Laughing Gas Relieves Pain by Selectively Releasing Specific Enkephalins in the Brain | Research

The takeaway

Nitrous oxide selectively increased met-enkephalin and met-enkephalin-Arg-Phe in brain CSF without affecting beta-endorphin, leu-enkephalin, or dynorphin.

Selective release
Only met-enkephalin and met-ENK-Arg-Phe increased — the other three opioid peptides were completely unaffected

What the researchers found

Nitrous oxide selectively increased met-enkephalin and met-enkephalin-Arg-Phe in third ventricular CSF without affecting beta-endorphin, leu-enkephalin, or dynorphin.

Why it matters

The mechanism of nitrous oxide analgesia has been debated for decades. This study provides the most direct evidence that it works through selective enkephalin release, resolving a long-standing controversy.

How the study worked

Eight acclimated dogs with chronically implanted third ventricle cannulae. CSF samples collected before and during nitrous oxide exposure. Five opioid peptides measured by radioimmunoassay.

What this study cannot tell us

Animal study in dogs. CSF collection from the third ventricle may not reflect peptide changes in all brain regions. Only acute exposure was tested.

How to read the evidence

Moderate — animal study with direct CSF measurement. Provides the most direct evidence to date for nitrous oxide's opioid mechanism.

When this study was published

Published in 1995 (31 years ago). This finding is now widely accepted as part of nitrous oxide's analgesic mechanism.

The bigger picture

Nitrous oxide is one of the most widely used anesthetics. Finally understanding its mechanism — selective enkephalin release — could help develop better versions or alternatives.

Questions still open

Could the selective enkephalin release be enhanced for better analgesia?
Do other anesthetic gases work through similar opioid mechanisms?

Common questions

How does laughing gas stop pain?

This study shows nitrous oxide selectively triggers the release of specific natural painkillers (met-enkephalin) in the brain. It doesn't broadly activate the opioid system — just these particular peptides.

Is this why naloxone can reverse nitrous oxide effects?

Yes — since nitrous oxide works by releasing enkephalins (which act on opioid receptors), blocking those receptors with naloxone partially reverses the pain relief, confirming the opioid mechanism.

Read the original research

Nitrous oxide selectively releases Met5-enkephalin and Met5-enkephalin-Arg6-Phe7 into canine third ventricular cerebrospinal fluid.

Anesthesia and analgesia, 80(4), 664-70

View on PubMed ↗

Citation

Finck, A D; Samaniego, E; Ngai, S H. (1995). Nitrous oxide selectively releases Met5-enkephalin and Met5-enkephalin-Arg6-Phe7 into canine third ventricular cerebrospinal fluid.. Anesthesia and analgesia, 80(4), 664-70.