Research Only Cognitive & Nootropic

Enkephalin

also known as: Met-Enkephalin, Leu-Enkephalin, YGGFM, YGGFL

The body's short-acting local painkillers — five-amino-acid opioid peptides that modulate pain, mood, and gut motility at the synaptic level.

Two pentapeptides (Met-enkephalin YGGFM and Leu-enkephalin YGGFL) that bind delta- and mu-opioid receptors in the spinal cord, brainstem, and enteric nervous system, functioning as fast-acting neurotransmitters in local pain and reward circuits.

Mechanism of action

Released from preproenkephalin-derived vesicles at synaptic terminals. Met-enkephalin preferentially binds delta-opioid receptors (DOR); both forms also activate mu-opioid receptors. DOR activation inhibits voltage-gated Ca2+ channels and opens K+ channels, hyperpolarizing postsynaptic neurons. Functions in spinal cord dorsal horn (pain gating), nucleus accumbens (reward), amygdala (anxiety modulation), and myenteric plexus (gut motility).

Primary uses

Endogenous synaptic pain modulation (gate control at spinal level)
Reward circuit signaling in nucleus accumbens
GI motility regulation via enteric nervous system
Research target for non-opioid analgesic strategies (enkephalinase inhibitors)

Typical dosing

N/A N/A N/A (endogenous)

Not used as a drug due to ultrashort half-life. Research into enkephalinase inhibitors seeks to boost endogenous enkephalin levels as a safer analgesic strategy.

Regulatory status

Not approved as a drug. Research into enkephalinase inhibitors (e.g., racecadotril, approved in some countries for diarrhea) aims to prolong endogenous enkephalin activity without exogenous opioid administration.

References

[pubmed] Hughes J, et al. "Identification of two related pentapeptides from the brain with potent opiate agonist activity." Nature. 1975;258(5536):577-580.
[review] Roques BP, et al. "Inhibiting the breakdown of endogenous opioids with dual enkephalinase inhibitors." Pharmacol Ther. 2012;133(1):40-69.

Related peptides

Beta-Endorphin

The body's most potent endogenous painkiller — the 31-amino-acid opioid peptide behind the 'runner's high' and natural pain modulation.

Dynorphin

The brain's 'anti-reward' opioid — a kappa-receptor agonist that produces dysphoria rather than euphoria, critical to understanding addiction, stress, and depression.

Dermorphin

⚠ Potent mu-opioid agonist — ~30–40× more potent than morphine; has been misused as a horse-racing doping agent and carries serious overdose/dependence risk. Included for reference and harm-reduction only. Not a therapeutic or "longevity" peptide.

Substance P

The pain and nausea neuropeptide — an 11-amino-acid tachykinin that transmits pain signals and triggers vomiting, targeted by aprepitant (Emend) and the entire NK1 antagonist drug class.

Disclaimer

This entry is for educational purposes only and does not constitute medical advice. Dosing information reflects published regulatory or research data and is not a recommendation. Many compounds described here are not approved for human use in the United States. Consult a licensed medical professional before considering any peptide therapy.