Editing Nitrous oxide (section)

===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.