Nitrous oxide

Neuropharmacology

Nitrous oxide (N2O) shares many pharmacological similarities with classical gaseous and intravenous anesthetics, however, as anyone who has experienced both knows, they have unquestionable differences.

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Like many classical anesthetics, N2O non-competitively inhibits the NMDA receptor with high affinity and efficacy at concentrations directly proportional to its anaesthetic concentrations (Jevtovic-Todorovic et al., 1998; Mennerick et al., 1998; Yamakura & Harris, 2000). The evidence on the effect of N2O on GABA-A currents in mixed, but tends to show a lower potency potentiation (Dzoljic & Van Duijn, 1998; Mennerick et al., 1998; Yamakura & Harris, 2000). N2O like other volatile anesthetics activates twin-pore potassium channels, though weakly. These channels are largely responsible for keeping neurons at the resting (unexcited) potential (Gruss et al., 2004). Unlike many anesthetics however, N2O does not seem to effect calcium channels (Mennerick et al., 1998).

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Unlike most general anesthetics, N2O seems to somehow effect the benzodiazepine receptor. In many behavioral tests of anxiety, low doses of N2O is a successful anxiolytic, however the anti-anxiety effect is partially reversed by benzodiazepine receptor antagonists, mirroring this, animals which have developed tolerance to the anxiolytic effects of benzodiazepines are partially tolerance to nitrous oxide (Czech & Green, 1992; Emmanouil et al., 1994; Quock et al., 1992). Indeed, in humans given 30% N2O, benzodiazepine receptor antagonists reduced the subjective reports of feeling ?high?, but did not alter psycho-motor performance (Zacny et al., 1995).

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Most interestingly, the effects of N2O seem somehow linked to the interaction between the endogenous opioid system and the descending noradrenergic system. When animals are given morphine chronically the develop tolerance to its antinociceptive (pain killing) effects, this also renders the animals tolerant to the antinocicpetive effects of N2O (Berkowitz et al., 1979). Administration of antibodies which bind and block the activity of some endogenous (not beta-endorphin) block the antinociceptive effects of N2O (Branda et al., 2000; Cahill et al., 2000). Drugs which inhibit the breakdown of endogenous opioids also potentiate the antinocicpetive effects of N2O (Branda et al., 2000). Several experiments have shows that opioid receptor antagonists applied directly to the brain block the antinocicpetive effects of N2O, but these drugs have no effect when injected into the spinal cord. Conversely alpha adrenoreceptor antagonists block the antinociceptive effects of N2O when given directly to the spinal cord, but not when applied directly to the brain (Fang et al., 1997; Guo et al., 1999; Guo et al., 1996). Indeed, alpha2B adrenoreceptor knockout mice or animals depleted in noradrenaline are nearly completely resistant to the antinociceptive effects of N2O (Sawamura et al., 2000; Zhang et al., 1999). It seems N2O-induced released of endogenous opioids causes disinhibition of brainstem noradrenergic neurons, which descend into the spinal cord and inhibit pain signaling. Exactly how N2O causes the release of opioids is still uncertain.

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In conclusion N2O induces its effects through classical volatile anaethetic mechanisms like NMDA receptor antagonist, GABA-A potentation and potassium channel activation as well as novel mechanisms such as a benzodiazepine-like effect and stimulating endogenous opioid receptor.

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