Diurnal pattern of plasma and cerebrospinal-fluid vasopressin levels in hydrocephalic patients: absence of a circadian rhythm and of a correlation between plasma and cerebrospinal-fluid variations

The arginine vasopressin (AVP) concentrations were determined in plasma and in cerebrospinal fluid (CSF) during a 24-hour period in 7 male patients suffering from hydrocephalus of differing etiologies. Blood and ventricular CSF samples were simultaneously collected every 2 h during the day (08.00-22.00) and every hour during the night (24.00-07.00). In both plasma and CSF, the AVP levels did not show significant time-related circadian variations. No significant correlation was found between the plasma and CSF AVP values during the 24-hour period. The data obtained indicate the absence of the plasma and CSF AVP circadian rhythm in hydrocephalic patients and suggest that in these patients, and possibly in healthy humans, physiological stimuli which are able to induce variations in the plasma AVP concentration during daily life do not alter the CSF AVP content.     

Caffeine stimulates beta-endorphin release in blood but not in cerebrospinal fluid

Plasma beta-endorphin and prolactin profiles were obtained from groups of unstressed, adult male rats. The infusion of caffeine (20 mg/kg) via a chronic, indwelling intra-atrial cannula results in a prompt and sustained (2-2.5 h) rise In plasma beta-endorphin levels. The infusion of the opiate antagonist naloxone causes a modest (40%) decrease in plasma beta-endorphin and blunts the elevation in plasma beta-endorphin following caffeine administration. In contrast, plasma prolactin levels were unchanged following caffeine administration and were decreased by treatment with naloxone. Caffeine treatment did not effect CSF beta-endorphin levels or the release of beta-endorphin from hemipituitaries incubated in vitro.     

Possible involvement of endogenous beta-endorphin in the pathophysiological mechanisms of Pichinde virus-infected guinea pigs.

Previously, we demonstrated that naloxone, an opiate antagonist, prolonged survival of strain 13 guinea pigs infected with Pichinde virus. Thus, endogenous opiates may be involved in the pathogenesis of this viral disease. To determine whether endogenous opiate levels were affected by Pichinde viral infection, beta-endorphin concentrations in plasma and cerebrospinal fluid (CSF) of normal and infected strain 13 guinea pigs were measured by radioimmunoassay. Cerebrospinal fluid beta-endorphin concentrations were 78.0 +/- 13.2 pg/ml on postinoculation day (PID) 7, 59.0 +/- 5.6 pg/ml on PID 12, and 58.8 +/- 5.4 pg/ml on PID 14. These values were significantly higher than baseline levels of CSF beta-endorphin: 30.8 +/- 1.9 pg/ml. Plasma beta-endorphin concentrations of infected animals increased significantly to 202.1 +/- 17.9 pg/ml on PID 7 and to 154.2 +/- 21.4 pg/ml on PID 12 from a mean baseline value of 84.2 +/- 13.1 pg/ml. After a primer intravenous injection of beta-endorphin (10, 15, or 30 micrograms/kg), followed by constant infusion of beta-endorphin (15, 45, or 90 micrograms/kg.hr) to control noninfected guinea pigs, heart rate (except with the lowest dose) and mean blood pressure decreased markedly. Under these experimental conditions, concentrations of plasma and CSF beta-endorphin increased simultaneously with different magnitude. Because both Pichinde viral infection and beta-endorphin administration produced a similar trend of cardiovascular disturbances, leading to hypotension and bradycardia, increased concentrations of plasma and CSF beta-endorphin may play a partial role in the pathophysiological mechanisms of Pichinde virus infection.     

Disassociated increases of adrenomedullin in the rat cerebrospinal fluid and plasma after salt loading and systemic administration of lipopolysaccharide

To determine the role of adrenomedullin (AM) in the fluid electrolyte homeostasis and endotoxin shock, cerebral spinal fluid (CSF) and plasma were sampled from rats after respective challenges. The AM levels were measured by a highly sensitive immunoassay. The AM levels in the CSF of the rats anesthetized with ether (10.7 +/- 0.60 fmol/ml) were significantly higher than those with isoflurane 5.17 +/- 0.70 fmol/ml, P < 0.01), while the plasma level did not differ significantly. The CSF levels of the rats received 2% saline drinking increased to 3 and 4 folds at day 5 and day 7, respectively, while the plasma levels did not differ from controls at both time points. The AM levels in CSF or plasma increased to 1.5 and 3 folds at 1.5 h after intraperitoneal (i.p.) administration of lipopolysaccharide (LPS, 5 mg/kg), reached 6.5 and 30 folds at 6 h, respectively, while no change was observed in the controls. The present findings suggest that AM in the CSF is regulated independently from that in the plasma, the centrally synthesized AM plays and important role in the regulation of the fluid electrolyte homeostasis. Furthermore, the circulatory AM plays an important role in the endotoxin shock.     

Proopiomelanocortin opioids in brain, CSF, and plasma of piglets during hypoxia

beta-Endorphin-like immunoreactivity (BELI), containing the biologically active beta-endorphin, its precursor beta-lipotropin (BLP), and deactivated product N-acetyl-beta-endorphin (ABE), were measured by radioimmunoassay in plasma, cerebrospinal fluid (CSF), and in a dorsal medullary slice containing the respiratory-related nucleus tractus solitarius (dmscNTS) of young and older piglets in normoxia and hypoxia. Significant increase with hypoxia occurred in the levels of BLP in the plasma and CSF and of BELI and ABE in the plasma of the young group. In the older group, such increases occurred in ABE levels of the dmscNTS, in BLP and ABE levels of the CSF, and in plasma BELI. Estimated levels of pure beta-endorphin were higher in the CSF of young piglets during both control and hypoxia. With hypoxia, these estimated levels increased significantly in the plasma of the young age group but showed only a borderline increase in the old group. It is possible that higher opioid levels in the CSF of young as compared with older neonates, enhanced by a greater opioid increase in their plasma during hypoxia, may help explain the suppressed respiratory response to hypoxia of the newborn.     

ACTH, corticosterone and beta-endorphin in the blood plasma of rats under prolonged immobilization stress

Radioimmunoassays were employed to study variation in the concentration of corticosterone, ACTH and beta-endorphin in rat blood plasma at different times of the 30-hour immobilization and under the effect of a short-term action of ecologically significant negative stimulation emanating from other animals. Both prolonged immobilization stress and short-term emotional reaction produced appreciable alterations in the blood plasma content of all the hormones under study. The findings indicate that variations in the corticosterone and beta-endorphin levels were in the best agreement.     

The influence of beta-endorphin on testicular endocrine function in adult rats.

The role of beta-endorphin in testicular steroidogenesis is poorly understood. To address this issue, we treated adult hypophysectomized rats intratesticularly with either saline-50% polyvinylpyrrolidone (SAL-PVP) or human beta-endorphin (0.5 microgram/testis; a total of 1 microgram/rat/day) in SAL-PVP for 3 days. Testicular injections were made under ether anesthesia. On Day 3, rats also received injections (s.c.) of either SAL-PVP or 5 micrograms beta-endorphin in SAL-PVP to minimize the dilution of ether in the testis. One hour later, rats were treated (i.p.) with either saline or ovine LH (25 micrograms/rat). One hour after saline or LH injection, blood was obtained via heart puncture for determination of plasma progesterone (P), androstenedione (A-dione), and testosterone (T) levels. The effects of beta-endorphin (50 ng, equivalent to 13.9 pM; or 250 ng, equivalent to 69.6 pM) on P and androgen secretions in vitro were also examined. Intratesticular injections of beta-endorphin significantly (p less than 0.025) decreased the T response to LH treatment, but failed to affect plasma P and A-dione levels. Response of P to LH treatment was increased (p less than 0.005) in medium containing testicular fragments exposed to 250 ng (69.6 pM) beta-endorphin. However, beta-endorphin attenuated LH effects on A-dione and T production in vitro. These studies demonstrate that beta-endorphin inhibits T secretion, possibly because of its effect on the synthesis of T precursors. Thus, testicular beta-endorphin modulates the endocrine function of the testis in adult rats.     

Stereoselective effect of morphine on antinociception and endogenous opioid peptide levels in plasma but not cerebrospinal fluid of dogs.

Morphine releases endogenous opioids into the circulation of dogs. To test the stereospecificity of this effect, as well as to determine whether morphine also releases endogenous opioids centrally, which might be involved in its antinociceptive action, the effects of (-)-morphine sulfate (10 mg/kg, sc) or (+)-morphine hydrobromide on antinociception in a dog tail-flick test, on semi-quantified morphine-induced signs of salivation, emesis, defecation and ataxia, and on the plasma and cerebrospinal fluid (CSF) levels of endogenous opioid peptides were studied. Plasma and CSF levels of immunoreactive beta-endorphin (i-BE), met-enkephalin (i-ME), leu-enkephalin (i-LE), and dynorphin (i-DY) were quantified by radioimmunoassay in octadecylsilyl-silica cartridge extracts. Immunoreactive morphine (i-M) levels were measured in unextracted samples. (-)-Morphine treatment significantly increased antinociception, morphine-induced signs, i-M levels in plasma and CSF, and i-BE, i-ME, and i-LE levels in plasma, but not CSF. Levels of i-DY remained constant in plasma and CSF. (+)-Morphine treatment did not alter any of these parameters, indicating that the effects of morphine on nociception, behavioral signs, and plasma endogenous opioids in dogs were stereoselective. It is concluded that morphine does not cause an increase in immunoreactive endogenous opioid peptides in the CSF at the time of its peak antinociceptive effect.     

Motor Activity Increases Tryptophan, 5-Hydroxyindoleacetic Acid, and Homovanillic Acid in Ventricular Cerebrospinal Fluid of the Conscious Rat

An investigation was made into the effects of running (1 h at 20 m/min) on central serotonergic and dopaminergic metabolism in trained rats. Methodology involved continuous withdrawal of cerebrospinal fluid (CSF) from the third ventricle of conscious rats and measurements of tryptophan (TRP), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA) levels during a 2 h post-exercise period. All three compounds were increased during the hour following exercise and returned to their basal values within an hour later. CSF flow rate was stable when metabolite levels were elevated. Brain determinations indicated that CSF metabolite variations only qualitatively paralleled brain changes. Indeed, post-exercise TRP, 5-HIAA, and HVA levels were increased to a greater extent in brain when compared to CSF. It is suggested that increased serotonergic and dopaminergic metabolism, caused by motor activity, may be involved in the behavioral effects of exercise.     

Effect of transcutaneous transcerebral electrostimulation as electroanesthesia on the beta-endorphin content of the cerebrospinal fluid and blood plasma

The beta-endorphin content was measured in the cerebrospinal fluid (CSF) and blood plasma of patients before and after 30 minutes of transcutaneous transcerebral electric stimulation in the electric anesthesia mode. The output current was biphasic and rectangular. It was composed of high-frequency pulse trains (peak-to-peak intensity 250-300 mA, frequency 167 kHz) modulated by low frequency (77 Hz). Electrical stimulation resulted in an appreciable increase in the beta-endorphin content in the CSF and blood plasma of patients. The data obtained attest to the intensification of the neuromodulator release to the CSF and blood plasma and to the involvement of the endorphinergic brain systems in the realization of the analgetic effect of transcutaneous transcerebral electric stimulation.     

Reduced cerebrospinal fluid levels of immunoreactive pro-opiomelanocortin related peptides (including beta-endorphin) in anorexia nervosa

The discovery that the endogenous opioid peptides contribute to the modulation of appetitive behavior and neuroendocrine function has raised questions as to whether disturbances of opioids contributes to the pathophysiology of eating disorders. To assess central nervous system (CNS) beta-endorphin in patients with anorexia nervosa we measured cerebrospinal fluid (CSF) beta-endorphin concentrations before, and at intervals after weight correction. In addition, we measured three sister peptides (beta-lipotropin, adrenocorticotropic hormone (ACTH), and the N-terminal fragment) derived from the same precursor molecule, pro-opiomelanocortin (POMC) to determine whether possible disturbances might extend to sister peptides. Underweight anorectics (58 +/- 5% of average body weight (ABW), n = 10) had significantly lower CSF concentrations of all 4 peptides compared to healthy controls (102 +/- 10% ABW, n = 11). CSF concentrations of all 4 POMC-related peptides were found to be significantly increased when the same anorectics were restudied 4 to 6 weeks after weight gain (83 +/- 4% ABW). After weight gain, levels of CSF beta-endorphin, beta-lipotropin, and ACTH were similar to controls, whereas levels of CSF N-POMC remained significantly less than controls. Another group of women, previously underweight with anorexia nervosa, but weight-restored (93 +/- 11% ABW, n = 12) for greater than 1 year had CSF concentrations of all 4 POMC-related peptides that were similar to controls. We conclude that underweight anorectics have state-associated disturbances of CNS beta-endorphin as well as other POMC-related peptides. These abnormalities are part of the neurobiological syndrome of anorexia nervosa and may contribute to the characteristic alterations in behavior and neuroendocrine function.     

Beta-endorphin and met-enkephalin in plasma of cattle during pregnancy, parturition and the neonatal period

Plasma concentrations of beta-endorphin and met-enkephalin were measured, with appropriate radioimmunoassays, in cows during gestation and at parturition and in newborn calves. During pregnancy beta-endorphin immunoreactivity (IR) concentration increased, but values during the last month of gestation were not different from those at parturition. Highest met-enkephalin IR levels were obtained in cows during calving. A term Caesarean section caused an increase in plasma beta-endorphin and met-enkephalin IR concentrations, but no such increase occurred in cases of a preterm Caesarean section. In calves beta-endorphin IR values were lower before umbilical cord rupture than immediately after birth. Values decreased continuously thereafter. This was also the case for met-enkephalin IR concentrations in calves born at term. In preterm calves met-enkephalin IR values were low immediately after delivery and increased during the first hour of life. A significant correlation existed between the degree of acidosis and plasma levels of both opioid peptides in the calves. We conclude that a direct stimulation of peripheral beta-endorphin release by the pain or stress associated with calving does not seem to exist in cattle, whereas met-enkephalin seems to be more directly related to parturition. In calves the change to the extrauterine environment causes an immediate, increased release of both opioids.     

Cerebrospinal fluid immunoreactive beta-endorphin concentration is increased by voluntary exercise in the spontaneously hypertensive rat

The effect of voluntary exercise on cerebrospinal fluid (CSF) levels of immunoreactive beta-endorphin has been studied in the spontaneously hypertensive rat (SHR). The exercise consisted of 5-6 weeks of spontaneous running in wheels and the average running distance was 3.5 +/- 0.4 km/24 h. CSF samples were obtained under anaesthesia from the cisterna magna. Five experimental groups were examined, four groups of runners and one group of sedentary controls. The runners were sampled either (a) shortly (0-3 h) after termination of exercise, or after the wheel had been locked for (b) 24, (c) 48 or (d) 96 h. The runners in group a had significantly higher immunoreactive beta-endorphin levels than the controls. The levels remained increased as compared with controls after 24 and 48 h of enforced abstinence but had returned to control after 96 h. The data indicate that voluntary exercise induces adaptive changes in central beta-endorphin systems.     

Demonstration of prolactin flow into the cerebrospinal fluid of the alert rat in a pulsatile circhoral manner by push-pull cannulation of the 3d ventricle

In 8 male unanesthetized rats, sequential sampling of cerebrospinal fluid (CSF) from a push-pull cannula implanted into the 3rd ventricle revealed that prolactin was present in this fluid, where it displayed circhoral pulsatility resembling the temporal variations in plasma prolactin observed in the same animals. Although basal prolactin levels were lower in the CSF than in the plasma, the amplitude of the circhoral prolactin pulses was twice as great in the CSF as in the plasma compartment. The possible origin and role of CSF prolactin are discussed.     

Preference for dietary fat induced by release of beta-endorphin in rats

AimsTo determine whether beta-endorphin contributes to the ingestion of and preference for dietary oil, we examined the relationship between the dynamics of beta-endorphin, before and after the ingestion of corn oil, and the intake volume of corn oil.Main methodsRats were offered 5% corn oil for 20 min for 5 consecutive days so they could acquire a preference for corn oil. On day 6, seven groups of rats were presented with the oil for defined time periods, and we measured the beta-endorphin levels in the serum and cerebrospinal fluid (CSF) before and after the presentation of corn oil as well as the consumed volume of corn oil at defined time points.Key findingsBeta-endorphin levels in serum and CSF were significantly increased 15 min after the ingestion of corn oil, followed by a rapid decrease and maintenance at the basal level throughout the rest of the experimental period. The intake of corn oil was the lowest in the time period of 15–30 min, when the beta-endorphin level reached a peak value. The intake volume of corn oil might be inversely correlated with beta-endorphin levels in serum and CSF. The pretreatment of naloxone, an antagonist of the opioid receptor, decreased the initial licking rate for corn oil and increased the latency for corn oil in the licking test.SignificanceThe beta-endorphin was rapidly released after oil ingestion, which contributed to the hedonic preference and ingestive behavior for fat.     

Hypoxia does not increase CSF or plasma beta-endorphin activity

The ability of moderate (30-50 Torr arterial PO2) and severe (less than 30 Torr arterial PO2) hypoxia to generate endogenous opioids that modulate ventilation was studied in unanesthetized goats. Ventilation and its components, arterial blood gas tensions and pH, and plasma and cerebrospinal fluid (CSF) beta-endorphin activity were measured before and after 4 h of sustained moderate or severe hypoxia. Ventilation, as expected, increased with hypoxia. There were no significant changes in either plasma or CSF beta-endorphin activity after sustained hypoxia. To rule out elaboration of endogenous opioids other than beta-endorphin after hypoxia, naloxone or saline was administered to five of the seven goats exposed to 4 h of severe hypoxia, and their ventilatory responses were compared for 30 additional min of hypoxic breathing. No significant differences in ventilation occurred in the two treatment groups during this time period. We conclude that, unlike increases in airway resistance, moderate and severe hypoxia do not cause the elaboration of endogenous opioids that modify respiratory output in unanesthetized adult goats. The apparent ability of hypoxia to cause elaboration of endogenous opioids in the neonate may represent a maturational phenomenon.     

Beta-lipotropin is the major component of the plasma opioid response to surgical stress in humans

There is growing experimental evidence that beta-endorphin immunoreactivity is raised by surgical stress in patients undergoing general anesthesia. As the assay methods employed to date did not allow to fully discriminate between beta-endorphin and its immediate precursor, beta-lipotropin, we have investigated in the present study plasma levels of these two peptides by separating them by chromatography on plasma extracts prior to radioimmunoassay in eighteen surgical patients under general anesthesia and eight under spinal anesthesia.Beta-lipotropin, but not beta-endorphin, plasma levels were found to be significantly elevated during surgery in the general anesthesia group, while no change was found in either peptide concentration in the spinal one. Cortisol plasma levels also increased significantly 90 minutes after the beginning of surgery, when they were positively correlated to beta-lipotropin ones. Although the sampling time we adopted may have prevented us from detecting an early peak of beta-endorphin during the first 30 minutes of surgery, the major component of the pituitary opioid response to surgical stress appears to be related to beta-lipotropin. This is in agreement with results of experimental work on various kinds of stress in animals and humans and seems to rule out a role for plasma beta-endorphin in post-operative analgesia.     

Adrenomedullin reduces the severity of cerulein-induced acute pancreatitis

We investigated the effect of Adrenomedullin (AM) on cerulein-induced acute pancreatitis in rats. AM treatment (100 ng/kg per rat, subcutaneous) after one hour of cerulein injection reduced the plasma amylase levels, pancreatic weight, pancreatic malondialdehyde (MDA) levels, and the severity of the lesions microscopically. These data suggest that AM has a protective effect on cerulein-induced acute pancreatitis. These could be due to anti-inflammatory properties of AM, inhibition of proinflammatory cytokine secretion, reducing the endothelial permeability increased by reactive oxygen species, endotoxins or cytokines.     

Bromocriptine is unable to suppress TRH-stimulated beta-endorphin/beta-lipotropin and cortisol secretion in normal pregnant women after delivery

The course of plasma beta-endorphin/beta-lipotropin, cortisol and prolactin (PRL) levels was followed from 0.5 till 5 h after normal delivery in 13 healthy women. Six subjects who did not want to breast-feed their child received 2.5 mg bromocriptine orally 1 h after delivery. After 3 h the effect of the intravenous administration of 200 micrograms thyrotropin-releasing hormone (TRH) was also measured. Elevated plasma beta-endorphin and cortisol levels decreased after delivery in a (log) linear fashion which was not influenced by bromocriptine. TRH elicited a significant short-lived identical increase in plasma beta-endorphin/beta-lipotropin concentrations in the control and the bromocriptine-treated subjects. TRH similarly delayed the rapid decline in plasma cortisol levels in both groups of women. Basal and TRH-induced PRL levels were rapidly suppressed by bromocriptine. These studies show the presence of a paradoxical increase of beta-endorphin/beta-lipotropin and cortisol levels in response to TRH occurring shortly after delivery in normal women. This response cannot be mediated by the placenta. The absence of an inhibiting effect of bromocriptine on basal and TRH-induced beta-endorphin and cortisol release does not lend support to the hypothesis of the presence of a functionally active intermediate pituitary lobe in man early in puerperium.     

Restriction of placental growth in sheep enhances placental metabolism of fetal beta-endorphin-like immunoreactivity

The opioid polypeptide beta-endorphin is present in fetal blood but it is not clear whether its source is the fetus or the placenta. We therefore measured beta-endorphin in extracts of fetal femoral arterial and umbilical venous blood plasma in sheep by radioimmunoassay to determine whether the fetus or the placenta is the major source of beta-endorphin in the fetal circulation. Chromatographic analysis of extracts of fetal arterial plasma showed that beta-lipotropin and other precursors of beta-endorphin made only a minor contribution to the immunoreactivity detected. Concentrations of immunoreactive beta-endorphin were higher in the femoral artery than in the umbilical vein in fetal sheep between 113 and 128 days of pregnancy. Therefore the placenta removes beta-endorphin or a closely related polypeptide of fetal origin from the umbilical circulation in sheep at this stage of gestation. Acute hypoxaemia and hypoglycaemia increase the concentrations of immunoassayable beta-endorphin in blood plasma of adult and fetal sheep, but little is known about the effects of chronic hypoxaemia or hypoglycaemia on the circulating levels of beta-endorphin and related polypeptides in the fetus. Therefore we also measured immunoreactive beta-endorphin in blood plasma from fetal sheep in which growth retardation in association with restricted placental growth was produced by removal of endometrial caruncles before mating. Intra-uterine growth retardation was accompanied by chronic hypoglycaemia and chronic hypoxaemia in the fetuses. This was not associated with higher concentrations of beta-endorphin-like immunoreactivity in fetal arterial or umbilical venous plasma, but was accompanied by significantly increased placental extraction of fetal immunoreactive beta-endorphin from the umbilical circulation.(ABSTRACT TRUNCATED AT 250 WORDS)