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Fertility and Sterility Nov 1985Immunoreactive (IR) beta-endorphin (beta-EP) and met-enkephalin (MET-ENK) have been found in peritoneal fluid (PF) and ovarian follicular fluid (FF). Gel chromatography...
Immunoreactive (IR) beta-endorphin (beta-EP) and met-enkephalin (MET-ENK) have been found in peritoneal fluid (PF) and ovarian follicular fluid (FF). Gel chromatography also revealed the presence of coeluting IR beta-lipotropin and gamma-lipotropin. IR beta-EP and IR MET-ENK levels in healthy menstruating women were from 10 to 40 times higher than those present in circulating plasma, which indicated a possible local production. The highest concentrations of IR beta-EP in FF were found in the largest follicles, whereas in the PF they correlated with the luteal period of the menstrual cycle and with progesterone concentrations. No relevant changes in IR MET-ENK were detected in the FF or in the PF in relation to the phase of the menstrual cycle. In postmenopausal women, the concentrations of the two IR opioid peptides were undetectable in both fluids.
Topics: Adult; Ascitic Fluid; Chromatography, Gel; Chromatography, High Pressure Liquid; Endorphins; Enkephalin, Methionine; Female; Humans; Luteal Phase; Menopause; Middle Aged; Ovarian Follicle; Progesterone; beta-Endorphin; beta-Lipotropin
PubMed: 2932351
DOI: 10.1016/s0015-0282(16)48976-4 -
Experimental Biology and Medicine... Sep 2017Low-dose naltrexone is a widely used off-label therapeutic prescribed for a variety of immune-related disorders. The mechanism underlying low-dose naltrexone's efficacy...
Low-dose naltrexone is a widely used off-label therapeutic prescribed for a variety of immune-related disorders. The mechanism underlying low-dose naltrexone's efficacy for fatigue, Crohn's disease, fibromyalgia, and multiple sclerosis is, in part, intermittent blockade of opioid receptors followed by upregulation of endogenous opioids. Short, intermittent blockade by naltrexone specifically blocks the opioid growth factor receptor resulting in biofeedback events that increase production of the endogenous opioid growth factor (OGF) (chemically termed [Met]-enkephalin) facilitating interactions between opioid growth factor and opioid growth factor receptor that ultimately, result in inhibited cell proliferation. Preclinical studies have reported that enkephalin levels are deficient in animal models of experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Our hypothesis is that serum enkephalin levels are diminished in humans with multiple sclerosis and experimental autoimmune encephalomyelitis mice, and that change in serum opioid growth factor levels may serve as a reasonable candidate biomarker for the onset of experimental autoimmune encephalomyelitis and response to therapy. To address this, we designed a two-part study to measure endogenous opioids in multiple sclerosis patients, and to investigate the temporal pattern of decline in serum enkephalin concentrations in mice with chronic progressive experimental autoimmune encephalomyelitis and treated with low-dose naltrexone. For comparison, we investigated whether low-dose naltrexone exposure in normal mice also resulted in altered enkephalin levels. In both animal models, we monitored tactile and heat sensitivity, as well as differential white blood cell counts as indicators of inflammation. Serum [Met]-enkephalin levels were lower in humans with multiple sclerosis relative to non-multiple sclerosis patients, and low-dose naltrexone restored their levels. In experimental autoimmune encephalomyelitis mice, [Met]-enkephalin levels were depressed prior to the appearance of clinical disease, and were restored with low-dose naltrexone treatment. Low-dose naltrexone therapy had no effect on serum [Met]-enkephalin or β-endorphin in normal mice. Thus, [Met]-enkephalin (i.e. opioid growth factor) may be a reasonable candidate biomarker for multiple sclerosis, and may signal new pathways for treatment of autoimmune disorders. Impact statement This report presents human and animal data identifying a novel biomarker for the onset and progression of multiple sclerosis (MS). Humans diagnosed with MS have reduced serum levels of OGF (i.e. [Met]-enkephalin) relative to non-MS neurologic patients, and low-dose naltrexone (LDN) therapy restored their enkephalin levels. Serum OGF levels were reduced in mice immunized with MOG prior to any clinical behavioral sign of experimental autoimmune encephalomyelitis, and LDN therapy restored their serum OGF levels. β-endorphin concentrations were not altered by LDN in humans or mice. Thus, blood levels of OGF may serve as a new, selective biomarker for the progression of MS, as well as response to therapy.
Topics: Adult; Aged; Aged, 80 and over; Animals; Biomarkers; Encephalomyelitis, Autoimmune, Experimental; Enkephalin, Methionine; Female; Humans; Male; Mice, Inbred C57BL; Middle Aged; Multiple Sclerosis; Naltrexone; Neuroprotective Agents; Serum; Treatment Outcome; Volunteers; Young Adult
PubMed: 28766982
DOI: 10.1177/1535370217724791 -
Acta Neurobiologiae Experimentalis 2023In the central nervous system, long‑term effects of a vagotomy include disturbance of monoaminergic activity of the limbic system. Since low vagal activity is observed...
In the central nervous system, long‑term effects of a vagotomy include disturbance of monoaminergic activity of the limbic system. Since low vagal activity is observed in major depression and autism spectrum disorder, the study aimed to determine whether animals fully recovered after subdiaphragmatic vagotomy demonstrates neurochemical indicators of altered well‑being and social component of sickness behavior. Bilateral vagotomy or sham surgery was performed in adult rats. After one month of recovery, rats were challenged with lipopolysaccharide or vehicle to determine the role of central signaling upon sickness. Striatal monoamines and met‑enkephalin concentrations were evaluated using HPLC and RIA methods. We also defined a concentration of immune‑derived plasma met‑enkephalin to establish a long‑term effect of vagotomy on peripheral analgesic mechanisms. The data indicate that 30 days after vagotomy procedure, striatal dopaminergic, serotoninergic, and enkephalinergic neurochemistry was altered, both under physiological and inflammatory conditions. Vagotomy prevented inflammation‑induced increases of plasma met‑enkephalin - an opioid analgesic. Our data suggest that in a long perspective, vagotomized rats may be more sensitive to pain and social stimuli during peripheral inflammation.
Topics: Rats; Animals; Enkephalin, Methionine; Autism Spectrum Disorder; Vagotomy; Vagus Nerve; Inflammation; Amines
PubMed: 37078817
DOI: 10.55782/ane-2023-009 -
Annals of the Rheumatic Diseases Jul 2007Intra-articularly applied opioid agonists or antagonists modulate pain after knee surgery and in chronic arthritis. Therefore, the expression of beta-endorphin (END),...
OBJECTIVE
Intra-articularly applied opioid agonists or antagonists modulate pain after knee surgery and in chronic arthritis. Therefore, the expression of beta-endorphin (END), Met-enkephalin (ENK), and mu and delta opioid receptors (ORs) within synovium of patients with joint trauma (JT), osteoarthritis (OA) and rheumatoid arthritis (RA) were examined.
METHODS
Synovial samples were subjected to double immunohistochemical analysis of opioid peptides with immune cell markers, and of ORs with the neuronal markers calcitonin gene-related peptide (CGRP) and tyrosine hydroxylase (TH).
RESULTS
END and ENK were expressed by macrophage-like (CD68(+)) and fibroblast-like (CD68(-)) cells within synovial lining layers of all disorders. In the sublining layers, END and ENK were mostly expressed by granulocytes in patients with JT, and by macrophages/monocytes, lymphocytes and plasma cells in those with OA and RA. Overall, END- and ENK-immunoreactive (IR) cells were more abundant in patients with RA than in those with OA and JT. ORs were found on nerve fibres and immune cells in all patients. OR-IR nerve fibres were significantly more abundant in patients with RA than in those with OA and JT. muORs and deltaORs were coexpressed with CGRP but not with TH.
CONCLUSIONS
Parallel to the severity of inflammation, END and ENK in immune cells and their receptors on sensory nerve terminals are more abundant in patients with RA than in those with JT and OA. These findings are consistent with the notion that, with prolonged and enhanced inflammation, the immune and peripheral nervous systems upregulate sensory nerves expressing ORs and their ligands to counterbalance pain and inflammation.
Topics: Adult; Aged; Aged, 80 and over; Arthritis; Arthritis, Rheumatoid; Biomarkers; Enkephalin, Methionine; Female; Humans; Immunohistochemistry; Joints; Leukocytes; Male; Middle Aged; Osteoarthritis; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu; Synovial Membrane; beta-Endorphin
PubMed: 17324971
DOI: 10.1136/ard.2006.067066 -
Fertility and Sterility Aug 1986The present study demonstrates the presence of the endogenous opioid peptides beta-endorphin (beta-EP) and methionine-enkephalin (MET-ENK), in the uterine fluid of...
The present study demonstrates the presence of the endogenous opioid peptides beta-endorphin (beta-EP) and methionine-enkephalin (MET-ENK), in the uterine fluid of fertile women and normally cycling and superovulated cows. The two peptides are undetectable in the uterine fluid of untreated postmenopausal women, whereas they are present following estrogen-progesterone treatment. Immunoreactive (IR) MET-ENK concentrations were higher in the secretory than in the proliferative phase of the menstrual cycle. IR beta-EP and IR MET-ENK are present also in the follicular, oviductal, and uterine fluid of cows, and in the uterine fluid, concentrations of IR MET-ENK are higher in the superovulated than in the control animals. Because opioids play important roles on endocrine and immune functions, the present data support the potential physiologic role of endometrial secretions.
Topics: Adult; Animals; Body Fluids; Cattle; Endometrium; Endorphins; Enkephalin, Methionine; Female; Humans; Menopause; Middle Aged; Ovary; Superovulation; Uterus; beta-Endorphin
PubMed: 2942425
DOI: 10.1016/s0015-0282(16)49520-8 -
International Journal of Biological... 2022Cold-inducible RNA-binding protein (CIRBP) is documented to be required for maintaining cardiac function, however, its role in chemotherapy-induced cardiotoxicity...
Cold-inducible RNA-binding protein (CIRBP) is documented to be required for maintaining cardiac function, however, its role in chemotherapy-induced cardiotoxicity remains obscured. Herein, we report that CIRBP decreases cardiomyocyte apoptosis and attenuates cardiotoxicity through disrupting OGF-OGFR signal. CIRBP deficiency is involved in diverse chemotherapeutic agents induced cardiomyocyte apoptosis. Delivery of exogenous CIRBP to the mouse myocardium significantly mitigated doxorubicin-induced cardiac apoptosis and dysfunction. Specifically, OGFR was identified as a downstream core effector responsible for chemotherapy-induced cardiomyocyte apoptosis. CIRBP was shown to interact with OGFR mRNA and to repress OGFR expression by reducing mRNA stability. CIRBP-mediated cytoprotection against doxorubicin-induced cardiac apoptosis was demonstrated to largely involve OGFR repression by CIRBP. NTX as a potent antagonist of OGFR successfully rescued CIRBP ablation-rendered susceptibility to cardiac dyshomeostasis upon exposure to doxorubicin, whereas another antagonist ALV acting only on opioid receptors did not. Taken together, our results demonstrate that CIRBP confers myocardium resistance to chemotherapy-induced cardiac apoptosis and dysfunction by dampening OGF/OGFR axis, shedding new light on the mechanisms of chemo-induced cardiotoxicity and providing insights into the development of an efficacious cardioprotective strategy for cancer patients.
Topics: Animals; Apoptosis; Cardiotoxicity; Cell Proliferation; Doxorubicin; Enkephalin, Methionine; Humans; Mice; Myocytes, Cardiac; RNA-Binding Proteins
PubMed: 35541895
DOI: 10.7150/ijbs.69655 -
Zhongguo Yao Li Xue Bao = Acta... May 1995To study the effect of methionine-enkephalin (met-enk) on the production and gene expression of interleukin-6 (IL-6) both in vivo and in vitro.
AIM
To study the effect of methionine-enkephalin (met-enk) on the production and gene expression of interleukin-6 (IL-6) both in vivo and in vitro.
METHODS
IL-6 was assayed using its dependent cell line MH60.BSF2 and measured by MTT spectrophotometry. IL-6 gene expression was proceeded by RNA isolation and hybridization with IL-6 cDNA.
RESULTS
Met-enk stimulated IL-6 mRNA expression and increased its stability. Met-enk 0.1 and 1 mg.kg-1 ip for 6 d enhanced serum IL-6 levels.
CONCLUSION
An up-regulation of IL-6 by met-enk was mediated through an increase in transcriptional activity and stability of IL-6 mRNA.
Topics: Animals; Enkephalin, Methionine; Gene Expression; Interleukin-6; Macrophages, Peritoneal; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; RNA, Messenger; Tumor Cells, Cultured; Up-Regulation
PubMed: 7660811
DOI: No ID Found -
Academic Emergency Medicine : Official... Aug 2006Acute myocardial ischemia is an important cause of morbidity and mortality worldwide. The heart and other organs can be rendered more resistant to the deleterious... (Comparative Study)
Comparative Study
BACKGROUND
Acute myocardial ischemia is an important cause of morbidity and mortality worldwide. The heart and other organs can be rendered more resistant to the deleterious effects of ischemia through a variety of preconditioning strategies, including treadmill exercise and brief ischemia of skeletal muscle. Some of the beneficial effects of these preconditioning strategies appear to be mediated by as-of-yet unidentified hormonal opioids.
OBJECTIVES
To test the hypothesis that endogenous opioids of the enkephalin class are capable of improving ischemic tolerance and acting in a hormonal manner.
METHODS
In phase one of the investigation, the authors assessed the cardioprotective potential of all four known enkephalins. This was achieved by subjecting isolated buffer-perfused rabbit hearts to a 25-minute period of test ischemia and two hours of reperfusion (protocol 1) after receiving treatment with either saline vehicle (controls) or increasing concentrations of purified enkephalins. On the basis of results from these initial studies, the authors performed additional experiments (protocol 2) to determine whether Met5-enkephalin-Arg6-Phe7 (MEAP) could be absorbed from skeletal muscle and exert a cardioprotective effect. Specifically, MEAP or vehicle (controls) was given intramuscularly 24 hours before the hearts were harvested. A similar assessment of ischemic tolerance as described in protocol 1 was then performed. Postischemic myocardial viability (infarct size) was assessed in all cases by triphenyltetrazolium chloride (TTC) staining. Hemodynamic parameters and infarct sizes for concentration-dependence studies were compared by two-way analysis of variance, and infarct sizes from protocol 2 studies were compared by using Student's t-test (significance set at p < or = 0.05).
RESULTS
Mean infarct size in control hearts (+/- SEM) was 33% (+/- 4%) and 36% (+/- 6%) for protocol 1 and 2, respectively. Of the four enkephalins tested in protocol 1, only MEAP treatment showed a tendency toward cardioprotection. Interestingly, an alternative enkephalin, methionine5-enkephalin-Arg6-Gly7-Leu8, tended to exert an injurious effect. In protocol 2, MEAP treatment 24 hours before ischemia significantly reduced infarct size (14% +/- 4%) compared with controls, suggesting that it can be released from muscle and exert a distant cardioprotective effect.
CONCLUSIONS
When given either directly to the heart or absorbed from a distant tissue, MEAP induces cardioprotection, supporting the hypothesis that it can act as a hormonal modulator of ischemic tolerance.
Topics: Animals; Cardiotonic Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Enkephalin, Methionine; Injections, Intramuscular; Myocardial Ischemia; Myocardial Reperfusion; Myocardial Reperfusion Injury; Rabbits; Random Allocation; Reference Values; Treatment Outcome
PubMed: 16766738
DOI: 10.1197/j.aem.2006.03.556 -
Anesthesiology Jul 2014Skin synthesis of endogenous opioids such as enkephalin is considered to be increased in cholestatic rodents, which may induce antinociception in cholestatic liver...
BACKGROUND
Skin synthesis of endogenous opioids such as enkephalin is considered to be increased in cholestatic rodents, which may induce antinociception in cholestatic liver disease. No studies have reported yet the expression of skin enkephalin in patients with cholestasis.
METHODS
Electrical pain threshold, postoperative morphine consumption, and skin enkephalin expression were measured in patients with jaundice (n = 18) and control patients (n = 16). Male Sprague-Dawley rats (n = 52) and human keratinocyte cell line HaCaT were used in vivo and in vitro studies, respectively. Nociceptive thresholds and plasma and skin levels of methionine-enkephalin were compared in protease-activated receptors-1-antagonized and control bile duct-ligated rats. In in vitro study, the effect on thrombin-induced enkephalin expression was examined and the role of extracellular regulated protein kinases 1/2 and p38 was investigated.
RESULTS
The authors found that: (1) the electrical pain threshold (mean ± SD) was 1.1 ± 0.1 mA in control patients, whereas it was significantly increased in patients with jaundice (1.7 ± 0.3 mA); 48-h postoperative morphine consumption was approximately 50% higher in the control group than that in the group with jaundice; (2) Skin keratinocytes enkephalin expression was increased in the patients with jaundice; (3) Protease-activated receptors-1 antagonist 1 μg·kg(-1)·day(-1) treatment to the bile duct-ligated rats significantly reduced plasma levels of methionine-enkephalin, nociceptive thresholds, and keratinocytes enkephalin expression; and (4) protease-activated receptors-1 activation induced enkephalin expression through phosphorylation of extracellular regulated protein kinases 1/2 and p38 in keratinocytes.
CONCLUSION
Protease-activated receptors-1 activation in peripheral keratinocytes may play an important role in the local synthesis of enkephalin during cholestasis.
Topics: Adult; Animals; Bile Ducts; Blotting, Western; Cell Line; Electric Stimulation; Enkephalin, Methionine; Humans; Immunohistochemistry; Jaundice, Obstructive; Keratinocytes; Ligation; Liver; MAP Kinase Signaling System; Male; Pain Measurement; Pain Threshold; Pain, Postoperative; Pyrroles; Quinazolines; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Receptor, PAR-1; Thrombin; Up-Regulation; p38 Mitogen-Activated Protein Kinases
PubMed: 24614324
DOI: 10.1097/ALN.0000000000000210 -
The Journal of Comparative Neurology May 1987The present study was carried out to examine if peptides similar to the various opioid peptide products of mammalian proenkephalin are present in the turtle central...
The present study was carried out to examine if peptides similar to the various opioid peptide products of mammalian proenkephalin are present in the turtle central nervous system and to determine their distribution. Antisera against several enkephalin peptides were used: leucine-enkephalin (LENK), methionine-enkephalin (MENK), methionine-enkephalin-arg6-phe7 (MERF), methionine-enkephalin-arg6-gly7-leu8 (MERGL), Peptide E (PEPE), and BAM22P. Their specificity and cross-reactivity were carefully examined. The results indicated that LENK, MENK, and MERF (or highly similar peptides) are present in the turtle central nervous system, and that a peptide showing immunological similarity to BAM22P and PEPE also appeared to be present. In contrast, MERGL did not appear to be present. The distributions of the immunoreactive labeling for LENK, MENK, MERF, BAM22P, and PEPE were indistinguishable, and double-label studies showed that LENK, MERF, and BAM22P were colocalized within individual neurons and fibers. Although all of the above substances were observed in the same cell groups, there was some regional variation, in terms of which enkephalin peptide appeared to be most abundant. The distributions of these enkephalin peptides were very similar to those previously described in mammals and birds. Enkephalin was more abundant in the basal ganglia than in overlying telencephalic regions. Within the basal ganglia, enkephalin was present in striatal neurons and fibers and in pallidal fibers, thereby suggesting the existence of an enkephalinergic striatopallidal projection. Sensory relay nuclei of the thalamus were generally poor in enkephalinergic fibers, whereas the hypothalamus was rich in enkephalinergic neurons and fibers. Enkephalinergic neurons and fibers were present in the midbrain central gray. As is true of neurons of the nucleus spiriformis lateralis of the avian pretectum, the neurons of the homologous cell group in turtles, the dorsal nucleus of the posterior commissure of the pretectum, were found to contain enkephalin and have an enkephalinergic projection to the deep layers of the ipsilateral tectum. Enkephalinergic neurons and fibers were also abundant in the entry zones of the trigeminal nerve and dorsal root fibers of the spinal cord.(ABSTRACT TRUNCATED AT 400 WORDS)
Topics: Animals; Antibody Specificity; Brain Chemistry; Enkephalin, Leucine; Enkephalin, Methionine; Enkephalins; Histocytochemistry; Immune Sera; Immunologic Techniques; Peptides; Protein Precursors; Turtles
PubMed: 3294930
DOI: 10.1002/cne.902590106