How does nitrous oxide work, what receptors and effects on neurological systems does it have?

[Druidus]

I'm very interested in how, exactly, nitrous oxide works. Without fully knowing how it works, it is impossible to know if there could be long term complications from its use (or how much could cause complications) and, moreover, it's just plain interesting to try to understand.

I'm aware of the fact that it reduces B12, but what else may be happening? Apparently, there is some evidence to suggest that it effects NMDA, GABA, and opiate receptors. I am still reading on it, myself, but I will provide a link to a document I've found helpful for if anyone is interested. I'd love to hear what anyone else could add/offer.

Here is a great resource I found:

Biologic Effects of Nitrous Oxide: A Mechanistic and Toxicologic Review

Nitrous oxide is the longest serving member of the anesthesiologist's pharmacologic armamentarium but remains a source of controversy because of fears over its adverse effects. Recently, the Evaluation of Nitrous oxide In a Gas Mixture for Anaesthesia (ENIGMA) trial reported that nitrous oxide...

pubs.asahq.org

 

[Druidus]

Sorry to self-bump but I didn't want to forget this.

Why does it also seem to modulate the effects of most other types of drugs, seemingly for quite a bit longer than the psychoactive effects of nitrous oxide itself, on it's own, as well? A prime example would be psychedelics, for which there is great synergy. But also for dissociates, again with great synergy. But there is also an interaction with opiates, in a way, because it seems that some of the effects of nitrous are greatly lessened when one is on opiates, leading one, perhaps, to only experience strongly the effects on other types of receptors.

I find it to be at least almost unique in this fashion and for this utility.

 

[Skorpio]

It directly alters a bunch of ion channels on the brain. This includes potassium, nicotinic acetlycholine, NMDA, and GABA A.. It has dopamine and opioid effects due to downstream actions on the ion channels, plus it degrades into nitric oxide, which can be vasodilatory.

Effects of gaseous anesthetics nitrous oxide and xenon on ligand-gated ion channels. Comparison with isoflurane and ethanol - PubMed

Nitrous oxide and xenon displayed a similar spectrum of receptor actions, but this spectrum is distinct from that of isoflurane or ethanol. These results suggest that NMDA receptors and nACh receptors composed of beta2 subunits are likely targets for nitrous oxide and xenon.

pubmed.ncbi.nlm.nih.gov

 

[Skorpio]

I guess I am going to double post because I kind of feel contradictory about what I have previously said. I do not think it is incorrect, just woefully incomplete.

The exact mechanism of nitrous oxide and pretty much all inhalational anesthetics is honestly fairly nebulous and up for debate. It was previously thought that they dissolve into the fatty cell membrane and make it more fluid, which would cause ion channels to change their open state.

This was thought because there is a really tight correlation between an anesthetic's lipophilicity (measured by octanol water coefficient), and the MAC, which is the minimum dose to produce anesthesia (minimum alveolar concentration).

Later studies demonstrated that a dose of anesthetic to produce anesthesia would donate so few molecules of drug to the plasma membrane that the membrane fluidity is not altered.

Next there was a paper that showed halothane (a common halogenated ether, previously used for anesthesia, but which was pulled due to rare but potent hepatotoxicicty) could inhibit the action of firefly luciferase, which was performed without membranes present.

Still, a direct channel mechanism is not a perfect explanation, because anesthetics tend to open some channels while closing others (which has always struck me as a very lucky trait, if the wrong channels were opened or closed, one would have a gas that causes anxiety and seizures). More likely is a mechanism one level of regulation that effects channels.

Most recently a hybrid theory has been proposed where activation of phospholipase d, which hydrolyzes membrane lipids into signaling molecules activates a few channels. (it's from the journal PNAS, whose motto is "please don't make fun of our name")

Studies on the mechanism of general anesthesia

Anesthetics are used every day in thousands of hospitals to induce loss of consciousness, yet scientists and the doctors who administer these compounds lack a molecular understanding for their action. The chemical properties of anesthetics suggest that they could target the plasma membrane. Here...

www.pnas.org

I like this paper because it really bridges the gap between the two strong points of each theory above, with direct kinase inhibiton and a good explanation for the meyer-overton correlation (the name for the lipophilicity thing).

That being said, while I was looking for that previous paper and its link, I came across a different paper demonstrating direct inhibition of a few ion channels using computational modeling.

Often the truth is non simple and a sum of a bunch of slightly minor factors. Inhalational anesthetics is one such nuanced field.

 

[Gaffy]

FYI some drugs like N-ISO play a role in N02 synthesis in the brain. How does that work?