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Biochemical Pharmacology Oct 2021Diabetes is a multi-faceted disorder with increasing prevalence and rising healthcare costs. The burden of diabetes is increased because of associated complications... (Review)
Review
Diabetes is a multi-faceted disorder with increasing prevalence and rising healthcare costs. The burden of diabetes is increased because of associated complications affecting nearly all organs including the eye. The underlying pathophysiology for the onset of these ocular surface disorders is not well known. Enkephalins are endogenous opioids that originate in the brain and have numerous actions in the human body. Opioid growth factor (OGF), chemically termed [Met]-enkephalin, binds to a novel, nuclear-associated receptor and mediates cellular homeostasis. Serum OGF levels are elevated in diabetic individuals and rodent models of diabetes. Sustained blockade of the OGF receptor (OGFr) with opioid receptor antagonists, such as naltrexone (NTX), reverses many complications of diabetes in the animal model, including delayed cutaneous wound healing, dry eye, altered corneal surface sensitivity, and keratopathy. The increased enkephalin levels observed in diabetes suggest a relationship between endogenous opioid peptides and the pathophysiology of diabetes. It is common for diabetic patients to undergo insulin therapy to restore normal blood glucose levels. However, this restoration does not alter OGF serum levels nor ameliorate ocular surface complications in the animal model of diabetes. Moreover, sex differences in the prevalence of diabetes, response to insulin therapy, and abnormalities in the OGF-OGFr axis have been reported. This review highlights current knowledge on the dysregulation of the OGF-OGFr pathway and possible relationships of insulin and enkephalins to the development of ocular surface defects in diabetes. It proposes that this dysregulation is a fundamental mechanism for the pathobiology of diabetic complications.
Topics: Animals; Corneal Diseases; Diabetes Complications; Diabetes Mellitus; Dry Eye Syndromes; Enkephalins; Humans; Insulin; Naltrexone; Narcotic Antagonists; Receptors, Opioid
PubMed: 34324868
DOI: 10.1016/j.bcp.2021.114712 -
Folia Histochemica Et Cytobiologica 2021A recent study has shown a close neuroanatomical relationship between the enkephalinergic (methionine-enkephalin) and tachykininergic (substance P) systems in the alpaca...
INTRODUCTION
A recent study has shown a close neuroanatomical relationship between the enkephalinergic (methionine-enkephalin) and tachykininergic (substance P) systems in the alpaca diencephalon. In this study, our aim is to show this relationship in the alpaca brainstem.
MATERIAL AND METHODS
Using an immunohistochemical technique, the distribution of immunoreactive (Ir) fibers and cell bodies containing substance P (SP) or methionine-enkephalin (MET) has been studied in the alpaca brainstem. Five adult males were used; brain tissue was fixed and processed by standard methods.
RESULTS
SP- and MET-Ir fibers showed a widespread and similar distribution in the mesencephalon, pons and medulla oblongata. The co-localization of fibers containing SP or MET was found in most of the nuclei/tracts of the alpaca brainstem. This close neuroanatomical relationship suggests multiple physiological interactions between both neuropeptides. The distribution of the cell bodies containing SP was very restricted (cell bodies were only observed in a few nuclei located in the mesencephalon and medulla oblongata), whereas MET-Ir perikarya showed a moderately widespread distribution in the mesencephalon, pons and medulla oblongata.
CONCLUSIONS
This study increases the knowledge on the neuroanatomical distribution/relationship of the tachykininergic (SP) and enkephalinergic (MET) systems in the alpaca central nervous system.
Topics: Animals; Brain Stem; Camelids, New World; Diencephalon; Enkephalin, Methionine; Male; Substance P
PubMed: 34309826
DOI: 10.5603/FHC.a2021.0016 -
Proceedings of the National Academy of... Apr 2021Positive allosteric modulators (PAMs) of the mu-opioid receptor (MOR) have been hypothesized as potentially safer analgesics than traditional opioid drugs. This is based...
Positive allosteric modulators (PAMs) of the mu-opioid receptor (MOR) have been hypothesized as potentially safer analgesics than traditional opioid drugs. This is based on the idea that PAMs will promote the action of endogenous opioid peptides while preserving their temporal and spatial release patterns and so have an improved therapeutic index. However, this hypothesis has never been tested. Here, we show that a mu-PAM, BMS-986122, enhances the ability of the endogenous opioid Methionine-enkephalin (Met-Enk) to stimulate G protein activity in mouse brain homogenates without activity on its own and to enhance G protein activation to a greater extent than β-arrestin recruitment in Chinese hamster ovary (CHO) cells expressing human mu-opioid receptors. Moreover, BMS-986122 increases the potency of Met-Enk to inhibit GABA release in the periaqueductal gray, an important site for antinociception. We describe in vivo experiments demonstrating that the mu-PAM produces antinociception in mouse models of acute noxious heat pain as well as inflammatory pain. These effects are blocked by MOR antagonists and are consistent with the hypothesis that in vivo mu-PAMs enhance the activity of endogenous opioid peptides. Because BMS-986122 does not bind to the orthosteric site and has no inherent agonist action at endogenously expressed levels of MOR, it produces a reduced level of morphine-like side effects of constipation, reward as measured by conditioned place preference, and respiratory depression. These data provide a rationale for the further exploration of the action and safety of mu-PAMs as an innovative approach to pain management.
Topics: Allosteric Regulation; Analgesia; Analgesics; Analgesics, Opioid; Animals; CHO Cells; Cricetulus; Female; Male; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Morphine; Narcotic Antagonists; Pain; Pain Management; Proof of Concept Study; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu
PubMed: 33846240
DOI: 10.1073/pnas.2000017118 -
Blockade of OGFr delays the onset and reduces the severity of diabetic ocular surface complications.Experimental Biology and Medicine... Mar 2021The opioid growth factor (OGF)-OGF receptor (OGFr) pathway is present in the ocular surface and functions to maintain homeostasis of the epithelium. The OGF-OGFr pathway...
The opioid growth factor (OGF)-OGF receptor (OGFr) pathway is present in the ocular surface and functions to maintain homeostasis of the epithelium. The OGF-OGFr pathway has been reported to be dysregulated in diabetic individuals and animal models, and is reflected in elevations of the inhibitory growth factor, OGF, chemically termed [Met]-enkephalin. Recently, our laboratory reported elevated levels of OGF and OGFr in the serum and corneal epithelium of type 1 diabetic rats, suggesting that dysregulation of the OGF-OGFr axis may lead to dry eye, abnormal corneal surface sensitivity, and delayed re-epithelialization. Blockade of OGF-OGFr pathway using naltrexone, a potent opioid receptor antagonist, reverses dry eye symptoms and restores corneal surface sensitivity in diabetic rats when used as a therapy. Based on the evidence that both OGF and OGFr are elevated in type 1 diabetic rats, this study examined whether systemic or topical naltrexone treatment initiated at the time of induction of hyperglycemia could protect against the development of diabetic ocular surface complications. Diabetic male Sprague-Dawley rats treated systemically or topically with naltrexone had a delayed onset of dry eye and altered corneal surface sensitivity, and an improved healing rate for corneal wounds, that were comparable to non-diabetic rats. Serum levels of OGF were normal for rats receiving systemic naltrexone, and OGF tissue levels were normal for type 1 diabetic rats receiving twice daily naltrexone drops. OGFr levels remained elevated. These data support the role of the OGF-OGFr axis in regulation of ocular surface complications, and suggest that naltrexone therapy may be beneficial for pre-diabetic and early diabetic individuals.
Topics: Animals; Blood Glucose; Body Weight; Cornea; Diabetes Complications; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Enkephalin, Methionine; Eye; Male; Naltrexone; Rats, Sprague-Dawley; Receptors, Opioid; Severity of Illness Index; Time Factors; Rats
PubMed: 33203224
DOI: 10.1177/1535370220972060 -
Immunology and Cell Biology Jan 2021In inguinal adipose tissue, beige adipocytes are interspersed among white adipocytes and in close communication with dynamic populations of immune cells. Recent data...
In inguinal adipose tissue, beige adipocytes are interspersed among white adipocytes and in close communication with dynamic populations of immune cells. Recent data have demonstrated that anti-inflammatory macrophages (M2) increase thermogenic activity of beige adipocytes, although the mechanism is currently under debate. ILC2, cells via secretion, of methionine enkephalin peptide were found to be able to increase beige thermogenesis. Knights et al. have recently generated a whole-body knock-out of KLF3 (KLF3-/-) to explore its contribution to thermogenesis and weight gain in a diet-induced obesity animal model.
Topics: Adipose Tissue; Animals; Eosinophils; Immunity, Innate; Lymphocytes; Thermogenesis
PubMed: 33167058
DOI: 10.1111/imcb.12407 -
Molecular Medicine Reports Nov 2020Endometriosis (EMS) is a common disease in women aged 25‑45 years, and pain is the main clinical symptom. The primary clinical treatment is surgical excision and drug...
Endometriosis (EMS) is a common disease in women aged 25‑45 years, and pain is the main clinical symptom. The primary clinical treatment is surgical excision and drug therapy targeting the ectopic lesions, but these have not been very effective. Botulinum neurotoxin serotype A (BTX‑A) has been reported to be useful in the treatment of pain in a variety of diseases. Based on this, the aim of the present study was to explore the therapeutic effect and mechanism of BTX‑A on EMS. A model of nerve injury induced by oxygen glucose deprivation (OGD) was constructed in PC12 cells and EMS mice. Model cells and mice were treated with different concentrations of BTX‑A to observe the changes in pain behavior, to detect cell viability and the secretion of norepinephrine (NE) and methionine enkephalin (M‑EK) in cells and the spinal cord, and to evaluate the expression of apoptosis‑related molecules in spinal cord nerves. The results revealed that BTX‑A significantly reduced the amount of writhing in model mice, enhanced the activity of PC12 OGD cells, increased the secretion of NE and M‑EK in model cells and the spinal cord of mice, and decreased the apoptosis of neural cells in the spinal cord of the model mice. Therefore, it was hypothesized that BTX‑A may alleviate the pain induced by EMS by increasing the secretion of analgesic substances and promoting the repair of nerve injury. The present study provided a theoretical basis for the treatment of pain induced by EMS.
Topics: Adult; Animals; Botulinum Toxins, Type A; Cell Survival; Disease Models, Animal; Endometriosis; Enkephalin, Methionine; Female; Glucose; Humans; Mice; Mice, Inbred BALB C; Norepinephrine; PC12 Cells; Pain; Rats
PubMed: 33000241
DOI: 10.3892/mmr.2020.11501 -
International Journal of Molecular... Aug 2020Opioids and their antagonists alter vitamin C metabolism. Morphine binds to glutathione (l-γ-glutamyl-l-cysteinyl-glycine), an intracellular ascorbic acid recycling...
Glutathione and Glutathione-Like Sequences of Opioid and Aminergic Receptors Bind Ascorbic Acid, Adrenergic and Opioid Drugs Mediating Antioxidant Function: Relevance for Anesthesia and Abuse.
Opioids and their antagonists alter vitamin C metabolism. Morphine binds to glutathione (l-γ-glutamyl-l-cysteinyl-glycine), an intracellular ascorbic acid recycling molecule with a wide range of additional activities. The morphine metabolite morphinone reacts with glutathione to form a covalent adduct that is then excreted in urine. Morphine also binds to adrenergic and histaminergic receptors in their extracellular loop regions, enhancing aminergic agonist activity. The first and second extracellular loops of adrenergic and histaminergic receptors are, like glutathione, characterized by the presence of cysteines and/or methionines, and recycle ascorbic acid with similar efficiency. Conversely, adrenergic drugs bind to extracellular loops of opioid receptors, enhancing their activity. These observations suggest functional interactions among opioids and amines, their receptors, and glutathione. We therefore explored the relative binding affinities of ascorbic acid, dehydroascorbic acid, opioid and adrenergic compounds, as well as various control compounds, to glutathione and glutathione-like peptides derived from the extracellular loop regions of the human beta 2-adrenergic, dopamine D1, histamine H1, and mu opioid receptors, as well as controls. Some cysteine-containing peptides derived from these receptors do bind ascorbic acid and/or dehydroascorbic acid and the same peptides generally bind opioid compounds. Glutathione binds not only morphine but also naloxone, methadone, and methionine enkephalin. Some adrenergic drugs also bind to glutathione and glutathione-like receptor regions. These sets of interactions provide a novel basis for understanding some ways that adrenergic, opioid and antioxidant systems interact during anesthesia and drug abuse and may have utility for understanding drug interactions.
Topics: Analgesics, Opioid; Ascorbic Acid; Dehydroascorbic Acid; Enkephalin, Methionine; Glutathione; Humans; Hydromorphone; Methadone; Morphine; Naloxone; Peptides; Receptors, Adrenergic, beta-2; Receptors, Dopamine D1; Receptors, Histamine H1; Receptors, Opioid; Receptors, Opioid, mu
PubMed: 32872204
DOI: 10.3390/ijms21176230 -
Proceedings of the National Academy of... Aug 2020Regulatory T (Treg) cells, expressing CD25 (interleukin-2 receptor α chain) and Foxp3 transcription factor, maintain immunological self-tolerance and suppress various...
Regulatory T (Treg) cells, expressing CD25 (interleukin-2 receptor α chain) and Foxp3 transcription factor, maintain immunological self-tolerance and suppress various immune responses. Here we report a feature of skin Treg cells expanded by ultraviolet B (UVB) exposure. We found that skin Treg cells possessing a healing function are expanded by UVB exposure with the expression of an endogenous opioid precursor, proenkephalin (PENK). Upon UVB exposure, skin Treg cells were expanded with a unique TCR repertoire. Also, they highly expressed a distinctive set of genes enriched in "wound healing involved in inflammatory responses" and the "neuropeptide signaling pathway," as indicated by the high expression of We found that not only was PENK expression at the protein level detected in the UVB-expanded skin Treg (UVB-skin Treg) cells, but that a PENK-derived neuropeptide, methionine enkephalin (Met-ENK), from Treg cells promoted the outgrowth of epidermal keratinocytes in an ex vivo skin explant assay. Notably, UVB-skin Treg cells also promoted wound healing in an in vivo wound closure assay. In addition, UVB-skin Treg cells produced amphiregulin (AREG), which plays a key role in Treg-mediated tissue repair. Identification of a unique function of PENK UVB-skin Treg cells provides a mechanism for maintaining skin homeostasis.
Topics: Amphiregulin; Animals; Cells, Cultured; Enkephalin, Methionine; Enkephalins; Female; Homeostasis; Humans; Immune Tolerance; Interleukin-2 Receptor alpha Subunit; Male; Mice; Mice, Inbred C57BL; Protein Precursors; Self Tolerance; Skin; T-Lymphocytes, Regulatory; Ultraviolet Rays; Wound Healing
PubMed: 32769209
DOI: 10.1073/pnas.2000372117 -
JBMR Plus Jul 2020Mechanical stress stimulates bone remodeling, which occurs through bone formation and resorption, resulting in bone adaptation in response to the mechanical stress....
Mechanical stress stimulates bone remodeling, which occurs through bone formation and resorption, resulting in bone adaptation in response to the mechanical stress. Osteocytes perceive mechanical stress loaded to bones and promote bone remodeling through various cellular processes. Osteocyte apoptosis is considered a cellular process to induce bone resorption during mechanical stress-induced bone remodeling, but the underlying molecular mechanisms are not fully understood. Recent studies have demonstrated that neuropeptides play crucial roles in bone metabolism. The neuropeptide, methionine enkephalin (MENK) regulates apoptosis positively and negatively depending on cell type, but the role of MENK in osteocyte apoptosis, followed by bone resorption, in response to mechanical stress is still unknown. Here, we examined the roles and mechanisms of MENK in osteocyte apoptosis induced by compressive force. We loaded compressive force to mouse parietal bones, resulting in a reduction of MENK expression in osteocytes. A neutralizing connective tissue growth factor (CTGF) antibody inhibited the compressive force-induced reduction of MENK. An increase in osteocyte apoptosis in the compressive force-loaded parietal bones was inhibited by MENK administration. Nuclear translocation of NFATc1 in osteocytes in the parietal bones was enhanced by compressive force. INCA-6, which inhibits NFAT translocation into nuclei, suppressed the increase in osteocyte apoptosis in the compressive force-loaded parietal bones. NFATc1-overexpressing MLO-Y4 cells showed increased expression of apoptosis-related genes. MENK administration reduced the nuclear translocation of NFATc1 in osteocytes in the compressive force-loaded parietal bones. Moreover, MENK suppressed Ca influx and calcineurin and calmodulin expression, which are known to induce the nuclear translocation of NFAT in MLO-Y4 cells. In summary, this study shows that osteocytes expressed MENK, whereas the MENK expression was suppressed by compressive force via CTGF signaling. MENK downregulated nuclear translocation of NFATc1 probably by suppressing Ca signaling in osteocytes and consequently inhibiting compressive force-induced osteocyte apoptosis, followed by bone resorption. © 2020 The Authors. published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
PubMed: 32666020
DOI: 10.1002/jbm4.10369 -
Experimental Biology and Medicine... Sep 2020This research extends our knowledge about the presence and role of the OGF-OGFr regulatory axis in type 1 diabetes (T1D) and demonstrates specific targets within the...
This research extends our knowledge about the presence and role of the OGF-OGFr regulatory axis in type 1 diabetes (T1D) and demonstrates specific targets within the pathway that are dysregulated. Serum levels of OGF, an inhibitory growth factor, are significantly elevated in male T1D rats, and OGFr serum values are increased in T1D. The onset of elevated OGF corresponds to the onset of ocular surface complications including dry eye, delayed corneal epithelial repair, and abnormal corneal surface sensitivity in T1D. Systemic insulin does not protect against elevated OGF levels or the onset of dry eye and sensitivity. These data are the first to associate some ocular surface defects in T1D with alterations in the OGF-OGFr pathway.
Topics: Analgesics, Opioid; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Epithelium, Corneal; Eye; Male; Neprilysin; Rats, Sprague-Dawley; Re-Epithelialization; Receptors, Opioid; Time Factors
PubMed: 32640891
DOI: 10.1177/1535370220940273