Biomedical subjects

F Nyberg

Publications and source records attributed to F Nyberg.

At least 163 records · Page 9Linked to original sources

PubMed1993

Concomitant increase in blood plasma levels of immunoreactive hemorphin-7 and beta-endorphin following long distance running.

Hemorphins are endogenous opioids derived by enzymatic degradation of hemoglobin, a protein released in blood plasma during long distance running. We examined levels of beta-endorphin and the heptapeptide hemorphin-7, in heparinized venous blood plasma from 15 sedentary controls (8 males, 7 females) and from 15 age- and sex-matched marathon runners at baseline and after running 42 km or 21 km. Baseline levels of beta-endorphin (range 0.2-4.3 fmol/ml) were neither dependent upon weight, body mass index weight/height, running status nor sex. Baseline levels of hemorphin-7 (range 0.2-6.9 pmol/ml) were lower in women (P < 0.04) and covariated positively with body weight (P = 0.06), explaining lower levels in runners by their lower body weight. Covariation with body mass index was positive, but not significant (P = 0.10), however, here the dependence upon sex appeared stronger (P = 0.014). Running induced significant and correlated increases in hemorphin-7 and beta-endorphin (r = 0.74; P < 0.002), possibly indicating a functional relationship between these two peptides.

Adult↗

PubMed1993

Age-related reduction of human growth hormone-binding sites in the human brain.

Previous studies have shown that alterations in various neuroendocrine functions occur with increasing age. We here report a study of growth hormone (GH)-binding sites in different areas of post-mortem human brains collected from individual males and females of different age. The results indicate that there exists a significant negative correlation between the density of GH-binding sites and increasing age. This phenomenon was observed in both sexes in brain areas such as choroid plexus, hippocampus, hypothalamus, pituitary and putamen but not in e.g. thalamus. In all tissues (except for choroid plexus), the GH binding was significantly higher in those originating from females than those from males. This discrepancy was found likely to be associated with the affinity of GH to lactogenic rather than to somatogenic sites as no pronounced sex difference in binding was observed in the presence of excessive amounts of human prolactin. Data also indicate that the putative GH receptors in the various brain regions differ with regard to binding constants and to the estimated molecular size of the hormone-binding units. The loss of GH receptors in brain of elderly people may have consequences in several physiological courses. The decrease in GH binding at hypothalamic and pituitary levels may be of importance for the mechanisms behind the release or secretion of the hormone.

Adult↗

PubMed1993

Cerebrospinal fluid dynorphin-converting enzyme activity is increased by voluntary exercise in the spontaneously hypertensive rat.

The activity in cerebrospinal fluid (CSF) of dynorphin-converting enzyme (DCE) has been studied after voluntary exercise in the spontaneously hypertensive (SH) rat. The exercise consisted of spontaneous running in wheels for 4-5 weeks and the average running distance during the last two weeks was 4.0 km/24h. CSF samples were obtained under anaesthesia from the cisterna magna after penetration of the atlanto-occipital membrane. DCE transforms the members of the dynorphin family of opioid peptides into Leu-enkephalin-Arg6. In the present investigation a radioimmunoassay was used for quantitation of Leu-enkephalin-Arg6 release from dynorphin A1-17 and dynorphin B1-13. The rats that were running had a DCE activity (vs. both substrates) in CSF that was approximately 6-12 times higher than in animals not given the running opportunity. A statistically significant correlation between the two prodynorphin-derived substrate peptides was found in terms of DCE activity. We therefore propose that a single enzyme activity may be responsible for the hydrolysis of dynorphin B1-13 and dynorphin A1-17. Furthermore, a significant correlation was also found between running activity and DCE activity 12-14 h before the CSF was withdrawn. Besides measurement of DCE activity by radioimmunoassay, the formation of Leu-enkephalin-Arg6 was identified by reversed-phase micro-column liquid chromatography and plasma desorption mass spectrometry. The experiment shows that voluntary exercise affects opioid peptidergic mechanisms.

Amino Acid Sequence↗

PubMed1993

Chronic administration of morphine decreases level of dynorphin A in the rat nucleus accumbens.

The effect of chronically administered morphine on the levels of dynorphin A in distinct regions of the brain (including medial frontal cortex, olfactory tubercule, nucleus accumbens, dorsal and medial striatum), was determined in male Sprague-Dawley rats. The drug was delivered through a subcutaneously implanted Azlet miniosmotic pump over a period of 5 days. The concentration of peptide was probed by radioimmunoassay, following pre-separation of tissue extracts by reversed phase separation on a SepPak C-18 cartridge. The result showed that the level of dynorphin A remained unaltered in all regions studied immediately before (tolerance) and 20 hr after (withdrawal) the pump was removed. A significant decrease in the level of dynorphin was found in the n. accumbens 48 hr (abstinence) after removal of the pump. It is suggested that previously observed changes in the reward system during abstinence may be connected with dynorphinergic neurones in the limbic system.

Animals↗

PubMed1993

Met-enkephalin-Arg6-Phe7 in spinal cord and brain following traumatic injury to the spinal cord: influence of p-chlorophenylalanine. An experimental study in the rat using radioimmunoassay technique.

The possibility that trauma to the dorsal horn may affect the release and distribution of enkephalin was examined using the opioid peptide Met-Enk-Arg6-Phe7 (MEAP) as a marker in a rat model. The peptide content of samples of spinal cord and whole brain was measured using a radioimmunoassay (RIA) technique. In addition, the possible functional relation between this peptide and serotonin was evaluated using a pharmacological approach that included depletion of endogenous serotonin. A focal trauma to the right dorsal horn in the T10-11 segments (2 mm deep and 5 mm long) markedly modified the content of MEAP of the adjacent rostral and caudal segments of the cord, as well as the content of MEAP of the brain. Depletion of serotonin with p-CPA (an inhibitor of the synthesis of serotonin) significantly elevated the content of MEAP in the whole brain without affecting the regions of the spinal cord (except T9 level which showed a 25% decrease from an intact control group). Trauma to the spinal cord in the serotonin-depleted animals did not alter the content of MEAP further, as compared to a p-CPA-treated but untraumatized group. These results indicate that enkephalin (i) participates in the pathophysiology of spinal cord trauma and (ii) suggest that the peptide is somehow functionally related with serotonin.

Animals↗

PubMed1993

Prostaglandins modulate alterations of microvascular permeability, blood flow, edema and serotonin levels following spinal cord injury: an experimental study in the rat.

The possibility that prostaglandins influence edema formation, microvascular permeability increase and reduction of blood flow following spinal cord trauma was examined in a rat model. In addition, the influence of prostaglandins on serotonin metabolism of the traumatized spinal cord was evaluated. Trauma to spinal cord (2-mm-deep and 5-mm-long incision in the right dorsal horn of T10-11 segments) resulted in a profound increase of the water content 5 h after injury. At this time, the microvascular permeability to Evans Blue and [131I]sodium was increased by 457 and 394%, respectively. The blood flow was reduced by 30%. The serotonin (5-hydroxytryptamine) content of the spinal cord increased by 205%. The plasma serotonin level rose by 152% in the injured group of rats. Pretreatment with indomethacin (10 mg/kg, i.p.) 30 min before trauma significantly reduced the edema and microvascular permeability increase. The local spinal cord blood flow of traumatized animals was partially restored. The increases of serotonin levels of the spinal cord and plasma were significantly attenuated. These beneficial effects of indomethacin were not present in rats given a lower dose (5 mg/kg). Indomethacin in either dose did not influence these parameters of control rats without trauma to the cord. Since indomethacin is a potential inhibitor of prostaglandins synthesis our observations indicate: (i) that prostaglandins participate in many microvascular responses (permeability changes, edema, blood flow) occurring after a trauma to the spinal cord; (ii) that these effects of the drug seem to be dose dependent, and (iii) that the prostaglandins may influence the serotonin metabolism following trauma to the spinal cord.

Animals↗

PubMed1993

Inhibition of dynorphin converting enzymes from human spinal cord by N-peptidyl-O-acyl hydroxylamines.

Two cysteine proteinases, cleaving dynorphins A and B to enkephalins, were isolated from the human spinal cord. These enzymes were found to be competitively inhibited by a new class of synthetic inhibitors: N-peptidyl-O-acyl hydroxylamines. The most potent (Ki < 20 microM) were the N-terminally protected peptides Z-Phe-Phe-NHO-Ma and Boc-Phe-Gly-NHO-Bz, both containing hydrophobic amino acids at the P2 position. N-Peptidyl-O-acyl hydroxylamines were converted in water solution to the corresponding hydroxamic acids and no cleavage of the peptide bond within the inhibitor sequence was observed after prolonged incubation with the enzymes. It is anticipated that these synthetic compounds may serve as potential pharmacological tools for in vitro studies on dynorphin processing.

Amino Acid Sequence↗

PubMed1993

[The content of dynorphin, Met-enk-Arg6-Phe7 and substance P (1-11) in the brain of mice with different levels of ethanol consumption].

The dynorphin A (1-17), Met-enkephalin-Arg6-Phe7 and substance P levels were determined by RIA following Sep-Pak separation in the striatum, hippocampus and spinal cord of three strains of mice (C57Bl10/D1, A/Sn, A. CA). The C57Bl10/D1 mice had high consumption of 10% ethanol at free choice schedule, whereas the A/Sn and A. CA mice had very low one. The Met-enkephalin-Arg6-Phe7 level was found to be decreased only in the spinal cord and striatum of C57Bl10/D1 mice. It is suggested that decreased synthesis or processing of the proenkephalin may at least partly determine the high level of ethanol consumption by this strain of mice.

Alcohol Drinking↗

PubMed1992

Characterization of dynorphin A-converting enzyme in human spinal cord. An endoprotease related to a distinct conversion pathway for the opioid heptadecapeptide?

A highly specific proteinase, converting dynorphin A (1-17) to enkephalins, was isolated from the human spinal cord and subjected to further characterization. The enzyme was found to be a thiol-dependent protein with a relative molecular mass of 50 kDa and a pH optimum between 5.0 and 5.5. This proteinase appears to exclusively convert dynorphin A (1-17) to Leu-enkephalin and its COOH-terminal extensions Leu-enkephalin-Arg6 (which was a major conversion product) and Leu-enkephalin-Arg6-Arg7 but not the other prodynorphin- or proenkephalin-derived peptides. This high specificity toward a single structure is suggested to be involved in a distinct processing pathway associated with the generation of the opioid peptides with selectivity for delta-opioid receptors.

Amino Acid Sequence↗

PubMed1992

Relationship between primary structure and activity in exorphins and endogenous opioid peptides.

We have found a correlation between the certain characteristics of primary structure and biologic activity in exorphins and endogenous opioid peptide family. The characteristics of primary structure are the content of certain segment pairs as well as the density of their arrangement in a peptide. These segment pairs represent basic elements of the regulatory peptide primary structure pattern, which was found recently [Dokl. Akad. Nauk USSR 289 (1986) 721-724; Int. J. Peptide Prot. Res. 38 (1991) 505-510].

Amino Acid Sequence↗

PubMed1992

Decreased cerebrospinal fluid neuropeptide-converting enzyme activity in monoarthritic rats.

The activity in rat cerebrospinal fluid (CSF) of dynorphin-converting enzyme (DCE) and substance P endopeptidase (SPE) was determined in control animals and in rats with monoarthritis. Enzymatic activities were measured with specific radioimmunoassays toward the N-terminal products Leu-enkephalin-Arg6 and substance P1-7, respectively. A monoarthritis stable during weeks 2-6 post-injection was induced by injection (0.05 ml) into one joint with Freund's adjuvant. Both SPE and DCE were significantly decreased 15 days after the intraarticular injection. Despite the degree of arthritis that was sustained equally at four weeks after inoculation, both DCE and SPE were back to control levels at that time. It can therefore be concluded that arthritis from a single joint is sufficient to elicit changes in CSF convertase activities, and that these effects disappear between 2 and 4 weeks after injection, although the arthritis persists.

Animals↗

PubMed1992

Decreased neuropeptide-converting enzyme activities in cerebrospinal fluid during acute but not chronic phases of collagen induced arthritis in rats.

We investigated the effects of collagen II-induced arthritis on two cerebrospinal fluid (CSF) enzymes converting dynorphin A and substance P (SP), namely dynorphin-converting enzyme (DCE) and substance P endopeptidase (SPE). The products generated by these enzymes are the bioactive fragments Leu-enkephalin-Arg6 and substance P, respectively. The strain used (DA rats) is very sensitive towards induction of arthritis. The collagen arthritis is a chronic autoimmune arthritis induced by native rat collagen type II (CII). Following intradermal injection of CII into the tailbase. CSF was sampled on day 21 (acute arthritis) and day 38 (chronic arthritis). Control rats were untreated because the strain used developed an acute and self-limited arthritis (adjuvant arthritis) when administered vehicle (i.e. incomplete Freund's adjuvant). The DCE activity was significantly lowered in the acute phase of arthritis (P less than 0.05) when analysed with two-factor analysis of variance (ANOVA). The enzyme converting SP (SPE) also showed a significant decrease in the acute phase of arthritis (P less than 0.05). These results demonstrate that both DCE and SPE are affected in the acute phase of arthritis. A functional role of these enzymes in processing pain-related neuropeptides is therefore implicated.

Acute Disease↗

PubMed1992

Isolation of a hemoglobin-derived opioid peptide from cerebrospinal fluid of patients with cerebrovascular bleedings.

The hemorphins are peptides with opioid activity, which are enzymatically released from hemoglobin. A decapeptide identical to the sequence 32-41 of the beta-, delta-, gamma- or epsilon-chains of hemoglobin has been isolated from human ventricular cerebrospinal fluid (CSF). The peptide, designated LVV-hemorphin-7, was recovered in relatively high amounts (115-300 pmol per ml) from samples of patients with cerebrovascular bleedings, but was not detectable in control CSF. Its identity with the hemoglobin fragment was confirmed by mass spectrometry and gas-phase sequencing.

Amino Acid Sequence↗

PubMed1992

Cerebrospinal fluid biogenic amine metabolites in fibromyalgia/fibrositis syndrome and rheumatoid arthritis.

OBJECTIVE: To compare the levels of biogenic amines in the cerebrospinal fluid (CSF) of primary fibromyalgia syndrome (PFS) patients with those in the CSF of controls. METHODS: Metabolites of serotonin, norepinephrine, and dopamine were identified in CSF, using high performance liquid chromatography with coulometric detection. RESULTS: CSF levels of metabolites from all 3 neurotransmitters were lower in PFS patients than in controls. CONCLUSION: A low rate of turnover of several neurotransmitters supports the proposed hypothesis of a metabolic defect in PFS and suggests that the defect occurs at a neuroregulatory level.

Adult↗

PubMed1992

Application of fast-atom bombardment mass spectrometry for sequencing of a hemoglobin fragment, naturally occurring in human cerebrospinal fluid.

Recent studies have revealed the presence of a new group of opioid peptides, the hemorphins, in the human pituitary as well as in human cerebrospinal fluid. The hemorphins are structurally related to sequence segments residing in the beta, delta, gamma or epsilon-chains of hemoglobin. In this study we have applied fast-atom bombardment mass spectrometry (FAB-MS) to elucidate the sequence of a hemorphin fragment isolated from the cerebrospinal fluid of patients with cerebrovascular bleedings. The FAB-MS was used in conjunction with carboxypeptidase Y digestion and results indicated that this procedure proved to be a powerful tool for rapid sequence determination. The recovered peptide was thus found to be identical with the sequence 32-41 of the above mentioned hemoglobin chains.

Amino Acid Sequence↗

PubMed1992

Dynorphin converting enzyme in the rat spinal cord. Decreased activities during acute phase of adjuvant induced arthritis.

This paper describes a study on a dynorphin converting enzyme in spinal cord homogenates from rats with experimental arthritis after adjuvant injection into one hindpaw. The enzyme resembles a neutral cysteine endopeptidase which cleaves the opioid peptide dynorphin B and generates its N-terminal fragment, Leu-enkephalin-Arg6 with opioid activity. It exhibits considerably lower activity against dynorphin A and alpha-neoendorphin, the two other prodynorphin derived peptides. The enzyme showed significantly higher activity in the dorsal part than in the ventral part of the spinal cord. A significant decrease in enzyme activity was observed in the dorsal spinal cord during inflammation as compared to vehicle-injected controls. This decrease paralleled a decrease in the tissue level of Leu-enkephalin-Arg6. These data thus indicate that adjuvant-induced arthritis may generate an important change in a converting enzyme acting on peptide structures, which may be involved in pain modulation. Therefore, a functional role of the present enzyme in the regulation of pain-related peptides is suggested.

Acute Disease↗

PubMed1992

Dynorphin A content in the rat brain and spinal cord after a localized trauma to the spinal cord and its modification with p-chlorophenylalanine. An experimental study using radioimmunoassay technique.

The distribution of dynorphin A in the spinal cord and brain of normal rats and of rats subjected to a focal injury of the spinal cord was examined in a rat model using a radioimmunoassay (RIA) technique. The validity of RIA was checked by high performance liquid chromatography (HPLC). Furthermore, the possibility that the peptide is somehow functionally related with endogenous 5-hydroxytryptamine (5-HT, serotonin), was also evaluated using a pharmacological approach. In normal animals, the peptide content was very similar in the spinal cord segments (T9, T10-11, and T12) examined whereas, the dynorphin content of the whole brain was about two-fold higher compared with that in the spinal cord. A focal injury to the spinal cord in the right dorsal horn (about 1.5 mm deep, 2.5 mm long and 1.5 mm to the right of the midline) of the lower thoracic cord (T10-11) in urethane anaesthetised animals significantly altered the peptide content in the whole brain as well as in the spinal cord. Thus, a decrease in the peptide level in whole brain, T10-11 and in the T12 segments of the spinal cord was observed 1 and 2 h after trauma. At 5 h, the peptide had accumulated markedly in the T9 segment (about a two-fold increase) as compared with the controls. At this time, the peptide content had been restored in the T10-11 and T12 segments. On the other hand, the whole brain dynorphin level continued to remain low (by 55%) as compared to the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Histamine modulates heat stress-induced changes in blood-brain barrier permeability, cerebral blood flow, brain oedema and serotonin levels: an experimental study in conscious young rats.

The possibility that endogenous histamine plays an important role in modulating the pathophysiology of heat stress was examined in young rats using a pharmacological approach. Subjection of young animals (six to seven weeks old) to heat stress at 38 degrees C for 4 h in a biological oxygen demand incubator (relative humidity 47-50%, wind velocity 20-25 cm/s) resulted in a profound increase in blood-brain barrier permeability to Evans Blue albumin (whole brain 375%) and [131I]sodium (whole brain 478%) along with a significant reduction in the cerebral blood flow (mean 34%). The water content of the whole brain was elevated by 4.5% (about 19% volume swelling) from the control. At this time-period, the plasma and whole brain 5-hydroxytryptamine levels were elevated by 656% and 328%, respectively, from the control group. Pretreatment with cimetidine (a histamine H2 receptor antagonist) significantly thwarted the increases in the brain water content and the blood-brain barrier permeability. In cimetidine-pretreated animals, the cerebral blood flow was significantly elevated and the plasma and brain 5-hydroxytryptamine (serotonin) levels were slightly but significantly reduced as compared with the untreated stressed group. However, prior treatment with mepyramine (a histamine H1 receptor antagonist) neither attenuated the changes in water content and the blood-brain barrier permeability nor altered the cerebral blood flow and 5-hydroxytryptamine levels. In fact, there was a significantly higher permeation of the tracers across the cerebral vessels in these drug-treated animals along with a greater accumulation of the brain water content as compared with the untreated stressed group. The cerebral blood flow and 5-hydroxytryptamine levels showed only minor changes from the untreated stressed group. These results show, probably for the first time, that (i) the endogenous histamine plays an important role in the pathophysiology of heat stress, and (ii) this effect appears to be mediated via specific histamine H2 receptors.

Animals↗