Editing Nitrous oxide (section)

==Mechanism of action==
The pharmacological [[mechanism of action]] of inhaled {{chem|N|2|O}} is not fully known. However, it has been shown to directly modulate a broad range of [[ligand-gated ion channel]]s, which likely plays a major role. It moderately blocks [[NMDA receptor|NMDAR]] and [[CHRNB2|β{{ssub|2}}-subunit]]-containing [[nicotinic acetylcholine receptor|nACh channels]], weakly inhibits [[AMPA receptor|AMPA]], [[kainate receptor|kainate]], [[GABAA-rho receptor|GABA{{ssub|C}}]] and [[5-HT3 receptor|5-HT{{ssub|3}} receptors]], and slightly potentiates [[GABAA receptor|GABA{{ssub|A}}]] and [[glycine receptor]]s.<ref name="pmid11020766">{{cite journal|vauthors=Yamakura T, Harris RA |title=Effects of gaseous anaesthetics nitrous oxide and xenon on ligand-gated ion channels. Comparison with isoflurane and ethanol |journal=Anesthesiology |volume=93 |issue=4 |pages=1095–101 |year=2000 |pmid=11020766 |doi=10.1097/00000542-200010000-00034|s2cid=4684919 |doi-access=free }}</ref><ref name="pmid9822732">{{cite journal |vauthors=Mennerick S, Jevtovic-Todorovic V, Todorovic SM, Shen W, Olney JW, Zorumski CF |title=Effect of nitrous oxide on excitatory and inhibitory synaptic transmission in hippocampal cultures |journal=Journal of Neuroscience |volume=18 |issue=23 |pages=9716–26 |year=1998 |pmid=9822732 |pmc=6793274 |doi=10.1523/JNEUROSCI.18-23-09716.1998 }}</ref> It also has been shown to activate [[Two-pore-domain potassium channel|two-pore-domain {{chem|K|+}} channels]].<ref name="pmid14742687">{{cite journal |vauthors=Gruss M, Bushell TJ, Bright DP, Lieb WR, Mathie A, Franks NP |title=Two-pore-domain K<sup>+</sup> channels are a novel target for the anesthetic gases xenon, nitrous oxide, and cyclopropane |journal=Molecular Pharmacology |volume=65 |issue=2 |pages=443–52 |year=2004 |pmid=14742687 |doi=10.1124/mol.65.2.443|s2cid=7762447 }}</ref> While {{chem|N|2|O}} affects several ion channels, its anaesthetic, [[hallucinogenic]] and [[euphoriant]] effects are likely caused mainly via inhibition of NMDA receptor-mediated currents.<ref name="pmid11020766" /><ref name="pmid17352529">{{cite journal|vauthors=Emmanouil DE, Quock RM |title=Advances in Understanding the Actions of Nitrous Oxide |journal=Anesthesia Progress |volume=54 |issue=1 |pages=9–18 |year=2007 |pmid=17352529 |pmc=1821130 |doi=10.2344/0003-3006(2007)54[9:AIUTAO]2.0.CO;2}}</ref> In addition to its effects on ion channels, {{chem|N|2|O}} may act similarly to [[nitric oxide]] (NO) in the central nervous system.<ref name="pmid17352529" /> Nitrous oxide is 30 to 40 times more soluble than nitrogen.

The effects of inhaling sub-anaesthetic doses of nitrous oxide may vary unpredictably with settings and individual differences;<ref>{{Cite journal|last1=Atkinson|first1=Roland M.|last2=Green|first2=J. DeWayne|last3=Chenoweth|first3=Dennis E.|last4=Atkinson|first4=Judith Holmes|date=1979-10-01|title=Subjective Effects of Nitrous Oxide: Cognitive, Emotional, Perceptual and Transcendental Experiences|journal=Journal of Psychedelic Drugs|volume=11|issue=4|pages=317–330|doi=10.1080/02791072.1979.10471415|pmid=522172}}</ref><ref>{{Cite journal|last1=Walker|first1=Diana J.|last2=Zacny|first2=James P.|date=2001-09-01|title=Within- and between-subject variability in the reinforcing and subjective effects of nitrous oxide in healthy volunteers|journal=Drug and Alcohol Dependence|volume=64|issue=1|pages=85–96|doi=10.1016/s0376-8716(00)00234-9|pmid=11470344}}</ref> however, Jay (2008)<ref name="Mike Jay 22–25">{{Cite journal|vauthors=Jay M |date=2008-09-01|title=Nitrous oxide: recreational use, regulation and harm reduction|journal=Drugs and Alcohol Today|volume=8|issue=3|pages=22–25|doi=10.1108/17459265200800022}}</ref> suggests that it reliably induces the following states and sensations:
* Intoxication
* Euphoria/dysphoria
* Spatial disorientation
* Temporal disorientation
* Reduced pain sensitivity
A minority of users also experience uncontrolled vocalisations and muscular spasms. These effects generally disappear minutes after removal of the nitrous oxide source.<ref name="Mike Jay 22–25"/>

===Anxiolytic effect===
In behavioural tests of [[anxiety]], a low dose of {{chem|N|2|O}} is an effective [[anxiolytic]]. This anti-anxiety effect is associated with enhanced activity of GABA{{ssub|A}} receptors, as it is partially reversed by [[GABAA receptor|benzodiazepine receptor]] [[receptor antagonist|antagonists]]. Mirroring this, animals that have developed tolerance to the anxiolytic effects of [[benzodiazepine]]s are partially tolerant to {{chem|N|2|O}}.<ref name="emmanouil">{{cite journal|title=Nitrous oxide anxiolytic effect in mice in the elevated plus maze: mediation by benzodiazepine receptors |vauthors=Emmanouil DE, Johnson CH, Quock RM |journal=Psychopharmacology |volume=115 |issue=1–2 |pages=167–72 |year=1994 |doi=10.1007/BF02244768 |pmid=7862891|s2cid=21652496 }}</ref> Indeed, in humans given 30% {{chem|N|2|O}}, benzodiazepine receptor antagonists reduced the subjective reports of feeling "high", but did not alter [[psychomotor learning|psychomotor]] performance.<ref name="zacny">{{cite journal|title=Flumazenil may attenuate some subjective effects of nitrous oxide in humans: a preliminary report |vauthors=Zacny JP, Yajnik S, Coalson D, Lichtor JL, Apfelbaum JL, Rupani G, Young C, Thapar P, Klafta J |journal=Pharmacology Biochemistry and Behavior |volume=51 |issue=4 |pages=815–9 |year=1995 |doi=10.1016/0091-3057(95)00039-Y |pmid=7675863|s2cid=39068081 }}</ref><ref>{{Cite journal |last=Gillman |first=Mark Akfred |date=2022 |title=What is better for psychiatry: Titrated or fixed concentrations of nitrous oxide? |journal=Front. Psychiatry |volume=13 |issue=773190 |pages=460–3|doi=10.3389/fpsyt.2022.773190 |pmid=36072452 |pmc=9441863 |doi-access=free }}</ref>

===Analgesic effect===
The analgesic effects of {{chem|N|2|O}} are linked to the interaction between the [[Opioid#Endogenous opioids|endogenous opioid]] system and the descending [[Norepinephrine|noradrenergic]] system. When animals are given morphine chronically, they develop tolerance to its pain-killing effects, and this also renders the animals tolerant to the analgesic effects of {{chem|N|2|O}}.<ref>{{cite journal|title=Tolerance to nitrous oxide analgesia in rats and mice |vauthors=Berkowitz BA, Finck AD, Hynes MD, Ngai SH |journal=Anesthesiology |volume=51 |issue=4 |pages=309–12 |year=1979 |doi=10.1097/00000542-197910000-00006 |pmid=484891|s2cid=26281498 |doi-access=free }}</ref> Administration of [[antibodies]] that bind and block the activity of some endogenous opioids (not [[Beta-Endorphin|β-endorphin]]) also block the antinociceptive effects of {{chem|N|2|O}}.<ref name="branda">{{cite journal|title=Role of brain dynorphin in nitrous oxide antinociception in mice |vauthors=Branda EM, Ramza JT, Cahill FJ, Tseng LF, Quock RM |journal=Pharmacology Biochemistry and Behavior |volume=65 |pages=217–21 |year=2000 |doi=10.1016/S0091-3057(99)00202-6 |pmid=10672972 |issue=2|s2cid=1978597 }}</ref> Drugs that inhibit the breakdown of endogenous opioids also potentiate the antinociceptive effects of {{chem|N|2|O}}.<ref name="branda" /> Several experiments have shown that opioid receptor antagonists applied directly to the brain block the antinociceptive effects of {{chem|N|2|O}}, but these drugs have no effect when injected into the [[spinal cord]].

Apart from an indirect action, nitrous oxide, like morphine<ref>Gillman M.A. [1986a]. Minireview: Analgesic [sub anaesthetic] nitrous oxide interacts with the endogenous opioid system : A review of the evidence. Life Sciences 39: 1209-1221</ref> also interacts directly with the endogenous opioid system by binding at opioid receptor binding sites.<ref>(Daras, C., Cantrill, R. C., Gillman, M. A. [1983]. 3[H]-Naloxone displacement: evidence for nitrous oxide as an opioid agonist. European Journal of Pharmacology 89: 177-8.</ref><ref>Ori, C., Ford-Rice, F., London, E. D. [1989]. Effects of nitrous oxide and halothane on mu and kappa opioid receptors in guinea-pig brain. Anesthesiology 70: 541-544.)</ref>

Conversely, [[alpha-2 adrenergic receptor|α{{ssub|2}}-adrenoceptor]] antagonists block the pain-reducing effects of {{chem|N|2|O}} when given directly to the spinal cord, but not when applied directly to the brain.<ref name="guo">{{cite journal|title=Nitrous oxide produces antinociceptive response via alpha2B and/or alpha2C adrenoceptor subtypes in mice |vauthors=Guo TZ, Davies MF, Kingery WS, Patterson AJ, Limbird LE, Maze M |journal=Anesthesiology |volume=90 |issue=2 |pages=470–6 |year=1999 |pmid=9952154 |doi=10.1097/00000542-199902000-00022|doi-access=free }}</ref> Indeed, [[alpha-2B adrenergic receptor|α{{ssub|2B}}-adrenoceptor]] knockout mice or animals depleted in [[norepinephrine]] are nearly completely resistant to the antinociceptive effects of {{chem|N|2|O}}.<ref>{{cite journal|title=Antinociceptive action of nitrous oxide is mediated by stimulation of noradrenergic neurons in the brainstem and activation of [alpha]{{ssub|2B}} adrenoceptors |vauthors=Sawamura S, Kingery WS, Davies MF, Agashe GS, Clark JD, Koblika BK, Hashimoto T, Maze M |journal=J. Neurosci. |volume=20 |issue=24 |pages=9242–51 |year=2000 |pmid=11125002 |pmc=6773006 |doi=10.1523/JNEUROSCI.20-24-09242.2000 }}</ref> Apparently {{chem|N|2|O}}-induced release of endogenous opioids causes disinhibition of [[brainstem]] noradrenergic neurons, which release norepinephrine into the spinal cord and inhibit pain signalling.<ref name="pmid10781114">{{cite journal|vauthors=Maze M, Fujinaga M |title=Recent advances in understanding the actions and toxicity of nitrous oxide |journal=Anaesthesia |volume=55 |issue=4 |pages=311–4 |year=2000 |pmid=10781114 |doi=10.1046/j.1365-2044.2000.01463.x|s2cid=39823627 |doi-access=free }}</ref> Exactly how {{chem|N|2|O}} causes the release of endogenous opioid peptides remains uncertain.