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1.
Endogenous opioid peptides serve as growth factors in developing, renewing, healing, and neoplastic cells and tissues. A native opioid peptide, [Met5]-enkephalin, termed opioid growth factor (OGF), has been discovered to regulate DNA synthesis in the epithelium of the ocular surface. OGF and its receptor ζ have been localized in both the basal and suprabasal cells of the epithelium. This study examined the hypothesis that OGF is an autocrine growth factor. Using probe for preproenkephalin (PPE) mRNA that encodes OGF, and in situ hybridization techniques, silver grains related to PPE mRNA were detected in both basal and suprabasal cells of the central and peripheral cornea, limbus, and conjunctiva. No distinct regional differences in the presence or location of message, as reflected by the density and distribution of PPE mRNA signal, were noted. These results demonstrate that a growth factor known to serve as a tonic, inhibitory, and receptor-mediated influence on the epithelium of the ocular surface is derived in an autocrine manner, thereby permitting local control of homeostatic cellular replication.  相似文献   

2.
The opioid growth factor (OGF)–OGF receptors (OGFr) axis plays an important role in the homeostasis and re-epithelialization of the mammalian cornea. This tonically active growth regulatory inhibitory pathway is involved in cell replication, and the endogenous neuropeptide OGF targets cyclin-dependent kinase inhibitors, p16 and/or p21. Blockade of OGF–OGFr interfacing by systemic or topical administration of opioid antagonists such as naltrexone (NTX) results in accelerated DNA synthesis, cell replication, and tissue repair. Molecular manipulation of OGFr using sense constructs delayed corneal re-epithelialization, whereas antisense constructs accelerated repair of the corneal surface. Corneal keratopathy, a significant complication of diabetes mellitus, is manifested by delays in corneal re-epithelialization following surgery, injury, or disease. Tissue culture studies have shown that addition of NTX stimulates DNA synthesis and explant outgrowth of rabbit corneal epithelium, whereas OGF depresses DNA synthesis and explant outgrowth in a receptor-mediated manner. NTX accelerated corneal re-epithelialization in organ cultures of human and rabbit cornea. Systemic application of NTX to the abraded corneas of rats, and topical administration of NTX to the injured rabbit ocular surface, increased re-epithelialization. Systemic injections or topical administration of NTX facilitates re-epithelialization of the cornea in diabetic rats. Given the vital role of the corneal epithelium in maintaining vision, the frequency of corneal complications related to diabetes (diabetic keratopathy), and the problems occurring in diabetic individuals postoperatively (e.g., vitrectomy), and that conventional therapies such as artificial tears and bandage contact lenses often fail, topical application of NTX merits clinical consideration.  相似文献   

3.
A native opioid peptide, [Met5]-enkephalin, termed opioid growth factor (OGF), serves as a constitutively expressed and autocrine produced inhibitory molecule related to developing, neoplastic, renewing, and healing tissues. The present study was designed to examine the effects of interfering with opioid–receptor interaction during re-epithelialization of the cornea in the rat using both systemic injections and topical applications of the potent opioid antagonist naltrexone (NTX). A 4 mm diameter epithelial defect was made in the center of the rat cornea. NTX injected twice daily or applied as eyedrops four times daily significantly accelerated re-epithelialization compared to controls. Beginning as early as 8 h after wounding, both the systemic and topical NTX treatment groups had defects that were approximately 10% to 67% smaller than control abrasions at the time points examined. Similarly, the rate of healing for the NTX groups was 4.7- and 2.8-fold greater than controls for systemic and topical paradigms, respectively. The incidence of complete re-epithelialization in animals given systemic administration of NTX was markedly accelerated in comparison to control rats; however, differences in incidence of repair between NTX and control groups receiving topical application were not observed. These results show that native opioid peptides function in wound healing, and exert a tonically inhibitory influence at the receptor level on repair of corneal epithelial injuries.  相似文献   

4.
In addition to neurotransmission, the native opioid peptide, [Met5]enkephalin, is a tonically active inhibitory growth molecule that is termed opioid growth factor (OGF). OGF interacts with the zeta (zeta) opioid receptor to influence cell proliferation and tissue organization. We now identify OGF and the zeta receptor in embryonic derivatives including ectoderm, mesoderm, and endoderm of the rat on gestation day 20. Messenger RNA for preproenkephalin (PPE), the precursor of OGF, was detected in the developing cells, suggesting an autocrine production of this peptide. Acute exposure of the pregnant female to OGF resulted in a decrease in DNA synthesis in cells of organs representing all three germ layers, and did so in a receptor-mediated fashion. The influence of OGF was direct, as evidenced in organ culture studies. Blockade of endogenous opioid interaction using naltrexone (NTX) produced an increase in DNA synthesis, indicating the constitutive and functional nature of opioid activity on growth during prenatal life. Human fetal cells contained OGF and the zeta receptor. These data support the hypothesis that endogenous opioid modulation of organ development is a fundamental principle of mammalian embryogenesis, and that OGF has a profound influence on ontogeny. Irregularities in the role of opioids as growth regulators in relationship to the more than 500,000 newborns suffering from birth defects each year in the US needs to be examined.  相似文献   

5.
In addition to neuromodulation, endogenous opioids serve as growth factors. The naturally occurring opioid peptide, [Met5]enkephalin, termed opioid growth factor (OGF), has been found to be a potent and tonic inhibitor of processes related to growth and renewal, particularly cell proliferation. OGF mediates its actions through the zeta (ζ) opioid receptor. In order to determine if OGF and/or the ζ receptor are present in human corneal epithelium, immunocytochemistry was utilized. Immunoreactivity with regard to OGF and to the ζ receptor could be detected in the cortical cytoplasm of both basal and suprabasal epithelial cells, but was not associated with the cell nucleus. Investigation of the ubiquity of OGF and ζ receptor in the vertebrate cornea showed that both elements are present in a wide variety of classes of the phylum Chordata, including mammalia, aves, reptilia, amphibia, and osteichthyes. These results suggest that an endogenous opioid system related to growth may have originated as early as 300 million years ago, and that the function of this system in cellular renewal and homeostasis is a requirement of the vertebrate corneal epithelium.  相似文献   

6.
This study was designed to examine the role of opioids on cell differentiation, with an emphasis on the mechanism of opioid growth factor (OGF, [Met5]-enkephalin)-dependent growth inhibition. Three human cancer cell lines (SK-N-SH neuroblastoma and SCC-1 and CAL-27 squamous cell carcinoma of the head and neck), along with OGF and the opioid antagonist naltrexone (NTX) at a dosage (10(-6) M) known to repress or increase, respectively, cell replication, were utilized. The effects on differentiation (neurite formation, process lengths, betaIII-tubulin, involucrin) were investigated in cells exposed to OGF or NTX for up to 6 days. In addition, the influence of a variety of other natural and synthetic opioids on differentiation was examined. OGF, NTX, naloxone, [D-Pen2,5]-enkephalin, dynorphin A1-8, beta-endorphin, endomorphin-1 and -2, [D-Ala2, MePhe4, Glycol5]-enkephalin (DAMGO), morphine, and U69,593 at concentrations of 10(-6) M did not alter cell differentiation of any cancer cell line. In NTX-treated SK-N-SH cells, cellular area was increased 23%, and nuclear area was decreased 17%, from control levels; no changes in cell or nuclear area were recorded in OGF-exposed cells. F-actin concentration was increased 40% from control values in SK-N-SH cells subjected to NTX, whereas alpha-tubulin was decreased 53% in OGF-treated cells. These results indicate that the inhibitory or stimulatory actions of OGF and NTX, respectively, on cell growth in tissue culture are not due to alterations in differentiation pathways. However, exposure to OGF and NTX modified some aspects of cell structure, but this was independent of differentiation. The absence of effects on cancer cell differentiation by a variety of other opioids supports the previously reported lack of growth effects of these compounds.  相似文献   

7.
This study was designed to examine the role of opioids on cell migration, chemotaxis, invasion, and adhesion, with an emphasis on whether the opioid growth factor (OGF, [Met(5)]-enkephalin) or the opioid antagonist naltrexone (NTX) impacts any or all of these processes. Drug concentrations of OGF and NTX known to depress or stimulate, respectively, cell proliferation and growth were analyzed. Three different human cancers (pancreatic, colon, and squamous cell carcinoma of the head and neck), represented by seven different cancer cell lines (PANC-1, MIA PaCa-2, BxPC-3, CAL-27, SCC-1, HCT-116, and HT-29), were evaluated. In addition, the influence of a variety of other natural and synthetic opioids on cell motility, invasion, and adhesion was assessed. Positive and negative controls were included for comparison. OGF and NTX at concentrations of 10(-4) to 10(-6)M, and dynorphin A1-8, beta-endorphin, endomorphin-1, endomorphin-2, leucine enkephalin, [D-Pen(2,5)]-enkephalin (DPDPE), [D-Ala(2), MePhe(4), Glycol(5)]-enkephalin (DAMGO), morphine, and U69,593 at concentrations of 10(-6)M, did not alter cell migration, chemotaxis, or invasion of any cancer cell line. OGF and NTX at a concentration of 10(-6)M, and incubation for 24 or 72h, did not change adhesion of these cancer cells to collagen I, collagen IV, fibronectin, laminin, or vitronectin. Moreover, all other opioids tested at 10(-6)M concentrations and for 24h had no effect on adhesion. These results indicate that the inhibitory or stimulatory actions of OGF and NTX, respectively, on cell replication and growth are independent of cell migration, chemotaxis, invasion, and adhesive properties. Moreover, a variety of other exogenous and endogenous opioids, many specific for the micro, delta, or kappa opioid receptors, also did not alter these biological processes, consonant with previous observations of a lack of effects of these compounds and their receptors on the biology of cancer cells.  相似文献   

8.
Summary A nonapeptide Thr-Ile-Ile-Asn-Val-Lys-Cys-Thr-Ser (NTX1–9) and a decapeptide Met-Asn-Gly-Lys-Cys-Lys-Cys-Tyr-Asn-Asn (NTX30–39) corresponding to the N-terminal and C-terminal sequences respectively of Noxiustoxin (NTX) were synthesized by the solid phase method of Merrifield (1963). The first synthetic peptide (NTX1–9) was shown to be toxic to mice independently of the route of administration: intraperitoneally, subcutaneously or intraventricularly (100–200 g/20 g mouse weight). The second (NTX30–39) was not toxic even at higher dose (400 g/20 g mouse). When the effects of the peptide NTX1–9 and of the authentic toxin (Noxiustoxin) were studied on the liberation of [3H] 4-aminobutyric acid (3H-GABA) from mouse synaptosomes, both gave essentially the same results, except that peptide NTX1–9 was needed at higher concentration. Synthetic peptide NTX30–39 had no effect in the same preparation at even higher doses. The GABA release produced by toxic peptide NTX1–9 was not affected by tetrodotoxin but was completely abolished by the presence of the K+ ionophore valinomycin, mimicking the effect of native NTX in the same system (Sitges et al., 1986). These results indicate that the toxic active site of Noxiustoxin is possibly located in or near the N-terminal amino acid portion of the molecule.Abbreviations used BOC amino acids ter-butyloxycarbonyl-amino acids - BOC amino acid-PAM-resin ter-butyloxycarbonyl-aminoacyl-4-(oxymethyl)-phenacetamidomethyl-resin - GABA 4 aminobutyric acid - HPLC high performance liquid chromatography - MSA mouse serum albumin - NTX Noxiustoxin - NTX (numbers) synthetic peptides with amino acid sequences of NTX at position start (first number) to position end (second number) of the sequence according to Fig. 1 - TTX tetrodotoxin Supported in part by the Mexican Council of Science and Technology (CONACyT), grants PVT/QF/NAL/84/2182, PVT/AI/NAL/85/3029 to L.D.P.; PCSACNA 022640 to A.B. A patent request claiming rights on the use of synthetic NTX and related peptides was presented in Washington, DC (U.S.A.), Serial number 07/132,169, filing date December 14, 1987.  相似文献   

9.
To determine the fate of ocular surface epithelial cells in response to corneal injury, epithelial cells undergoing DNA synthesis were labeled at discrete time points following abrasion. A 3-mm diameter epithelial defect was made in the center of the rat cornea. One hour prior to sacrifice, animals received an intraperitoneal injection of [3H]-thymidine. DNA synthesis in the regenerating epithelium was of low abundance (<2%). The undamaged corneal epithelium had a labeling index (LI) that was markedly elevated from unwounded specimens in the first 48 h after abrasion. The LIs of suprabasal cells were increased at 24 h and 36 h; these cells were believed to be displaced basal epithelial cells. Basal and suprabasal cells of the limbus and conjunctiva exhibited increases in LIs from unwounded subjects at singular timepoints (within 24 h of injury). These results, using rigorous statistical analysis, show that DNA synthesis is not impeded — but rather often accelerated — following denuding of the corneal epithelium. Re-epithelialization is not dependent on DNA synthesis in the regenerating region, but appears to be related to an increase in DNA synthesis (along with centripetal migration) in the adjacent, undamaged epithelium. The increase in DNA synthesis occurring in the limbus and conjunctiva does not directly supply cells to the regenerating region within the 72 h required for epithelial restitution, but is conjectured to serve in replenishing ocular surface epithelial cells used in the repair process.  相似文献   

10.
Naltrexone (NTX) is an opioid antagonist that accelerates wound healing of corneal epithelium in normal and diabetic animals. Junctional complexes (hemidesmosomes) are important in establishing adhesion of the corneal epithelium to the stroma. This study was designed to examine whether NTX, at a concentration that enhances corneal re-epithelialization, influences the appearance and number of hemidesmosomes in Normal, diabetic (DB) (hyperglycemic), and DB animals receiving insulin (DB-IN) (normoglycemic), and treated topically with NTX (10−4 M) or sterile vehicle (SV) for 7 days following abrasion. Electron microscopic analysis of the peripheral cornea 2 weeks after removal of the epithelium indicated hemidesmosomes that could be classified into four sectional profiles. No differences were detected in either the structure or the number of junctional complexes in the cornea between Normal, DB, or DB-IN groups receiving vehicle or treated with NTX. Moreover, the fine structure of the basal and suprabasal layers of the corneal epithelium in all groups – including those treated with NTX – were comparable. These results indicate that topical application of NTX accelerates diabetic corneal epithelial healing without causing morphologic abnormalities in the reassembly of adhesion structures. Furthermore, controlled and uncontrolled diabetes for up to 3 months does not affect corneal adhesion complexes when compared to normal corneas. Thus, recurrent erosion following abrasion of the diabetic cornea, with preservation of the basal lamina, cannot be explained by structural abnormalities in the reformation of the epithelial adhesion complex.  相似文献   

11.
Low frequency electroacupuncture (EA) analgesia has been thought to be mediated by endogenous opioids. Among other lines of evidence, it has been reported that EA stimulation delivered at 2 and 2-15 Hz in rats could be blocked or partially antagonized by naloxone (NAL) and naltrexone (NTX). In contrast, experiments in one of our laboratories (D.J.M.) showed that NAL did not inhibit 2 Hz, and even potentiated 125 Hz EA analgesia. In an attempt to resolve these discrepancies, we conducted joint experiments in the U.S.A. and in China using the methods which previously yielded NAL reversibility of EA analgesia. In no experiment did opiate antagonists block or reduce EA analgesia. On the contrary, we found that, in most experiments, NAL and NTX potentiated 2 and 2-15 Hz EA analgesia respectively. The potentiation occurred independently of laboratory methods, geographic location of the experiment, strain (Chinese or American), tail temperature, sex, and weight of rats. This potentiation suggests the existence of an opioid anti-analgesic system or that NAL and NTX acquired analgesic properties following EA. These results indicate that EA analgesia in rats is a variable phenomenon even when laboratory methods are rigorously replicated. The EA stimulation may activate multiple conflicting neural circuits which interact and ultimately modulate the analgesic outcome.  相似文献   

12.
Opioid peptides act as growth factors in neural and non-neural cells and tissues, in addition to serving for neurotransmission/neuromodulation in the nervous system. The native opioid growth factor (OGF), [Met5]-enkephalin, is a tonic inhibitory peptide that plays a role in cell proliferation and tissue organization during development, cancer, cellular renewal, wound healing, and angiogenesis. OGF action is mediated by a receptor mechanism. Assays with radiolabeled OGF have detected specific and saturable binding, with a one-site model of kinetics. Subcellular fractionation studies show that the receptor for OGF (OGFr) is an integral membrane protein associated with the nucleus. Using antibodies generated to a binding fragment of OGFr, this receptor has been cloned and sequenced in human, rat, and mouse. OGFr is distinguished by containing a series of imperfect repeats. The molecular and protein structure of OGFr have no resemblance to that of classical opioid receptors, and have no significant homologies to known domains or functional motifs with the exception of a bipartite nuclear localization signal. Immunoelectron microscopy and immunocytochemistry investigations, including co-localization studies, have detected OGFr on the outer nuclear envelope where it interfaces with OGF. The peptide–receptor complex associates with karyopherin, translocates through the nuclear pore, and can be observed in the inner nuclear matrix and at the periphery of heterochromatin of the nucleus. Signal transduction for modulation of DNA activity is dependent on the presence of an appropriate confirmation of peptide and receptor. This report reviews the history of OGF–OGFr, examines emerging insights into the mechanisms of action of opioid peptide–receptor interfacing, and discusses the clinical significance of these observations.  相似文献   

13.
Opioids and the apoptotic pathway in human cancer cells   总被引:9,自引:0,他引:9  
This study was designed to examine the role of opioids in cell survival, with an emphasis on the mechanism of opioid growth factor (OGF, [Met(5)]-enkephalin)-dependent growth inhibition. Using three human cancer cell lines: MIA PaCa-2 pancreatic adenocarcinoma, HT-29 colon adenocarcinoma, and CAL-27 squamous cell carcinoma of the head and neck, and OGF and the opioid antagonist naltrexone (NTX) at a dosage (10(-6)M) selected because it is known to repress or increase, respectively, cell replication, the effects on apoptosis (TUNEL, Annexin V) and necrosis (trypan blue) were investigated on days 2, 5, and 7 of exposure. In addition, the influence of a variety of other natural and synthetic opioids on apoptosis and necrosis was examined at a dosage of 10(-6)M. OGF, NTX, naloxone, [D-Pen(2,5)]-enkephalin, [Leu(5)]-enkephalin, dynorphin A1-8, beta-endorphin, endomorphin-1 and -2, and methadone at concentrations of 10(-6)M did not alter cell viability of any cancer cell line. Exposure of cultures to [D-Ala(2),MePhe(4),Glycol(5)]-enkephalin (DAMGO), morphine, or etorphine at 10(-6)M significantly increased the number of adherent cells positively stained for TUNEL and Annexin V, as well as the number of necrotic cells in the supernatant, from control levels at all time points studied. The effects of DAMGO, morphine, and etorphine on apoptosis/necrosis were not fully blocked by concomitant administration of naloxone. Despite the increase in cell death in some opioid-treated groups, the number of apoptotic and necrotic adherent cells, and the number of necrotic cells in the supernatant, was no more than 1-2% of the total cell population. These results indicate that the inhibitory (OGF) or stimulatory (NTX) action on cell growth in tissue culture is not due to alterations in apoptotic or necrotic pathways. Moreover, although some opioids increased cell death, and dose-effect relationships need to be established, this activity was not of great magnitude and supports the previously reported lack of growth inhibition of many of these compounds.  相似文献   

14.
This study was conducted to determine the cellular and subcellular location(s) of the opioid growth factor receptor (OGFr), and the opioid growth factor (OGF), [Met(5)]-enkephalin, in the corneal epithelium. Laser scanning confocal microscopy analysis revealed that both OGFr and OGF were colocalized in the paranuclear cytoplasm and cell nuclei in basal, as well as suprabasal, cells of adult rat corneal epithelium. Using a postembedding immunogold procedure for immunoelectron microscopy that included embedding in Unicryl, both single- and double-face labeling studies were performed. Immunogold labeling of OGFr was detected on the outer nuclear envelope, in the paranuclear cytoplasm proximal to the nuclear envelope, perpendicular to the nuclear envelope in a putative nuclear pore complex, and within the nucleus adjacent to heterochromatin. Immunoreactivity for OGF was noted in locations similar to that for OGFr. In addition, aggregates of staining for OGF were found throughout the cytoplasm, including subjacent to the plasma membrane. Double labeling experiments revealed that complexes of OGF-OGFr were colocalized on the outer nuclear envelope, in the paranuclear cytoplasm, extending across the nuclear pore complex, and in the nucleus. Anti-OGFr IgG by itself, but not anti-OGF IgG alone, was associated with the outer nuclear envelope, and uncomplexed OGF immunoreactivity was detected in the cytoplasm in dual labeling experiments. These results based on complementary approaches of confocal microscopy and immunoelectron microscopy, suggest that: (i) OGFr resides on the outer nuclear envelope, (ii) OGF interacts with OGFr at the outer nuclear envelope, (iii) the colocalized receptor and peptide translocates between the cytoplasm and the nucleus at the nuclear pore, and (iv) signal transduction for modulation of cell proliferation necessitates a peptide-receptor complex that interfaces with chromatin in the nucleus.  相似文献   

15.
In previous studies we showed that low (pM) concentrations of naloxone (NLX), naltrexone (NTX) or etorphine selectively antagonize excitatory, but not inhibitory, opioid receptor-mediated functions in nociceptive types of sensory neurons in culture. Cotreatment of these neurons with pM NTX or etorphine not only results in marked enhancement of the inhibitory potency of acutely applied nM morphine [or other bimodally-acting (inhibitory/excitatory) opioid agonists], but also prevents development of cellular manifestations of tolerance and dependence during chronic exposure to μM morphine. These in vitro studies were confirmed in vivo by demonstrating that acute cotreatment of mice with morphine plus a remarkably low dose of NTX (ca. 10 ng/kg) does, in fact, enhance the antinociceptive potency of morphine, as measured by hot-water tail-flick assays. Furthermore, chronic cotreatment of mice with morphine plus low doses of NTX markedly attenuates development of naloxone-precipitated withdrawal-jumping in physical dependence assays. The present study provides systematic dose-response analyses indicating that NTX elicited optimal enhancement of morphine's antinociceptive potency in mice when co-administered (i.p.) at about 100 ng/kg together with morphine (3 mg/kg). Doses of NTX as low as 1 ng/kg or as high as 1 μg/kg were still effective, but to a lesser degree. Oral administration of NTX in the drinking water of mice was equally effective as i.p. injections in enhancing the antinociceptive potency of acute morphine injections and even more effective in attenuating development of tolerance and NLX-precipitated withdrawal-jumping during chronic cotreatment. Cotreatment with a subanalgesic dose of etorphine (10 ng/kg) was equally effective as NTX in enhancing morphine's antinociceptive potency and attenuating withdrawal-jumping after chronic exposure. These studies provide a rationale for the clinical use of ultra-low-dose NTX or etorphine so as to increase the antinociceptive potency while attenuating the tolerance/dependence liability of morphine or other conventional bimodally-acting opioid analgesics.  相似文献   

16.
This study was designed to examine the presence and role of the opioid growth factor (OGF, [Met(5)]-enkephalin) and the OGF receptor (OGFr) in COS-7 cells; these cells lack classical opioid receptors. Preproenkephalin mRNA, which encodes OGF, was detected by Northern blot analysis, and OGFr mRNA was recorded by RT-PCR. Receptor binding analysis showed specific and saturable binding (K(d)=3.5nm, B(max)=44fmol/mg protein) for OGFr in the nuclear fraction. Both OGF and OGFr were recorded in COS-7 cells by immunocytochemistry. Addition of OGF to log-phase COS-7 cultures depressed growth by 41.6% from control levels, whereas opioid-receptor blockade by the opioid antagonist, naltrexone, increased the number of cells by 29.8% from control values. The effect of OGF was receptor mediated. Exposure to a wide variety of synthetic and natural opioid peptides, including those selective for micro, delta, and kappa opioid receptors, showed that only OGF had an effect. Treatment with antisense OGFr oligonucleotides increased the number of cells by over 2-fold compared to wild-type cultures of COS-7 cells and preparations receiving scrambled oligonucleotides. These results indicate that the OGF-OGFr axis is present and functions in COS-7 cells, and in the absence of classical opioid receptors.  相似文献   

17.
Delayed corneal reepithelialization is a complication of diabetes, and may lead to ulcers and erosions, which cause ocular morbidity and visual loss. This study examined the efficacy of naltrexone (NTX), a long-acting, potent opioid antagonist, applied topically, to facilitate the repair of standardized corneal abrasions in diabetic (alloxan-induced) New Zealand White rabbits (glucose levels > 450 mg/dL). NTX at a concentration of 10?4 M, or sterile vehicle (SV), was administered topically 4 times per day for 7 days to the abraded eye of uncontrolled Type 1 diabetic (DB), insulin-controlled Type 1 diabetic (DB-IN), or non-diabetic (Normal) rabbits. Wound healing was monitored, and non-invasive (tonopen, pachymeter, hand-held slit lamp, and retinal camera) and invasive (histopathology) measurements evaluated. Corneal reepithelialization in the uncontrolled DB rabbits was significantly enhanced (up to a 47% reduction in wound area) following treatment with NTX relative to both Normal SV and DB SV rabbits at 24, 48, and 56 h following surgery. At 72 h, DB NTX rabbits had residual defects that were 64–82% smaller than Normal and DB SV animals. NTX treated DB-IN rabbits had residual defects that were 9–37% smaller than DB-IN rabbits receiving SV, and 6–40% smaller than Normal rabbits. No signs of toxicity from topical applications were noted. These data confirm and extend those documented in rats that demonstrated a lack of toxicity of NTX at a wide range of dosages, as well as efficacy for enhanced corneal epithelialization. These studies set the stage for clinical trials using NTX as a therapy for diabetic keratopathy.  相似文献   

18.
Opioid receptors are expressed throughout the brain and play a major role in regulating striatal dopamine (DA) release. Clinical studies have shown that naloxone (NAL, a nonspecific opioid antagonist) in individuals with opioid use disorder and morphine (MRP, a nonspecific opioid agonist) in healthy controls, resulted in DA release in the dorsal and ventral striatum, respectively. It is not known whether the underlying patterns of striatal DA release are associated with the striatal distribution of opioid receptors. We leveraged previously published PET datasets (collected in independent cohorts) to study the brain‐wide distribution of opioid receptors and to compare striatal opioid receptor availability with striatal DA release patterns. We identified three major gray matter segments based on availability maps of DA and opioid receptors: striatum, and primary and secondary opioid segments with high and intermediate opioid receptor availability, respectively. Patterns of DA release induced by NAL and MRP were inversely associated and correlated with kappa (NAL: r(68) = −0.81, MRP: r(68) = 0.54), and mu (NAL: r(68) = −0.62, MRP: r(68) = 0.46) opioid receptor availability. Kappa opioid receptor availability accounted for a unique part of variance in NAL‐ and MRP‐DA release patterns (ΔR 2 >0.14, p <.0001). In sum, distributions of opioid receptors distinguished major cortical and subcortical regions. Patterns of NAL‐ and MRP‐induced DA release had inverse associations with striatal opioid receptor availability. Our approach provides a pattern‐based characterization of drug‐induced DA targets and is relevant for modeling the role of opioid receptors in modulating striatal DA release.  相似文献   

19.
Relapse-remitting multiple sclerosis (MS) is an immune-mediated disease of the central nervous system that affects more than 2.5 million individuals worldwide. While the etiology of MS is unclear, disease manifestation involves proliferation and activation of lymphocytes and astrocytes, leading to demyelination and neuronal damage. Current therapies are not completely effective, and few target the underlying pathophysiology of MS. The purpose of this study was to examine the therapeutic efficacy of a novel biological pathway, the opioid growth factor (OGF)–OGF receptor (OGFr) axis. OGF inhibits DNA synthesis and has been shown to repress proliferation of T lymphocytes, microglia, and astrocytes in other autoimmune disorders. An animal model for relapse-remitting experimental autoimmune encephalomyelitis (RR-EAE) was established by immunization of SJL/J mice with proteolipid protein. Treatment with OGF or saline was initiated simultaneously with immunization, and within 9 days, behavioral signs of RR-EAE were observed. OGF-treated RR-EAE animals had less severe clinical disease than mice receiving saline and exhibited 66% reductions in median cumulative disease scores, as well as prolonged periods of remission and diminished number and length of disease relapses. Neuropathological examination of lumbar spinal cord revealed reductions in the number of T lymphocytes, microglia/macrophages, and activated astrocytes, with cell proliferation being the mechanism targeted by OGF. Areas of demyelination and neuronal damage were markedly reduced during the 55-day observation period. These data are the first to demonstrate that OGF prevented relapses in RR-EAE and diminished underlying neuropathology, corroborating the potential of the OGF–OGF receptor pathway for treatment of MS.  相似文献   

20.
Recent studies of whole brain in rat pups have shown a marked decrease in DNA synthesis following intracisternal (i.c.) administration of beta-endorphin (BE). This investigation examines DNA synthesis in the cerebral cortex and cerebellum to determine whether the effect shows regional selectivity. Two- to twenty-day-old rats were given a single ic injection of BE, and DNA synthesis was assessed 1 h later. In the cerebral cortex, a region that undergoes major phases of cell multiplication in the immediate pre- and postnatal periods, BE significantly decreased DNA synthesis in 2-day-old rats, and a maximal inhibition was obtained by 4 days of age. In contrast, the cerebellum, a region that grows predominantly after birth, showed less sensitivity to BE during the early postnatal days, and a maximal effect was not attained until 10 days of age. While at 15 days of age the inhibition began to diminish in the cortex, a maximal effect was still seen in the cerebellum. Naloxone prevented the response in both brain regions, indicating the participation of opioid receptors. These results indicate that CNS BE is apparently able to alter DNA synthesis throughout the brain, with the greatest sensitivity occurring in those regions with highest mitotic rates at the time of exposure to BE.  相似文献   

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