Significance of opioid peptides and other potential markers of neuropeptide systems in cerebrospinal fluid.
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Animals↗
Biomedical subjects
L Terenius
Publications and source records attributed to L Terenius.
Coexistence and gene expression of phenylethanolamine N-methyltransferase, tyrosine hydroxylase, and neuropeptide tyrosine in the rat and bovine adrenal gland: effects of reserpine.
Expression and regulation of the catecholamine-synthesizing enzymes phenylethanolamine N-methyltransferase (PNMTase; S-adenosyl-L-methionine:phenylethanolamine N-methyltransferase, EC 2.1.1.28) and tyrosine hydroxylase [TyrOHase; tyrosine 3-monooxygenase, L-tyrosine, tetrahydropteridine:oxygen oxidoreductase (3-hydroxylating), EC 1.14.16.2] and the coexisting neuropeptide tyrosine (NPY) were studied in rat and bovine adrenal medulla. By using both immunohistochemistry and in situ hybridization, PNMTase- and NPY-positive cells exhibited a close overlap in bovine medulla and were preferentially localized in the outer two-thirds of the medulla. Although TyrOHase and its mRNA were observed in virtually all medullary gland cells, TyrOHase mRNA levels were much higher in the PNMTase- and NPY-positive cells. After administration of the catecholamine-depleting drug reserpine to rats, a brief increase, followed by a dramatic decrease, in the level of PNMTase mRNA was observed in the adrenal medulla. In contrast, mRNA for both TyrOHase and NPY only exhibited an increase, whereby the TyrOHase mRNA peak preceded that of NPY mRNA. Different regulatory mechanisms may thus operate for these three compounds coexisting in the adrenal medulla.
Adrenal Glands↗
Cerebrospinal fluid concentrations of substance P and (met)enkephalin-Arg6-Phe7 during surgery and patient-controlled analgesia.
The possible role of two neuropeptides (substance P and (Met)enkephalin-Arg6-Phe7) in nociception were studied in 14 surgical patients. Lumbar cerebrospinal fluid (CSF) concentrations of the putative excitatory afferent transmitter substance P and the mu and delta receptor agonist (Met)enkephalin-Arg6-Phe7 were measured during general anesthesia for abdominal surgery and during the postoperative period when patient-controlled analgesia (PCA) was used for control of pain. The CSF was sampled through an intrathecal catheter. Seven of the patients were randomly assigned to receive neurolept anesthesia; the rest were given isoflurane anesthesia without narcotics. No statistically significant changes occurred in substance P concentrations in CSF during surgery or postoperative PCA, nor were there significant differences between the two groups. There was, however, a significant correlation between CSF substance P concentrations before the start of PCA and pain assessment on a visual analogue scale. The individual changes in substance P concentrations during PCA was also inversely correlated to the consumption of meperidine. The CSF (Met)enkephalin-Arg6-Phe7 concentrations were below the level of detection in seven of the patients before anesthesia. A large interindividual variability in both substance P and (Met)enkephalin-Arg6-Phe7 concentrations was evident. The absence of major changes in CSF neuropeptide concentrations was unexpected. Apparently inter-individual variations in neuropeptide output are considerable.
Adult↗
Neurobiochemical changes in tardive dyskinesia.
There is evidence for the view that both up- and downregulation of nigral GABA may give rise to dyskinetic movements. Intranigral infusion of GABA agonists causes stereotyped licking and gnawing in rats, while intranigral GABA antagonists produce vacuous chewing movements. It is hypothesized that during long-term neuroleptic treatment there may be a succession of changes within striatonigral GABA neurons: down-regulation caused by neuroleptic drugs may increase receptor sensitivity, and this may lead to overcompensation and withdrawal dyskinesia during periods of cessation of drug treatment. Reduced nigral GAD activity may be a marker of irreversible brain damage and has not been observed in all chronic experiments, but only in individuals with long-standing or irreversible dyskinesia. Changes within the GABA system seem to be accompanied by changes in the striatal and nigral levels of substance P.
Animals↗
Cerebrospinal fluid levels of beta-endorphin in patients with fibromyalgia (fibrositis syndrome).
Cerebrospinal fluid (CSF) samples from 18 female patients with fibromyalgia (fibrositis syndrome) were analyzed for beta-endorphin. The mean CSF level of beta-endorphin was 20.7 +/- 0.7 fmol/ml in the patients compared to 20.5 +/- 2.0 fmol/ml (mean +/- SEM) in healthy controls (p greater than 0.05). Thus, patients with fibromyalgia (fibrositis syndrome) seem to have normal CSF levels of the pain modulatory neuropeptide beta-endorphin.
Adult↗
Cerebrospinal fluid activity of dynorphin-converting enzyme at term pregnancy.
Cerebrospinal fluid activity of a dynorphin-converting enzyme transforming prodynorphin-derived peptides to [Leu]enkephalin-Arg6 was measured in 12 women at term pregnancy before cesarean section and in eight nonpregnant, nonpuerperal controls. In pregnant women, the dynorphin-converting enzyme activity was significantly lower (mean +/- SD 6.8 +/- 3.8 U/L) than in nonpregnant controls (11.7 +/- 2.6 U/L; P less than .01). Furthermore, prodynorphin-derived [Leu]enkephalin-Arg6-containing polypeptides were significantly increased in samples from pregnant women (P less than .05). This indicates that a reduced activity of opioid peptide-degrading enzymes might contribute to an increased resistance to pain at term pregnancy.
Cesarean Section↗
Beta-adrenoceptor, vasoactive intestinal polypeptide (VIP) and neuropeptide tyrosine (NPY) receptors functionally coupled to adenylate cyclase in the human neuroblastoma SK-N-MC cell line.
Neurotransmitter receptor coupling to adenylate cyclase (AC) was studied in the cultured human neuroblastoma SK-N-MC cell line. Activation of beta-adrenoceptors with isoprenaline (ISO) or vasoactive intestinal polypeptide (VIP) receptors, increased AC activity in a dose-dependent manner. Preincubation with ISO and VIP induced a ligand specific, i.e. homologous type of desensitization of the respective receptor. Neuropeptide tyrosine (NPY) was able to inhibit ISO as well as VIP induced AC activity. The effect of NPY was totally abolished in cells pretreated with pertussis toxin to inactivate inhibitory G-proteins. Thus, SK-N-MC cells possess functionally coupled beta-adrenoceptors, VIP and NPY receptors, and may be used to study interactions between ligands and receptors which couple to the AC system.
Adenylyl Cyclases↗
Neurons of the ventral medulla oblongata that contain both somatostatin and enkephalin immunoreactivities project to nucleus tractus solitarii and spinal cord.
The ventral aspect of the medulla oblongata of colchicine-treated rats was examined immunohistochemically using mouse monoclonal antibodies raised against somatostatin (SOM) and rabbit polyclonal antibodies to methionine enkephalin (ENK). Numerous perikarya showed positive immunostaining for both antisera. For the most part, the double-labelled cells were located (1) along the ventrolateral surface in a region that corresponds to nucleus paragigantocellularis, (2) in the region of nucleus gigantocellularis-nucleus raphe magnus and (3) in a discrete area just above the inferior olivary nucleus. In an attempt to determine the projection sites of the SOM/ENK somata, the retrogradely transported fluorescent dye Fluoro-Gold was injected into either the nucleus tractus solitarii (NTS) or the upper part of the thoracic spinal cord. SOM/ENK cells in all 3 regions were labelled by dye administered into the spinal cord whereas only those SOM/ENK cells located in nucleus paragigantocellularis were stained by dye microinjected into NTS. This is the first evidence of a SOM/ENK projection from the ventral medulla to either the spinal cord or NTS.
Animals↗
Characterization of a substance P-Gly12 amidating enzyme in human cerebrospinal fluid.
Enzyme activity capable of converting the glycine-extended substance P precursor, substance P-Gly12, into substance P was purified from human cerebrospinal fluid. The conversion reaction was monitored by radioimmunoassay measurement of substance P formation. The chemical identity of the product was verified by reversed-phase HPLC. The enzyme reaction was stimulated by Cu(II) ion and ascorbic acid and inhibited by the presence of diethyldithiocarbamate. By HPLC molecular sieving, the major enzyme activity appeared as a protein of 26,000 molecular weight.
Chromatography, High Pressure Liquid↗
Opioid peptides in man--analytical aspects.
The opioid peptides present extraordinary problems for analysis, since they are structurally homologous yet substantially different. Within each of the three systems, proopiomelanocortin, proenkephalin and prodynorphin, a whole set of peptides of successively smaller sizes are generated. The biological relevance of the different peptides is not fully understood. Analytical strategies may either be specifically directed to individual peptide species or to identification of total system output.
Endorphins↗
Neuropeptide Y-immunoreactive perikarya and nerve terminals in the rat medulla oblongata: relationship to cytoarchitecture and catecholaminergic cell groups.
The aim of this study was to examine details of the distribution of neuropeptide Y (NPY)-immunoreactive perikarya and nerve terminals in the medulla oblongata in relation to cytoarchitectonically and functionally distinct catecholaminergic regions. The immunoperoxidase method was combined with Nissl staining to determine nuclear boundaries of transmitter-identified nerve cell bodies and to examine the relationship between populations of NPY-immunoreactive neurons and catecholaminergic cell groups (A1, A2, C1, C2, and C3) in serial sections. Previous studies using immunofluorescence have described the existence of NPY catecholaminergic immunoreactive nerve cell bodies in the brainstem. No information is currently available with regard to details of the distribution of these peptidergic neurons and nerve terminals in the functional subnuclear units of the medulla oblongata. In this study we have delineated the anatomical association of NPY immunoreactivity with cardiovascular function. Neuropeptide Y-immunoreactive neurons were found located in close association with noradrenergic neurons of the A1 cell group in the caudal ventrolateral medulla oblongata, where they were usually found located dorsal to the lateral reticular nucleus (LRt). A second population of NPY-immunoreactive neurons was found located medial to the A1 cell group in the ventral subdivision of the reticular nucleus of the medulla (MdV). Neuropeptide Y-immunoreactive neurons in the rostral medulla were found located in regions corresponding to the principal distribution of adrenergic neurons in the C1, C2, and C3 cell groups. In the dorsomedial medulla (A2 region) NPY-immunoreactive neurons were localized in the area postrema (ap) and in a number of subnuclei of the nucleus of the tractus solitarius (nTS), i.e., the dorsal parasolitary region (dPSR), the dorsal strip (ds), the periventricular region (PVR), and the ventral parasolitary region (vPSR). The location of NPY-immunoreactive perikarya and nerve terminals in the dorsal subnuclei of the nTS, i.e., the dPSR and ds, is of particular significance, since this distribution corresponds with the location of small adrenergic neurons as well as with the site of termination of aortic and carotid sinus nerve afferent fibers. NPY-immunoreactive neurons in the dorsomedial medulla are ideally situated for receiving monosynaptic input from baroreceptor afferents and could play a key role in the central integration of cardiovascular reflexes.
Adrenergic Fibers↗
Neuropeptide Y inhibits cardiac adenylate cyclase through a pertussis toxin-sensitive G protein.
Neuropeptide Y, a major neuropeptide and potent vasoconstrictor, inhibited isoproterenol-stimulated adenylate cyclase activity in cultured rat atrial cells as well as in atrial membranes. Prior treatment of the cells with pertussis toxin blocked the inhibitory action of neuropeptide Y. Pertussis toxin is known to uncouple the receptors for other inhibitors of adenylate cyclase by ADP-ribosylation of the alpha-subunit of Gi, the inhibitory guanine nucleotide binding component of adenylate cyclase. The toxin specifically catalyzed the ADP-ribosylation of a 41-kilodalton atrial membrane protein which corresponded to the Gi subunit. These results suggest that neuropeptide Y may mediate some of its physiological effects through specific receptors linked to the inhibitory pathway of adenylate cyclase.
Adenylate Cyclase Toxin↗
[Postpartum psychosis--new discoveries in an old disease].
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Female↗
Glutamic acid decarboxylase- and peptide-immunoreactive neurons in cortex cerebri following development in isolation: evidence of homotypic and disturbed patterns in intraocular grafts.
Fetal parietal cerebral cortex was transplanted to the anterior eye chamber of adult Sprague-Dawley rats. After two to three months the grafts, with or without colchicine treatment, were subjected to immunohistochemical analysis using antibodies against cholecystokinin (CCK), somatostatin (SOM), neuropeptide tyrosine (NPY), vasoactive intestinal polypeptide (VIP), peptide histidine isoleucine (PHI) and the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD). Cerebral cortex in situ of untreated and colchicine-treated rats was always analyzed in parallel. A dense plexus of CCK-immunoreactive fibers was distributed in all parts of the transplants, and after colchicine treatment a large number of CCK-positive cells was observed. These cells were markedly increased in number as compared to normal cortical tissue in colchicine-pretreated rats. The amount of NPY-immunoreactive cells was also markedly increased, whereas somatostatin-positive cells were found in numbers similar to those seen in cortex in situ. In the grafts only a few VIP- and PHI-positive fibers were seen with a few VIP-positive cell bodies, but no clearly discernible PHI-positive cells. A very dense plexus of GAD-positive fibers with an even distribution throughout the grafts was observed. Cortex in situ exhibited a lower density of GAD-immunoreactive fibers. Even after colchicine treatment the number of GAD-positive cells in the grafts was low. Using double-staining techniques, it was found that most of the few GAD-positive cells in the grafts were also NPY-positive, SOM-positive or, to a minor extent, CCK-positive. The present results demonstrate that several peptides and transmitter markers are expressed in cortical grafts in oculo, but marked differences in their expression can be observed in cortical tissue that has developed in isolation. Thus, the intraocular cortex graft, alone and in combination with other brain areas, should provide a useful model in which to study factors that regulate brain development.
Animals↗
Somatostatin- and enkephalin-like immunoreactivities are frequently colocalized in neurons in the caudal brain stem of rat.
The medulla oblongata and pons of colchicine treated rats were analyzed with a double-staining technique using mouse monoclonal antibodies to somatostatin and rabbit polyclonal antibodies raised against methionine-enkephalin. Numerous cells reacted with both antisera but cells reacting with only one antiserum were also observed. Double-stained cells were most frequently encountered at all levels of the nucleus tractus solitarii, in a well defined group in the caudal medullary reticular formation, along the lateral ventral surface of the medulla oblongata, dorsolateral to the inferior olive and in the nucleus raphe magnus. These findings provide further examples of coexistence of two peptides and indicate the possibility that somatostatin- and enkephalin-like peptides are co-released.
Animals↗
Analysis of peptide histidine-isoleucine/vasoactive intestinal polypeptide-immunoreactive neurons in the central nervous system with special reference to their relation to corticotropin releasing factor- and enkephalin-like immunoreactivities in the paraventricular hypothalamic nucleus.
The distribution of peptide histidine-isoleucine (PHI) and vasoactive intestinal polypeptide (VIP), two peptides derived from the same precursor molecule, was analysed with immunohistochemistry in the central nervous system of the rat, and to a limited extent in some other species including sheep, monkey and man. Special attention was focused on possible cross-reactivity between PHI antisera and corticotropin releasing factor in parvocellular neurons in the hypothalamic paraventricular nucleus projecting to the external layer of the median eminence. (1) Characterization of the PHI and VIP antisera revealed that they recognized different sequences of the peptide molecules. One of the PHI antisera (PHI-N), although mainly N-terminally directed, also probably contained an antibody population directed against the C-terminal amino acid in PHI which is an amidated isoleucine. Rat and human corticotropin releasing factor but not ovine also have an amidated isoleucine in C-terminal position. (2) PHI- and VIP-like immunoreactivity were found with parallel and overlapping distribution in all areas investigated in the rat central nervous system. In many cases coexistence of the two immunoreactivities could be directly demonstrated. PHI neurons were found in some areas so far not know to contain PHI/VIP neurons, including the dorsal septum, the septofimbrial nucleus, the stria terminalis and lamina V of the spinal cord. (3) Using an antiserum directed against the amino acid sequence 111-122 of the VIP/PHI precursor, immunoreactive cell bodies were seen in some areas containing VIP and PHI neurons. PHI- and VIP-like immunoreactivity were expressed in parallel in increasing amounts in the superficial laminae of the dorsal horn after transection of the sciatic nerve [G. P. McGregor et al. (1984) Neuroscience 13, 207-216; S. A. S. Shehab and M. E. Atkinson (1984) J. Anat. 139, 725; S. A. S. Shehab and M. E. Atkinson (1986) Expl Brain Res. 62, 422-430]. (5) The PHI-N antiserum stains large numbers of immunoreactive cells in the parvocellular part of the paraventricular nucleus and these cells are mostly identical with corticotropin releasing factor-positive neurons. Absorption experiments suggested that this PHI-N-like immunoreactivity to a large extent represented cross-reactivity with rat CRF and that earlier demonstration of many PHI-positive neurons in the paraventricular nucleus probably represents an artefact as proposed by F. Berkenbosch et al. (Neuroendocrinology 44, 338-346). However, some cells did, in fact, contain VIP- as well as PHI-like immunoreactivity as was shown with antisera not cross-reacting with corticotropin releasing factor.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
A naloxone-steroid hybrid azine with selective and long-acting opioid antagonism at delta receptors in vitro.
The interaction of naloxone estrone azine (N-EH) with various opioid receptor types was studied in vitro. Its potency as an antagonist of opioid effects was compared to that of naloxone on the electrically evoked contractions of mouse vas deferens (Mvd) and guinea pig ileum myenteric plexus longitudinal muscle (Gpi) preparations. N-EH was found to be 9-fold more potent than naloxone in antagonizing the effects of D-Ala2-Leu5-enkephalin in the Mvd and 22-fold less potent in antagonizing normorphine in the Gpi. In the Mvd, the recovery half-time for N-EH was longer than 1000 min. Neither compound showed agonism. The two compounds were also compared for their capacity to displace the binding of 3H-D-Ala2-Leu5-enkephalin, 3H-dihydromorphine, and 3H-ethylketocyclazocine to rat brain membranes under conditions where delta, mu, and kappa sites were labeled. The relative affinities were 0.70, 0.16, and 0.14 for N-EH and 0.05, 0.87, and 0.08 for naloxone, respectively. Thus, compared to naloxone, which is mu selective, N-EH is a delta-selective antagonist.
Animals↗
Endorphin activity in cerebrospinal fluid prior to elective cesarean section and in early puerperium.
Opioid activity in cerebrospinal fluid (CSF) was estimated by radioreceptor-assay (RRA) in samples obtained from ten women at term pregnancy and in the early puerperal period. The samples were fractioned on Sephadex G-10 columns and two opioid receptor active fractions, FI and FII, were recovered. Two pools of FII materials from pregnant and puerperal women, respectively, were further analyzed by electrophoresis and the concentrations of opioid activity were measured by radioreceptor assay. There was a significant rise in receptor-assayed FII opioid activity in late pregnancy as well as in the early puerperal period compared to that of healthy, nonpregnant, nonpuerperal females. Pooled FII material obtained before delivery could be separated into two major components tentatively assigned the hexapeptide [Met]enkephalin-Lys6 and the heptapeptide [Met]enkephalin-Arg6-Phe7. These two opioid peptides both have their origin in the [Met]enkephalin precursor, proenkephalin A. In the puerperal period there was predominance of only one of these components.
Adult↗