methionine enkephalin (STAT-401) / Biostax Corp, Statera BioPharma - LARVOL DELTA

Extracellular processing of proopiomelanocortin generates short beta endorphin that regulates rat keratinocytes via the delta opioid receptor. (PubMed, Sci Rep) - "Functional assays showed β-END(1-9) reduced cAMP levels via DOR signaling, acting as a full agonist with about half the potency of methionine-enkephalin...Differential gene expression analysis revealed modulation of genes involved in collagen maturation and hyaluronic acid synthesis, suggesting roles in skin barrier function. Collectively, these findings suggest that POMC is processed into β-END(1-9) in atopic-inflammatory skin, and this peptide acts via DOR expressed in keratinocytes to promote the expression of skin-protective factors."

Journal • Preclinical • Atopic Dermatitis • Dermatitis • Dermatology • Immunology • POMC-null Obesity • Pruritus

Metabolic syndrome reduces but does not eliminate the cardioprotective effect of adaptation to hypoxia: the link with changes in the opioid system. (PubMed, Pflugers Arch) - "Endomorphin-2, β-endorphin, dynorphin A (1-13), and met-enkephalin content in myocardial tissue was increased in response to CCH...A correlation was identified between plasma and myocardial tissue opioid peptide levels and the extent of myocardial injury, as well as between myocardial opioid peptide content and contractility. Furthermore, CCH and MS caused a reduction in the expression of δ- (DOR) and κ- (KOR) opioid receptors, and also an increase in µ- (MOR) opioid receptor expression. These findings suggest that a decrease in opioid peptide content could impair adaptive cardioprotection in MS."

Journal • Cardiovascular • Coronary Artery Disease • Metabolic Disorders • Myocardial Ischemia • Reperfusion Injury

The Involvement of the Peptidergic Systems in Breast Cancer Development. (PubMed, Cancers (Basel)) - "Breast cancer cells overexpress peptide receptors; at the same time they are known to interact with peptides that (a) exert an oncogenic action (adrenomedullin 2, endothelin, gastrin-releasing peptide, neurokinin A, neuromedin, neuropeptide Y, neurotensin, substance P, vasoactive intestinal peptide), (b) exert an anticancer action (angiotensin (1-7), ghrelin, peptide YY) or (c) exert dual oncogenic and anticancer effects (adrenomedullin, angiotensin II, bradykinin, corticotropin-releasing factor, β-endorphin, glucagon-like peptide 1, gonadotropin-releasing hormone, kisspeptin, methionine-enkephalin, oxytocin)...Future lines of research are suggested in breast cancer using promising anti-breast-cancer peptide receptor antagonists (HOE-140, exendin (9-39), bosentan, macitentan, PD168,368, CGP71,683A, SR48,692, aprepitant) or agonists (FR190,997, semaglutide, exendin 4, goserelin) mentioned in this review...Taken together, the available data highlight the enormous promise..."

Journal • Review • Breast Cancer • Oncology • Solid Tumor • GRP-10

Constructing Generalized Sample Transition Probabilities with Biased Simulations. (PubMed, J Chem Theory Comput) - "The proposed algorithm is validated on model systems such as a harmonic oscillator, Müller-Brown potential system, alanine dipeptide in vacuum, and met-enkephalin in solvent. The results demonstrate that GSTP effectively recovers the unbiased eigenvalues and eigenstates from the biased data. GSTP provides a general framework for analyzing kinetic information in complex systems, where biased simulations are necessary to access longer time scales."

Journal

Mechanism(s)-of-Action for Arginine Therapy in Children with Sickle Cell Disease and Vaso-Occlusive Pain: Results of a Pharmacokinetics/Pharmacodynamics Study (ASH 2023) - "Its nociceptive effects are through induction of Met-enkephalins release in the brain... A total of 13 patients (age 13±3 years, 56% male, 88% Hb-SS, 85% on hydroxyurea) were enrolled... IV Arg therapy increased plasma arginine concentration 2-5 times above baseline at presentation for VOE, and GABR also increased as expected in this pharmacokinetics study with both reaching a maximum concentration within 1 hour of infusion initiation in all dosing schemes. IV Arg supplementation increases plasma NOx levels suggesting a role for vasodilation as a potential mechanism-of-action during SCD-VOE. Exhaled NO also increased significantly, consistent with previous reports."

Clinical • PK/PD data • Genetic Disorders • Hematological Disorders • Musculoskeletal Pain • Pain • Sickle Cell Disease

Unveiling Dopamine and Met-Enkephalin Dynamics: Simultaneous Co-Detection in Rat Striatum. (PubMed, Anal Chem) - "Finally, a series of experiments combined solid-phase extraction with liquid-chromatography mass spectrometry to independently verify ENK release. The findings provide direct evidence to support widely held assumptions regarding neuropeptide release, and they demonstrate how different classes of signaling molecules can potentially affect distinct cellular populations in striatum─even when released at the same site."

Journal • Preclinical • Addiction (Opioid and Alcohol) • Pain • PENK

Effects of two structurally diverse positive allosteric modulators on signaling bias at the μ-opioid receptor. (PubMed, Mol Pharmacol) - "We determined the potency and efficacy of 6 orthosteric agonists (DAMGO, fentanyl, methadone, morphine, Met-enkephalin, and SR17018) with and without BMS-986187 or BMS-986122, and determined bias factors for the agonists themselves and in the presence of a modulator. SIGNIFICANCE STATEMENT: Biased agonism and positive allosteric modulation at the μ-opioid receptor have been suggested as approaches to improve the therapeutic index of opioid agonists. This work shows how allosteric modulation alters the bias signaling profile of μ-opioid agonists."

Journal • Addiction (Opioid and Alcohol) • CNS Disorders • Depression • Pain • Psychiatry

Exploiting the angiotensin-converting enzyme pathway to augment endogenous opioid signaling. (PubMed, Commun Biol) - "We recently identified a non-canonical central role of ACE in the degradation of enkephalin heptapeptide, Met-enkephalin-Arg-Phe (MERF)...Our primary hits (thiorphan, D609, and raloxifene) were selected for dose-response characterization, in vitro enkephalin release, in vivo analgesic potency, and in silico analysis...Molecular docking provided additional insight into the active site interactions of these scaffolds, which could be exploited further for creation of more potent inhibitors. These results showcase the potential of central ACE inhibitors to modulate endogenous MERF signaling."

Journal • Pain • PENK

CORRELATION BETWEEN OPIOID LIGANDS AND RESPONSE TO OPIOID ANTAGONIST IN CHOLESTATIC PATIENTS WITH PRURITUS (AASLD 2025) - "In our recent work, we showed that nalmefene—a Mu and delta opioid receptor antagonist and kappa receptor agonist—reduced pruritus intensity in individuals with cholestatic liver disease...ELISA kits (Qayeebio, China) were used to test the following ligands: Dynorphin (Kappa agonist), Beta-Endorphin (Mu agonist), Met-Enkephalin and Leu-Enkephalin (Mu and Kappa agonists)... Leu-Enkephalin is an endogenous opioid peptide that primarily acts on delta-opioid receptors but also interacts with mu-opioid receptors. Previous studies, such as Dull (2021), found no correlation between endogenous opioid ligand levels and pruritus severity in cholestatic liver disease. Our findings represent the first reported association between Leu-enkephalin levels and itch reduction following treatment with an opioid antagonist, and suggest a potential role for delta opioid receptors in cholestatic pruritus (Smith KM, 2023)."

Clinical • Cholestasis • Dermatology • Hepatology • Pruritus • PENK

Methionine enkephalin upregulates the immune function of RAW264.7 cells to inhibit the infection of Nelson Bay orthoreoviruses. (PubMed, Sci Rep) - "Genomic analysis showed that MENK enhanced the immune function of macrophages by upregulating cytokine-related molecules such as CCL24, IL6ST, and TNFR2 to recruit and induce inflammatory responses. Moreover, MENK upregulated the expression of MHC I, MHC II, and CD28 to promote antigen presentation and initiate adaptive immune responses and regulated the FOXO-CYCD1 pathway to inhibit the cell cycle, thereby exerting antiviral effects during reovirus infection."

Journal • Infectious Disease • Inflammation • Influenza • Respiratory Diseases • CD28 • IL6ST • SYK

Research note: Peripheral administration of Met-enkephalin: Novel attenuation of the adrenal medullary and thyroidal stress responses in young female chickens. (PubMed, Poult Sci) - "Plasma concentrations of epinephrine (EP), norepinephrine (NE), thyroxine (T4) and triiodothyronine (T3) were increased by restraint stress (placing pullets into a small cage in darkness) in 14-week-old pullets. Plasma concentrations of EP and NE were modestly increased in chickens receiving Met-enkephalin injection peripherally. The increase in plasma concentrations of EP, NE, T3 and T4 together with the decrease in reverse T3 in chickens subjected to restraint stress were markedly attenuated in pullets receiving Met-enkephalin injection peripherally."

Journal

Elevated opioid signaling in the arcuate nucleus dopaminergic (A12) neurons in lactating rats (ENDO 2025) - "Four weeks later, the basal calcium activity (rhythmicity index; RI) of the TH neurons was monitored and compared following treatment with met-enkephalin (Enk; 3uM) with or without naloxone (nal; 1M).The A12 neurons co-express mu- and kappa-OPR subtypes but not the delta-OPR subtype...This effect was blocked by naloxone pre-treatment in both groups.Collectively, our findings demonstrate that the increased percentage of A12 neurons producing enkephalin, along with the elevated expression of kappa-OPR in these neurons, may suppress their own activity, thereby reducing dopamine output. This elevated opioid signaling in A12 neurons allows prolactin levels to rise, supporting lactation."

Preclinical

Beta-endorphin is the key endogenous opioid influencing morphine µ-opioid receptor occupancy in rat hypothalamus: a binding kinetic model analysis. (PubMed, Eur J Pharm Sci) - "µ-OR occupancies were simulated using morphine brain extracellular fluid concentration data, for different static levels of the endogenous opioids, including beta-endorphin, Dynorphin-A 1-17, Endomorphin-2, Leu-enkephalin, and Met-enkephalin. We conclude that beta-endorphin plays an important role in morphine µ-OR occupancy, which could therefore play a key role in explaining interindividual variability in the analgesic effects of morphine. Finally, this study demonstrates the utility of a mathematical model workflow in deciphering the role of endogenous ligands in morphine's µ-OR occupancy."

Journal • Preclinical • Pain

Neurotransmitter Imbalance in Tension-Type Headache: A Systematic Review of Mechanisms and Therapeutic Targets. (PubMed, Pain Ther) - "Despite variability in results, substance P, endogenous opioids, and nitric oxide emerged as the most promising targets for further studies. Future research should prioritize standardized methodologies to clarify the role of these pathways in TTH pathophysiology."

Journal • Review • Addiction (Opioid and Alcohol) • CNS Disorders • Migraine • Pain

Effects of Cholinergic and Opioid Antagonists on In Vitro Release of Met-Enkephalin, Somatostatin and Insulin-like Growth Factor-1 by and PENK Expression in Crop, Proventriculus and Duodenum of Newly Hatched Chickens. (PubMed, Animals (Basel)) - "This is the first report of IGF-1 and Met-enkephalin stimulating (p < 0.001) the proliferation of duodenal cells and, together, exerting a synergist effect. It is concluded that the release of Met-enkephalin, IGF-1 and SRIF from foregut regions is under tonic cholinergic and opioid control."

Journal • Preclinical • Gastrointestinal Disorder • IGF1 • PENK

Involvement of enkephalinergic system in the reproductive stress response of the gecko Hemidactylus frenatus. (PubMed, Psychoneuroendocrinology) - "Nonetheless, the functional importance of the two forms of enkephalins, methionine-enkephalin (M-ENK) and leucine-enkephalin (L-ENK), remains inadequately understood in the context of the reproductive stress response in reptiles...In the second experiment, the administration of mu or delta opioid receptor antagonists, naltrexone or naltrindole, respectively, reinstated the stress-induced reduction of gonadotropin-releasing hormone immunoreactivity in the hypothalamus, ME, and PD. These treatments also restored the presence of stage IV and V (vitellogenic) follicles, which were absent in the stress-only group. The findings for the first time indicate the activation of enkephalinergic system in the hypothalamus, ME, and PD during the stress response and suggest that the stress-induced suppression of the seasonal ovarian recrudescence phase is attenuated through the administration of mu or delta opioid receptor antagonists in reptiles."

Journal • PENK

The role of the endogenous opioid system in modulating orthodontic-induced neurogenic inflammation of the dental pulp: A comprehensive review of the literature. (PubMed, Int Endod J) - "The opioid system regulates neurogenic pulpal inflammation and pain at the level of the central and peripheral nervous systems by releasing endogenous substances, including SST, opioid peptides, endocannabinoids and anti-inflammatory cytokines."

Journal • Review • Dental Disorders • Inflammation • Pain

Proenkephalin produced by neonatal T-bet+ Treg cells promotes periportal hepatocyte maturation. (PubMed, Hepatology) - "Depletion of Penk in Tregs or the administration of naltrexone, an antagonist of the opioid growth factor receptor (OGFr), results in similar liver defects. The supplementation of PENK-derived methionine enkephalin (Met-ENK) reduces ductal plate cholangiocytes and enhances hepatocyte maturation in mice lacking T-bet+ Tregs and in 3-dimensional hepatocyte culture...Our findings uncover a previously unrecognized mechanism through which periportal T-bet+ Treg cells foster liver maturation independently of their immune regulatory functions. It also underscores the critical role of Treg-associated immune zonation in facilitating periportal hepatocyte maturation in neonatal mice."

Journal • Addiction (Opioid and Alcohol) • ADAM10 • CD4 • PENK

Structure elucidation and discrimination of peptides epimers induced by chiral residue by ion mobility mass spectrometry. (PubMed, Anal Chim Acta) - "The method has been successfully applied to the identification of peptide epimers in neuropeptides with single chiral residue and amyloid truncated peptides with multiple chiral residues. This work provides possibility for rapid discovery and efficient identification of peptide isomers and method support for the establishment of comprehensive biomolecular collision cross section (CCS) database."

Journal

Locating Multiple Transition Pathways for Complex Biomolecules. (PubMed, J Chem Inf Model) - "Through this protocol, we successfully sampled eight LFEPs for the transition of Met-enkephalin from its 310-helix to the β-turn form, whose highest barriers range from 4.57 to 14.72 kBT...Among them, the dominant and second preferable paths (barrier of 11.8 and 19.2 kBT) resemble previously reported mechanisms, while the other two (barrier of 23.7 and 25.3 kBT) offer novel mechanistic insights of the flipping of residues M102/M106 and anticlock flipping of F114. These results demonstrate our protocol's robustness and efficiency in providing multiple transition paths for complex conformational changes of biomolecules."

Journal

Effects of Central Administration of Opioid Peptides, Vasotocin, Mesotocin, and Corticotrophin-Releasing Factor on Water Intake in Chicks. (PubMed, J Poult Sci) - "Intracerebroventricular administration of Met-enkephalin (a δ-opioid receptor agonist), β-endorphin (a δ-opioid receptor agonist), and nociception (a κ-opioid receptor and opioid receptor-like protein agonist) significantly suppressed water intake in chicks, whereas dynorphin B (a κ-opioid receptor agonist) and endomorphin-1 and 2 (μ-opioid receptor agonists) did not affect water intake. Intracerebroventricular administration of vasotocin, mesotocin, and CRF significantly suppressed water intake in chicks. Our findings suggest that none of the neuropeptides used in this study function as thirst-inducing peptides in the central nervous system of chicks."

Journal

Exploiting the Angiotensin-Converting Enzyme Pathway to Augment Endogenous Opioid Signaling. (PubMed, bioRxiv) - "We recently identified a non-canonical central role of ACE in the degradation of enkephalin heptapeptide, Met-enkephalin-Arg-Phe (MERF)...Our primary hits (thiorphan, D609, and raloxifene) were selected for dose-response characterization, in vitro enkephalin release, in vivo analgesic potency, and in silico analysis...Molecular docking provided additional insight into the active site interactions of these scaffolds, which could be exploited further for creation of more potent inhibitors. These results showcase the potential of central ACE inhibitors to modulate endogenous MERF signalling."

Journal • Pain • PENK

Inhibition of the angiotensin-converting enzyme N-terminal catalytic domain prevents endogenous opioid degradation in brain tissue. (PubMed, bioRxiv) - "Additionally, application of a selective N-terminal domain inhibitor (RXP 407) reduced degradation of both exogenously applied and endogenously released MERF, without affecting degradation of endogenously released Met-enkephalin or Leu-enkephalin. Taken together, our results suggest that the ACE N-terminal domain is the primary site of MERF degradation in brain tissue, and that N-terminal domain inhibition is sufficient to reduce degradation of this specific endogenous opioid peptide. Our results have exciting implications for the development of novel pharmacotherapies that target the endogenous opioid system to treat psychiatric and neurological disorders."

Journal • CNS Disorders • Psychiatry • PENK

Opioid Receptor Signaling Throughout Ontogeny: Shaping Neural and Behavioral Trajectories. (PubMed, Neurosci Biobehav Rev) - "This review explores the ontogeny and function of the Mu, Kappa and Delta opioid receptor systems throughout the lifespan, highlighting their importance in guiding neurobehavioral development. We argue for a paradigm shift in conceptualization of opioids as not only contributors within their own system, but also vital regulators of a multitude of downstream neurodevelopmental processes."

Journal • Review • Substance Abuse

The severity and outcome of Covid-19 depend on the various activities of the renin-angiotensin-aldosterone system, level of the opioid growth factor, [met5]-enkephalin and pre-existing comorbidities. (PubMed, Pol Merkur Lekarski) - " We found that in different categories of patients with COVID-19, the severity and outcome depend on the different activity of the renin-angiotensinaldosterone and enkephalinergic systems."

Journal • Cardiovascular • Genito-urinary Cancer • Infectious Disease • Novel Coronavirus Disease • Oncology • Peripheral Arterial Disease • Renal Cell Carcinoma • Solid Tumor • PENK