Met-Enkephalin

Mechanism of Action

• Classic opioid role: same as leu-enkephalin via DOR Gi/Go signaling; analgesic and anxiolytic at synaptic release
• OGF (tonic inhibitory) role: at low concentrations met-enkephalin acts via OGFr (a non-classical nuclear receptor) to increase cyclin-dependent kinase inhibitor p16 and p21, blocking G1/S cell cycle transition
• OGF-OGFr axis is constitutively active in most proliferating tissues; naltrexone blocks this axis transiently, paradoxically releasing a rebound OGF surge
• Immune modulation: DOR on T cells and NK cells; met-enkephalin restores NK cytotoxicity in immunocompromised states
• Anti-angiogenic at OGFr: tonic OGF-OGFr inhibits endothelial cell proliferation, limiting pathological angiogenesis

Research Findings

• Low-dose naltrexone (LDN) mechanism: transient OGFr blockade causes OGF/met-enkephalin rebound, driving sustained immune normalization and cell growth inhibition
• Met-enkephalin (methionine-enkephalin or MENK) administered to cancer patients in early trials showed immune enhancement and modest anti-tumor effects
• OGF injections reduced proliferation in pancreatic, head and neck, and ovarian cancer xenograft models
• OGF-OGFr axis regulates wound healing speed: excess OGF slows healing, low-dose naltrexone (boosting OGF) paradoxically accelerates it via rebound kinetics
• Multiple sclerosis patients treated with LDN showed increased met-enkephalin levels and clinical improvement in some trials

Research Protocols

• OGF tumor growth inhibition: 10 mg/kg IP met-enkephalin daily in tumor-bearing nude mice; tumor volume measurement
• Low-dose naltrexone (OGF axis indirectly): 1-4.5 mg/day LDN to raise endogenous OGF in autoimmune and cancer patients
• Immune restoration: 50-200 mcg/kg SC met-enkephalin in HIV or cancer patients in older pilot trials
• OGFr binding: met-enkephalin Kd ~3 nM at OGFr; classical opioid antagonists (naloxone, naltrexone) block binding

Interactions

• Leu-enkephalin: sibling peptide; met-enkephalin has marginally higher OGFr potency and slightly greater MOR activity
• Low-dose naltrexone: blocks OGFr transiently, triggering rebound OGF synthesis; indirect way to amplify met-enkephalin signaling
• Cyclin-dependent kinase inhibitors (p16, p21): downstream effectors of OGFr-mediated growth inhibition; DKI levels increase with OGF treatment

Safety Profile

Endogenous opioid. Not approved as therapeutic. Pilot IV/SC studies showed acceptable short-term tolerability. LDN (which raises met-enkephalin) has excellent safety profile. The OGF pathway offers promising anti-cancer and anti-autoimmune avenues with potentially favorable safety.

Legal & Regulatory

Research peptide; not approved as therapeutic (LDN is off-label use that indirectly elevates OGF)