Transumbilical venous access with small diameter silastic catheters in very low birth weight infants.
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Catheterization, Central Venous↗
Biomedical subjects
B Scharrer
Publications and source records attributed to B Scharrer.
The presence and effects of mammalian signal molecules in immunocytes of the insect Leucophaea maderae.
Opioid peptides activate immunocytes and opiate alkaloids inhibit this activation in the mussel, Mytilus edulis. Here we present evidence that cells of another invertebrate, Leucophaea maderae, can be influenced in a similar way by the Met-enkephalin analogue D-Ala2-Met5-enkephalin (DAMA) and morphine. Effects of different signal molecules on Leucophaea hemocytes were evaluated by computer-assisted image analysis of their conformational state. A small percentage of the untreated cells were found to display spontaneous conformational changes after 25 min of incubation without pharmacological agents which was noted as a decrease in both circularity factor and shape factor values. Activation caused the cells to become elliptical, a feature that appears to be characteristic of Leucophaea immunocytes. Administration of DAMA induced a similar activation of most of the cells. After 30 min these DAMA-activated cells started to display distinct locomotory activity not seen in the controls. alpha-Melanocyte-stimulating hormone (MSH, 10(-7)) added to the incubation medium after DAMA-activation caused the cells to return to their original "rounded" conformation. In addition, the presence of immunoreactive interleukin (IL-1), adrenocorticotropin (ACTH) and tumor necrosis factor (TNF) in the hemolymph was demonstrated. These data suggest an interaction between both vertebrate-type immunological signal molecules and neuropeptides in the regulation of immunological cells in Leucophaea.
Adrenocorticotropic Hormone↗
The presence of the mu3 opiate receptor in invertebrate neural tissues.
A previous report demonstrated the presence of the newly discovered opiate alkaloid selective and opioid peptide insensitive mu3 receptor in ganglia of several invertebrate- and one vertebrate species as well as in microglial cells that had egressed from these ganglia after their maintenance in culture medium for several days. In the present study carried out in two representatives of invertebrates, the binding densities of this receptor determined in intact ganglia were compared with those in ganglia depleted of microglial cells. The aim was to ascertain whether the differences in binding capacity recorded in those two groups of ganglia might give an indication of the possible presence of this opiate receptor in nonmicroglial components of the nervous tissue, i.e., neurons. Within a period of 72 h of incubation, the gradual reduction in binding density had reached a plateau, in accordance with the termination of the egress of microglia. The fact that at least two thirds of the binding capacity of mu3 receptors were retained by the ganglia strongly suggests that part of this capacity may be attributed to neurons. This view is supported by additional data, in particular the demonstration of endogenous morphine in nervous tissue and its localization within distinct neurons.
Animals↗
A novel view of opiate tolerance.
Opiate substances occur as natural compounds in various invertebrate and vertebrate neural tissues. Recently we have discovered a novel opiate alkaloid-selective and opioid peptide-insensitive receptor, designated mu 3, that provides further evidence of the existence of separate morphine processes. Interestingly morphine biosynthesis appears to be linked to the dopamine pathway. Based on studies documenting the presence of morphine after stress, e.g., trauma, it is noted that this signal substance emerges after a timely delay. From this we speculate that this molecule can serve a specific effect to downregulate physiological processes after stress. We conclude that tolerance represents a natural process that terminates its action. In this regard a morphine hypothesis may be essential to a complete picture of motive circuitry. A speculative view of the psychiatric implications in schizophrenia, depression, and autism are presented with this in mind.
Alkaloids↗
Opioid and opiate immunoregulatory processes.
The discovery of the ability of the nervous system to communicate through "public" circuits with other systems of the body is attributed to Ernst and Berta Scharrer, who described the neurosecretory process in 1928. Indeed, the immune system has been identified as another important neuroendocrine target tissue. Opioid peptides are involved in this communication (i.e., neuroimmune) and with that of autoimmunoregulation (communication between immunocytes). The significance of opioid neuropeptide involvement with the immune system is ascertained from the presence of novel delta, mu, and kappa receptors on inflammatory cells that result in modulation of cellular activity after activation, as well as the presence of specific enzymatic degradation and regulation processes. In contrast to the relatively uniform antinociceptive action of opiate and opioid signal molecules in neural tissues, the presence of naturally occurring morphine in plasma and a novel mu3, opiate-specific receptor on inflammatory cells adds to the growing knowledge that opioid and opiate signal molecules may have antagonistic actions in select tissues. In examining various disorders (e.g., human immunodeficiency virus, substance abuse, parasitism, and the diffuse inflammatory response associated with surgery) evidence has also been found for the involvement of opiate/opioid signaling in prominent mechanisms. In addition, the presence of similar mechanisms in man and organisms 500 million years divergent in evolution bespeaks the importance of this family of signal molecules. The present review provides an overview of recent advances in the field of opiate and opioid immunoregulatory processes and speculates as to their significance in diverse biological systems.
Animals↗
Effect of prolonged exposure to morphine on responsiveness of human and invertebrate immunocytes to stimulatory molecules.
This study deals with a novel role of morphine in the modulation of cellular responsiveness to immunostimulatory substances that, at first glance, appears to be in contrast to the well documented immunoinhibitory short-term effects of opiate alkaloids on cells simultaneously exposed to stimulatory molecules. Vertebrate and invertebrate immunocytes pre-exposed to morphine (10(-6) M) in vitro for at least 24 h prior to the administration of lipopolysaccharide (LPS; 1.0 micrograms/ml) or other immunoactivating substances have revealed a distinct enhancement of their responsiveness to these signals, e.g. monocytes exposed to LPS alone resulted in 21% activation, whereas the morphine pretreated level was at 40% (P < 0.01). Prolonged pretreatment with morphine of naive human monocytes had the same effect on their sensitivity to plasma from patients having undergone cardiopulmonary bypass (CPB) operations followed by a diffuse inflammatory response. These results suggest that endogenous opiates may participate, in more than one way, in re-establishing an organism's readiness to meet a new demand on its immune system. Additional support for the concept of a role of endogenous opiates in immunomodulation was obtained by the results of in vivo tests with experimentally induced stress in Mytilus. Following their stress-induced stimulation, these animals' immunocytes could be shown to become exposed for some time to a measurable rise in endogenous morphine-like material (9 pmol/ml increasing to 59). These immunocytes, like those preincubated with exogenous morphine, displayed a heightened sensitivity to stimulation by LPS (control 21.3 +/- 3.1% activation compared to 47.2 +/- 5.1) when the morphine levels dropped. The mechanism of this enhancement of responsiveness to immunostimulation following the prolonged exposure of immunocytes to morphine, and its relationship with the known short-term immunoinhibitory opiate effects on the immune system, remains to be ascertained.
Animals↗
Microglia in invertebrate ganglia.
The results of this study lend strong support to the concept of the existence in insects and molluscs of a distinctive class of neuroglial cells comparable to vertebrate microglia. The evidence presented is as valid as that used in reference to the separate status of vertebrate microglia--i.e., the demonstration of a close structural and functional relationship of these cells with cells of the immune system. As in vertebrates, the excision of ganglia from three invertebrate species (the molluscs Planorbarius corneus and Mytilus edulis and the insect Leucophaea maderae) and their maintenance in incubation media led to an exodus of small cells and their accumulation in the culture dish. During this process, they underwent conformational changes from stellate to rounded, and then to more or less ameboid, comparable to those indicative of the process of activation in the animals' immunocytes. Functional characteristics which these translocated microglia-like cells share with immunocytes are motility, phagocytotic activity, and adherence to the culture dish. Furthermore, the two cells have certain biochemical features in common--e.g., the presence of certain cytokines and (at least in Planorbarius) that of corticotropin. An additional phenomenon of particular interest for the classification of microglial elements is their response to morphine. At 10(-6) M, this drug decreases not only the number of cells emerging from the excised ganglia but also the degree of their transformation to the "active" ameboid form. This dose-dependent and naloxone-sensitive effect of morphine on microglial cells parallels that on activated immunocytes of the same species. Corresponding results demonstrating an inhibitory effect of morphine on mobilized microglial cells of the frog Rana pipiens indicate that this relationship between the two cell types under consideration also exists in vertebrates. Binding and displacement experiments with membrane homogenates of microglial cells as well as immunocytes of Mytilus have shown that the effects of morphine on both cell types are mediated by the same special opiate receptor (mu 3).
Animals↗
Endogenous morphine and related opiates, a new class of chemical messengers.
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Animals↗
Opiate-like substances in an invertebrate, an opiate receptor on invertebrate and human immunocytes, and a role in immunosuppression.
The presence of morphine-like and codeine-like substances was demonstrated in the pedal ganglia, hemolymph, and mantle tissues of the mollusc Mytilus edulis. The pharmacological activities of the endogenous morphine-like material resemble those of authentic morphine. Both substances were found to counteract, in a dose-dependent manner, the stimulatory effect of tumor necrosis factor alpha or interleukin 1 alpha on human monocytes and Mytilus immunocytes, when added simultaneously to the incubation medium. The immunosuppressive effect of this opiate material expresses itself in a lowering of chemotactic activity, cellular velocity, and adherence. Codeine mimics the activity of authentic morphine, but only at much higher concentrations. Specific high-affinity receptor sites (mu 3) for morphine have been identified on human monocytes and Mytilus immunocytes. In Mytilus recovering from experimentally induced stress, the return of "altered" immunocytes to a more inactive state appears to be due to a significant rise in the content of morphine-like material in the pedal ganglia and hemolymph at this time. Thus, morphine may have a role in calming or terminating the state of immune alertness.
Animals↗
Water turnover of healthy children measured by deuterated water elimination.
For healthy children up to 15 years of age, no data exist regarding water turnover as directly measured using stable isotope techniques. Water turnover was measured in 171 healthy children (88 girls, 83 boys, age: 6 weeks-15 years) whilst living in their normal environment. Water turnover was calculated from the equilibrium of 2H2O concentration reached in the urine 2-3 h after an oral test load of 2 ml 2H2O/kg and the subsequent elimination rate of 2H2O. Daily water turnover decreased from 160 ml/kg (3 months), 100 ml/kg (12 months), 65 ml/kg (3 years) to 40 ml/kg at 15 years of age. Fluid intake was then calculated by subtracting the estimated metabolic water production from water turnover and this data was compared with recommended values. Our calculation of spontaneous daily fluid intake for these healthy children is within the recommended range during the 1st year of life, whereas for older children the recommendations exceed the spontaneous intake by a factor of 1.2-2.
Adolescent↗
[D-Ala2]deltorphin I binding and pharmacological evidence for a special subtype of delta opioid receptor on human and invertebrate immune cells.
The effects of the opioid neuropeptide [D-Ala2]deltorphin I, isolated from amphibian skin, on immunoregulatory activities were studied in representatives of vertebrates and invertebrates. The high potency of this compound parallels that of [Met]enkephalin, which was previously demonstrated in vertebrate plasma and invertebrate hemolymph. The addition of [D-Ala2]deltorphin I at 10(-11) M to human granulocytes or immunocytes of the mollusc Mytilus edulis resulted in cellular adherence and conformational changes indicative of cellular activation. This value is in line with the concentrations obtained with [Met]enkephalin, tested in the presence of the specific neutral endopeptidase 24.11 inhibitor phosphoramidon, and this opioid's synthetic analog [D-Ala2, Met5]enkephalin which, like [D-Ala2]deltorphin I, is resistant to proteolytic degradation. Both ligands appear to be acting on the same population of immunocytes. The same relationship was estimated to exist in the insect Leucophaea maderae, in which the high viscosity of the hemolymph makes the quantification of reactive cells more difficult than in Mytilus. In addition, [D-Ala2]deltorphin I is as potent as beta-endorphin in affecting the proliferation of lymphocytes in response to mitogen. Saturation experiments with unlabeled ligands and the radioligands [3H][D-Ala2]deltorphin I and [3H][D-Ala2,Met5]enkephalinamide revealed the presence of two high-affinity binding sites on human granulocytes, one sensitive to the nonequilibrium delta opioid antagonist [D-Ala2,Leu5,Cys6]enkephalinamide and the other relatively insensitive. The results obtained with [D-Ala2]deltorphin I support the view that the special role played by endogenous [Met]enkephalin in immunobiological activities of vertebrates and invertebrates is mediated by a special subtype of delta opioid receptor.
Animals↗
A possible immunoregulatory function for [Met]-enkephalin-Arg6-Phe7 involving human and invertebrate granulocytes.
Opioid peptides and their analogs have been shown to stimulate adherence, conformational changes and locomotory activity in human as well as invertebrate granulocytes. The present study demonstrates that [Met]-enkephalin-Arg6-Phe7, an opioid substance thus far not included in these immunological tests, exhibits stimulatory effects comparable to those of [Met]-enkephalin in this regard. Furthermore, since neutral endopeptidase 24.11 (enkephalinase; CD10/NEP) exists in invertebrate immunocyte membranes, we demonstrate that its specific inhibitor, phosphoramidon, potentiates the effects of the heptapeptide in inducing conformational change in both human and invertebrate granulocytes. Additionally, the major metabolic products of NEP activity, Phe-Met-Arg-Phe and Tyr-Gly-Gly, appear to be potent antagonists of this enzyme activity, especially the tetrapeptide. The effects of heptapeptide stimulation showed a major difference between vertebrate and invertebrate immunocytes with respect to their time course, namely, the speed of their onset. [Met]-enkephalin-Arg6-Phe7 markedly stimulated the locomotory activity of these cells which becomes most noticeable within 15-45 min for Mytilus cells and in a 5-15 min period for human cells. It also enhanced the mobility and velocity of the responsive human (5 microns/min) and invertebrate cells (2.1 microns/min).
Animals↗
Downregulation of enkephalin-mediated inflammatory responses by CD10/neutral endopeptidase 24.11.
The antigen CD10 (common acute lymphoblastic leukaemia antigen), which is the zinc metalloprotease, neutral endopeptidase 24.11 (also known as NEP or 'enkephalinase'), is expressed by acute lymphoblastic leukaemias, normal lymphoid progenitors, mature polymorphonuclear leukocytes and certain nonhaematopoietic cells. CD10/NEP hydrolyses several naturally occurring peptides, including the endogenous opioid pentapeptides Met- and Leu-enkephalin. In invertebrate organisms such as the mollusc Mytilus edulis, Met-enkephalin triggers inflammatory responses by inducing morphological changes, directed migration and aggregation of haemocytes. We report here that a structure related to CD10/NEP is expressed by M. edulis haemocytes and that abrogation of CD10/NEP enzymatic activity reduces the amount of Met-enkephalin required for haemocyte activation by five orders of magnitude. Similar results are obtained with CD10+ human polymorphonuclear leukocytes, indicating that CD10/NEP related structures regulate enkephalin-mediated inflammatory responses in organisms whose ancestors diverged approximately 500 million years ago.
Animals↗
Immunocytochemical localization and immunochemical characterization of an insulin-related peptide in the insect Leucophaea maderae.
Immunocytochemical tests with eight monoclonal antibodies against either bovine or human insulin and seven polyclonal antibodies against bovine insulin were carried out to determine the presence of insulin-like neuropeptides in the brain and affiliated neuroendocrine structures of the insect Leucophaea maderae. Reaction products identified in the brain, subesophageal ganglion, and corpus cardiacum-corpus allatum complex indicate the presence of materials resembling mammalian insulins in its antigenic properties. The immunostaining observed with monoclonal antibodies appears to indicate the occurrence of an insulin-related peptide that shows sequential similarities with parts of both the A- and B-chains of mammalian insulin molecules. These suppositions are supported by the results of dot-blot and two-site time-resolved immunofluorometric assay (TRI-IFMA) screenings of fractions of Leucophaea tissue extracts obtained by chromatography. The polyclonal antibodies yielded reaction products in some of the same areas and in additional parts of the neuroendocrine system not visualized by the monoclonal antibodies. Immunoreaction was observed in the following areas: the pars intercerebralis of the protocerebrum, the nervi corporis cardiaci I transporting insulin-like material to the corpus cardiacum, the dorsolateral protocerebral area and the optic lobes, the deutocerebrum, the tritocerebrum, and the subesophageal ganglion. In addition, smaller cell bodies with immunoreactive deposits occur at the border between proto- and deuto-cerebrum, and in the central area of the protocerebrum. The distribution of reactive material in the corpus cardiacum-corpus allatum complex after use of both groups of antibodies was the same.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
A neuroimmunoregulatory-like mechanism responding to stress in the marine bivalve Mytilus edulis.
Mytilus edulis has been the subject of recent studies to determine whether the relationship between the immune and nervous systems seen in vertebrates also exists in invertebrates. In the present study the effects of experimentally induced "stressful" stimuli on immunoactive hemocytes were studied in this mollusc. This subpopulation of invertebrate blood cells, resembling vertebrate granulocytes, has been previously shown to produce and react to opioid peptides. Their activation, like that of vertebrate immunocytes, expresses itself in distinctive conformational changes preceding cellular mobilization. The cellular response to "stress" observed is the same as that to the administration of exogenous mammalian opioid peptides. This strongly suggests that under the conditions of stressful stimuli, the immune/defense system can be altered by endogenous neuropeptides. The involvement of opioids in neuroimmunoregulatory phenomena appears to have a long evolutionary history.
Animals↗
Interaction of immunoactive monokines (interleukin 1 and tumor necrosis factor) in the bivalve mollusc Mytilus edulis.
Mytilus edulis has been the subject of recent studies to determine whether the relationship between the immune and neuroendocrine systems seen in vertebrates also exists in invertebrates. The effects of mammalian monokines were studied in Mytilus immunocytes previously shown to produce and react to opioid peptides. These invertebrate cells respond to interleukin 1 (IL-1) and tumor necrosis factor (TNF), both in vitro and in vivo, in a manner similar to that of human granulocytes. As in the mammalian monokine network, the effect of IL-1 on the immunocytes is brought about, at least in part, by its stimulatory effect on the formation of TNF. In addition, the presence of immunoreactive IL-1 and TNF in Mytilus hemolymph was demonstrated.
Animals↗
Stimulatory effects of opioid neuropeptides on locomotory activity and conformational changes in invertebrate and human immunocytes: evidence for a subtype of delta receptor.
The presence of opioid neuropeptides was shown to stimulate conformational changes and locomotory activity in immunocytes of two representatives of invertebrates as well as in human leukocytes. Cells were examined by use of phase-contrast and Nomarski optics coupled with a Zeiss Axiophot microscope, and of the Zeiss Videoplan/Vidas Image Analysis system. Immunocompetent blood cells, activated by exogenous opioids or stressful stimuli presumed to engage endogenous opioids, showed flattening, elongation, and formation of pseudopodia. In the mollusc Mytilus edulis, ameboid movements resulted in the formation of cell clusters, an activity not observed in untreated controls, or in immunocytes simultaneously exposed to opioid and naloxone. Tests with nine immunoreactive substances revealed immunocyte stimulation by delta, mu-, kappa-, and epsilon(?)-selective ligands. One of these, [D-Ala2,D-Met5]enkephalinamide (DAMA), active at a concentration of 10 pM, proved to be considerably more effective than the rest. The high pharmacological potency of DAMA, observed in both human and invertebrate immunocytes, sets this opioid apart from the closely related [D-Ala2,D-Leu5]enkephalin, a discrepancy not occurring in the mammalian nervous system. This suggests a specific function for [Met]enkephalin in immunoregulation, mediated perhaps by a special subtype of delta receptor.
Animals↗
Evidence for the involvement of opioid neuropeptides in the adherence and migration of immunocompetent invertebrate hemocytes.
Evidence for the participation of opioid neuropeptides in immunoregulatory activities, especially cellular adherence and migration, has been obtained in representatives of two phyla of invertebrates, the mollusc Mytilus edulis and the insect Leucophaea maderae. The injection of a synthetic analog of [Met]enkephalin [( D-Ala2,Met5]enkephalinamide, DAMA; 10(-6) M) had a stimulatory, naloxone-reversible effect on the directed migration of immunocompetent hemocytes. Incubation of hemolymph in the presence of exogenous or endogenous opioid material significantly enhanced the adherence of hemocytes on albumin-coated slides as demonstrated by use of indirect Zeiss-Zonax reflectance computer analysis. Conversely, hemocyte adherence was markedly reduced by the addition of naloxone (10(-8) M) to the incubation medium, either alone or in combination with DAMA. The antagonistic effects of naloxone on the stimulatory activities of opioids indicate that, like those previously reported in mammals, they are receptor-mediated. The presence of an endogenous [Met]enkephalin-like material was demonstrated in cell-free hemolymph as well as sequestered hemocytes by use of high-pressure liquid chromatography and radioimmunoassay. These results demonstrate that the capacity of immunocytes to release and respond to opioid neuropeptide messengers is not restricted to mammalian organisms but was developed early in the course of evolution.
Animals↗