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Enkephalin (Met-Enkephalin)
A five-amino acid endogenous opioid peptide that was among the first endorphins discovered, with roles in pain modulation, immune regulation, and cell growth control.
Overview
Met-enkephalin (methionine-enkephalin, Tyr-Gly-Gly-Phe-Met) is a five-amino acid endogenous opioid peptide discovered in 1975 by John Hughes and Hans Kosterlitz in Aberdeen, Scotland. Together with Leu-enkephalin (leucine-enkephalin, Tyr-Gly-Gly-Phe-Leu), these were the first endogenous opioid peptides to be identified, a landmark discovery that demonstrated the brain produces its own morphine-like substances. Met-enkephalin is derived from the precursor protein proenkephalin A and is widely distributed throughout the central and peripheral nervous systems.
Met-enkephalin acts primarily at delta-opioid receptors (DOR) and to a lesser extent at mu-opioid receptors (MOR). In the central nervous system, it functions as a neurotransmitter/neuromodulator involved in pain processing, mood regulation, and reward circuitry. Enkephalin-containing interneurons in the spinal cord dorsal horn modulate incoming pain signals, while enkephalinergic neurons in the brain participate in the regulation of emotional states, stress responses, and motivational behavior.
A particularly interesting aspect of met-enkephalin biology is its role as an "opioid growth factor" (OGF). Dr. Ian Zagon and colleagues discovered that met-enkephalin, acting through the OGF receptor (OGFr, a nuclear-associated receptor distinct from classical opioid receptors), inhibits cell proliferation and DNA synthesis. This growth-regulatory function has been investigated for cancer treatment, with met-enkephalin showing the ability to inhibit the growth of various cancer cell lines including pancreatic, hepatocellular, and squamous cell carcinoma.
Clinical trials have explored met-enkephalin (as the OGF) in combination with standard chemotherapy for pancreatic cancer. Low-dose naltrexone (LDN), which temporarily blocks opioid receptors and causes a rebound increase in endogenous enkephalin and endorphin levels, has gained attention as an indirect approach to enhance the OGF pathway, with research ongoing in cancer, autoimmune diseases, and chronic pain conditions.