Mechanism of Action
Delta and Mu Opioid Receptor Activation
Enkephalins bind delta-opioid receptors (DOR) with highest affinity and mu-opioid receptors (MOR) with moderate affinity. Both are Gi-coupled GPCRs that inhibit adenylyl cyclase, increase GIRK channel conductance (hyperpolarizing neurons), and inhibit voltage-gated calcium channels. In the spinal cord dorsal horn, DOR activation on presynaptic primary afferents reduces substance P and glutamate release, producing segmental analgesia.
Enkephalinase and Degradation
Enkephalins are extremely rapidly degraded by two cell surface enzymes: neprilysin (neutral endopeptidase, NEP) cleaves the Gly-Phe bond, and aminopeptidase N cleaves the Tyr-Gly bond. This rapid degradation (plasma half-life under 1 minute) severely limits the duration of action of endogenous enkephalins. Enkephalinase inhibitors (thiorphan, racecadotril) that prolong endogenous enkephalin/" class="wiki-internal-link">enkephalin action have been developed as GI antidiarrheals.
Met-Enkephalin as Opioid Growth Factor
Met-enkephalin (OGF, Opioid Growth Factor) signals through the OGF receptor (OGFr), a nuclear receptor distinct from classical opioid receptors. OGF-OGFr signaling inhibits cell proliferation by upregulating cyclin-dependent kinase inhibitors (p16, p21). This growth-inhibitory pathway explains the anti-tumor and autoimmune-modulating effects investigated in OGF clinical research.
Research Summary
Analgesia and Pain Research
AnimalEnkephalins produce spinal and supraspinal analgesia in animal models, mediated by DOR and MOR. DOR-selective agonists have entered human trials as non-addictive analgesics, with fewer respiratory depression and abuse liability concerns than MOR-selective opioids. Enkephalinase inhibitors applied spinally or orally enhance endogenous enkephalin levels to produce anti-nociception.
Met-Enkephalin / OGF in Cancer and Autoimmunity
HumanSmall clinical trials of exogenous Met-enkephalin as OGF showed reduced tumor growth rates in pancreatic and head/neck cancers in combination with standard therapy. Low-dose naltrexone (LDN), by transiently blocking opioid receptors, induces rebound upregulation of OGF and OGFr expression, which is the proposed mechanism behind LDN's effects in multiple sclerosis, Crohn's disease, and cancers.
Immune Modulation
AnimalMet-enkephalin enhances natural killer cell activity, T-cell proliferation, and cytokine production through delta-opioid receptors on immune cells. These immunomodulatory properties motivated clinical investigation of Met-enkephalin as an immune booster in HIV and cancer patients.
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Research Protocols
| Goal | Dose | Frequency | Route |
|---|---|---|---|
| Analgesia research | 10-100 nmol | Single intrathecal injection | Intrathecal (animal) |
| OGF / immune research | 250 mcg/kg | Daily IV or SC x weeks | IV or subcutaneous |
Native enkephalins are too rapidly degraded for convenient administration. Low-dose naltrexone (LDN, 1.5-4.5 mg) is an indirect approach to enhancing endogenous enkephalin/OGF signaling and has extensive anecdotal and emerging clinical literature.
Interactions
Safety Profile
Native enkephalins have too short a half-life to produce sustained opioid effects when administered peripherally. Met-enkephalin clinical trials at OGF doses have been well tolerated with no significant opioid side effects, reflecting the distinct OGFr mechanism. DOR-selective analogs have shown reduced abuse liability compared to MOR agonists in early human trials. Enkephalinase inhibitors (used clinically as antidiarrheals) have an excellent safety record.
References
- [1]Hughes J, et al. Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature. 1975;258(5536):577-580.
- [2]Zagon IS, McLaughlin PJ. Opioid growth factor (OGF) inhibits anchorage-independent growth in human cancer. Int J Oncol. 2003.
- [3]Fichna J, et al. The endomorphin system and its evolving neurophysiological role. Pharmacol Rev. 2007.