receptors and nitric oxide in the periaqueductal gray region of the midbrain

Previous studies have shown that nitrous oxide (N2O)-induced antinociception is sensitive to antagonism by blockade of opioid receptors and also by inhibition of nitric oxide (NO) production. The present study was conducted to determine whether these occur within the same brain site. Mice were stereotaxically implanted with microinjection cannulae in the periaqueductal gray (PAG) area of the midbrain. In saline-pretreated mice, exposure to 70% N2O resulted in a concentration-dependent antinociceptive effect in the mouse abdominal constriction test. Pretreatment with an opioid antagonist in the PAG significantly antagonized the antinociceptive effect. Pretreatment with an inhibitor of NO production in the PAG also significantly antagonized the antinociceptive effect. These findings suggest that N2O acts in the PAG via an NO-dependent, opioid receptor-mediated mechanism to induce antinociception. © 2007 Elsevier B.V. and ECNP