Neuropeptides in cerebrospinal fluid

Most neuropeptides can now be assayed in human cerebrospinal fluid (CSF). Some, such as beta-endorphin and arginine vasopressin, seem to be secreted directly into CSF. Others may reach CSF from plasma either by passage through the blood-brain barrier or by absorption through the circumventricular organs, which lack a blood-brain barrier. The role of neuropeptides in CSF is still unclear. Thyrotropin-releasing hormone, somatostatin, arginine vasopressin, angiotensin II, substance P, vasoactive intestinal polypeptide, beta-endorphin, gastrin, and cholecystokinin are all present in assayable quantities in human CSF. Their functions in this fluid are liable to be as diverse as their functions elsewhere in the body. The release of hypothalamic releasing factors into the CSF may be part of the pathway of pituitary hormone release. Pituitary hormones may function in CSF as part of a feedback loop from the hypothalamus. Other neuropeptides may affect receptors in the central nervous system far away from their release site. Intraventricular neuropeptide injection, anatomical and physiological ablation experiments, receptor studies, and neurobiological techniques now being developed will allow a more complete understanding of CSF neuropeptide function in the future.     

Hypothalamic neuropeptides and memory

Summary Vasopressin and oxytocin exert pronounced effects on behavior by a direct action on the brain. A single injection of vasopressin results in a long-term inhibition of extinction of a conditioned avoidance response suggesting that vasopressin triggers a long-term effect on the maintenance of a learned response, probably by facilitation of memory processes. In addition vasopressin improves passive avoidance behavior, facilitates retention of sexually motivated T-maze choice behavior in male rats, delays extinction of an appetitive discrimination task, affects approach behavior to an imprinting stimulus in ducklings, delays the postcastration decline in copulatory behavior in male rats, prevents or reverses amnesia induced by electroconvulsive shock, CO₂ inhalation, pentylenetetrazol or puromycin. The majority of these effects may be explained by stimulatory influences of vasopressin on memory processes. Generally oxytocin exerts effects which are opposite to those of vasopressin and it has been suggested that oxytocin may be an amnesic neuropeptide.Evidence has been obtained that endogenous vasopressin and oxytocin play a physiological role in brain processes related to memory.Various limbic system structures seem to act as the anatomical substrate for the behavioral effects of vasopressin and different neurotransmitter systems seem to be involved. It is postulated that in case vasopressin affects retrieval processes the site of action is located in the amygdala and the dentate gyrus of the hippocampal complex with dopamine and serotonin as the respective neurotransmitter systems involved. In case the behavioral effect is due to changes in storage processes (memory consolidation) the main sites of action include the noradrenaline terminals in the dorsal septum, dorsal raphe and dentate gyrus of the dorsal hippocampus.Generally the clinical data obtained so far with vasopressin treatment are in agreement with the results from animal experiments and they support the notion on the involvement of vasopressin in memory function. The sometimes reported conflicting results on vasopressin effects in certain patients (Korsakoff or Alzheimer) may have to do with the wide-spread pathology in these diseases.     

Neuropeptides

This review summarizes the revolutionary impact of brain peptides on our understanding of the nervous system and then discusses the localization, distribution, synthesis, receptor sites, and possible function of 32 brain peptides. The peptides are discussed in three subgroups: I) the opioid peptides, which include beta-endorphin, the enkephalins, and dynorphin; II) the pituitary releasing hormones, most of which are wide-spread in the brain and include corticotropin-releasing hormone, luteinizing hormone-releasing hormone, somatostatin, and thyrotropin-releasing hormone; and III) a selection of 12 other peptides potentially important for neurological function, including vasopressin, oxytocin, substance P, cholecystokinin, bombesin, neurotensin, renin, angiotensin, vasoactive intestinal polypeptide, neuropeptide Y, calcitonin gene-related peptide, and calcitonin.Within each individual peptide section, the possible physiological roles in anterior pituitary hormone release, blood-flow regulation, feeding behavior, temperature regulation, nociception, memory and learning, and movement are reviewed. Further, where noted, the peptide findings in Huntington's, Alzheimer's, Parkinson's and psychiatric diseases are emphasized.     

Effects of transcutaneous nerve stimulation on the plasma and CSF concentrations of beta-endorphin and the plasma concentrations of ACTH, cortisol and prolactin in hysterectomized women with postoperative pain]

Plasmatic and cerebrospinal fluid levels of beta-endorphin and plasmatic concentration of ACTH, cortisol, and prolactin were investigated in 10 healthy volunteers free of pain and in a group of 38 patients who presented moderate or intense postoperative pain. The analgesic technique was transcutaneous neural stimulation. In 28 patients the stimulation was delivered at 40-80 Hz (high frequency) whereas in the remaining 10 patients it was administered in a placebo form. Measurements of hormone concentrations were performed using radioimmunoassay techniques. In patients free of pain hormone analysis was done at once, whereas in patients with pain this analysis was performed before and one hour after transcutaneous neural stimulation. We compared data obtained in control subjects with data collected in patients before and one hour after high frequency and placebo transcutaneous neural stimulation. Levels of beta-endorphin were comparable in patients with and without pain. However, ACTH, cortisol, and prolactin were increased in patients with pain. High frequency stimulation induced greater beta-endorphin levels than placebo neural stimulation and slightly lower concentration of prolactin. There were no significant differences in ACTH and cortisol levels.     

Opiate receptors: an introduction

Current status of opiate receptors and their agonists is reviewed--basic aspects of receptor theory, the importance of stereospecificity in drug-receptor interactions and the role of 'second messengers' in drug action. The three classes of endogenous opioids, originating from three distinct genes, are discussed: pro-opiomelanocortin, giving rise to beta-endorphin, ACTH and various MSHs; pro-enkephalin, giving methionine enkephalin and leucine enkephalin; and prodynorphin; their anatomical distribution and the main classes of receptors with which they interact, the mu-receptor, with a high affinity for met-enkephalin and beta-endorphin (as well as morphine and dynorphin A); the delta-receptor for which the primary ligand is leu-enkephalin; and the kappa-receptor which is the main target for the dynorphins. Functional roles for endogenous opioids are considered. Essentially they are inhibitory to target neurones, depressing motor reflexes, baroreflexes and nociception. They also have roles in the response to physical and psychological stress.     

Beta endorphin enhances in vitro lymphokine production in patients with squamous carcinoma of the head and neck

Recent studies of the effects of endorphins and other neuropeptides on immune mechanisms suggest that immune reactive cells have specific opioid-like and nonopioid endorphin receptors, and indicate that neuropeptides may participate in regulating in vivo immune functions. Earlier demonstrations of impaired cellular immunity and impaired lymphokine production in patients with cancer of the head and neck prompted an investigation of the in vitro effects of beta-endorphin on the production of leukocyte migration inhibitory factor (LIF) in 29 patients with head and neck cancer and in 45 normal subjects. LIF production in response to phytohemagglutinin was significantly less in the cancer patients compared to normal subjects (p less than .001). beta-endorphin significantly enhanced LIF production in the cancer patients (p = .01) to levels that did not differ significantly from normal levels. A correlation of levels of lymphocyte subpopulations in the cancer patients suggested that enhancement of lymphokine production by beta-endorphin was related to levels of T8 (suppressor/cytotoxic) cells. The results confirm earlier demonstrations of impaired lymphokine production in patients with head and neck cancer and indicate that beta-endorphin can modulate in vitro lymphokine responses in such patients. These findings suggest that neuroendocrine peptides may play an important role in regulating immune function. Further study of the role of neuropeptides in the immune response should provide additional insight into the characterization of cellular immune dysfunction associated with head and neck cancer and should lead to the development of innovative immunotherapeutic treatment strategies.     

Opioids modulate human neutrophil and lymphocyte function: thermal injury alters plasma beta-endorphin levels

To investigate the role of opioids in the acquired immune dysfunctional state that occurs after burns or trauma, plasma beta-endorphin levels were measured serially in nine severely burned patients, and the effect of four different opioids on normal neutrophil and lymphocyte function was quantitated. The rationale for these studies is that the neuroendocrine system appears capable of interacting with and modulating immune function. The plasma levels of beta-endorphin increased to higher than normal during the first 36 hours after burn (15 versus 3.4 pmol/L, p less than 0.05) but quickly returned toward normal. Morphine had the most profound effect on in vitro neutrophil function; it decreased neutrophil chemotaxis but increased neutrophil bactericidal activity for Staphylococcus aureus, as well as resting and zymosan-stimulated oxygen consumption. Other opioids (naloxone, met-enkephalin, and beta-endorphin) had no direct effect on neutrophil chemotaxis or bactericidal activity. Both naloxone and met-enkephalin increased neutrophil oxygen consumption in a dose-dependent fashion, whereas beta-endorphin impaired neutrophil oxygen consumption. None of the opioids altered resting lymphocyte blastogenesis. The only opioid that impaired the ability of normal lymphocytes to respond to mitogen stimulation at physiologically relevant doses was beta-endorphin. These results, documenting that beta-endorphin levels are altered after thermal injury and that opioids can modulate normal neutrophil and lymphocyte function in vitro, support the concept that changes in neuroendocrine activity may occur and potentially alter immune function.     

Exercise induced asthma and endogenous opioids.

Concentrations of endogenous opioid peptides in the plasma are increased during exercise and these substances have been implicated in the pathogenesis of asthma induced by chloropropramide and alcohol in diabetic patients. This work was undertaken to determine whether exercise induced asthma might be mediated by endogenous opioids. Plasma beta endorphin, met-enkephalin, and adrenocorticotrophic hormone (ACTH) concentrations were measured in five asthmatic patients and five normal volunteers breathing cold air during exercise. In four of the patients the effect of an infusion of naloxone on FEV1 was also measured during exercise induced asthma. Exercise produced acute bronchoconstriction in all asthmatics, characterised by a fall in FEV1; whereas no change occurred in normal subjects. There was no difference in plasma met-enkephalin, beta endorphin, and ACTH concentration between the two groups. Infusion of naloxone neither prevented nor worsened exercise induced asthma. These data suggest that endogenous opioids probably do not play a part in the development of exercise induced asthma.     

A system for psychomotor evaluation; design, implementation and practice effects in volunteers

This paper describes the design, implementation and assessment of PsychE, a psychomotor evaluation system. Six standard tests are included: numeric vigilance, a dual task, probed memory recall, simple reaction time, choice reaction time and semantic long-term memory. The test presentations are described in detail. Practice effects were assessed in 10 healthy volunteers and were only evident in the performance measures for the simple reaction time test. For the remaining five tests, stable performance was reached within a single test session. The volunteers were healthy and most were regular users of computers. Therefore, the lack of practice effects cannot be assumed for the general population. A control group is essential for all studies using these tests. The system is implemented on an IBM-compatible personal computer and includes a database shell for the convenient collection, storage and analysis of performance data.     

Better memory and neural efficiency in young apolipoprotein E epsilon4 carriers

The apolipoprotein E (APOE) epsilon4 allele is the major genetic risk factor for Alzheimer's disease, but an APOE effect on memory performance and memory-related neurophysiology in young, healthy subjects is unknown. We found an association of APOE epsilon4 with better episodic memory compared with APOE epsilon2 and epsilon3 in 340 young, healthy persons. Neuroimaging was performed in a subset of 34 memory-matched individuals to study genetic effects on memory-related brain activity independently of differential performance. E4 carriers decreased brain activity over 3 learning runs, whereas epsilon2 and epsilon3 carriers increased activity. This smaller neural investment of epsilon4 carriers into learning reappeared during retrieval: epsilon4 carriers exhibited reduced retrieval-related activity with equal retrieval performance. APOE isoforms had no differential effects on cognitive measures other than memory, brain volumes, and brain activity related to working memory. We suggest that APOE epsilon4 is associated with good episodic memory and an economic use of memory-related neural resources in young, healthy humans.     

Endocrinological changes following etomidate, midazolam, or methohexital for minor surgery

Etomidate is known to inhibit adrenocorticosteroid synthesis. The extent and duration of the effects of etomidate (63 +/- 6.4 mg) on spontaneous and stimulated corticosteroid levels, as well as on plasma concentrations of ACTH, beta-endorphin, and catecholamines were examined and compared to those following administration of the new benzodiazepine, midazolam, or of methohexital. Twenty-nine healthy, young, male orthopedic patients were randomized into three groups receiving either etomidate/fentanyl (n = 12), midazolam/fentanyl (n = 8), or methohexital/fentanyl (n = 9). Etomidate caused cortisol levels to decrease from 12.5 +/- 1.2 micrograms/dl preoperatively to 5.9 +/- 0.8 micrograms/dl after operation (P less than 0.001), compared to an increase from 12.0 +/- 1.9 micrograms/dl to 18.5 +/- 2.9 micrograms/dl in the group receiving methohexital. At 6 and 20 h postoperatively, all cortisol levels were normal. The cortisol decrease from 12.5 +/- 1.7 to 7.6 +/- 1.5 caused by midazolam was similar to that following etomidate, but the response to exogenous ACTH was significantly impaired in patients receiving etomidate as compared to those receiving midazolam. ACTH and beta-endorphin levels increased in patients receiving etomidate, presumably as a result of the interruption of negative feedback due to cortisol synthesis inhibition. Midazolam on the other hand prevented the increase of ACTH and beta-endorphin levels. Etomidate completely suppressed spontaneous aldosterone levels (from 33 +/- 6.7 to 7 +/- 2.1 pg/ml), as well as the response to stimulation with exogenous ACTH without affecting serum electrolytes. Etomidate had no influence on plasma catecholamines, but midazolam attenuated the stress-related epinephrine increase.     

Do opioid receptors participate in the regulation of atrial natriuretic peptide (ANP) secretion in hypertensive patients?

Experimental and clinical studies seem to prove that both endogenous opioids and atrial natriuretic peptide (ANP) are involved in blood pressure regulation. This raised the question, whether these two factors are functionally interrelated to each other. We tried to answer this question by assessing plasma ANP levels in 15 patients with II degrees essential hypertension and in 15 healthy subjects under water immersion (WI) conditions. In all subjects two WI tests were performed--one without pretreatment with naloxone, and a second one after blockade of opioid receptors by this opioid receptor antagonist. Parallel to ANP, plasma renin activity (PRA), aldosterone (ALD) and vasopressin (AVP) were assessed. In hypertensive patients significantly higher basal plasma ANP levels were found than in control subjects. WI induced a significant increase of plasma ANP in both examined groups which became markedly reduced after blockade of opioid receptors by naloxone. Naloxone did not influence the WI induced decrease of PRA, ALD and AVP respectively. From results presented in this study we conclude, that a.) opioid receptors seem to influence regulation of ANP secretion both in healthy normotensive subjects and patients with essential hypertension, and b.) that WI induced alterations of ANP on the one side and of PRA, ALD and AVP on the other side are not interrelated.     

Medial temporal lobe involvement in an implicit memory task: evidence of collaborating implicit and explicit memory systems from FMRI and Alzheimer's disease

We used a prototype extraction task to assess implicit learning of a meaningful novel visual category. Cortical activation was monitored in young adults with functional magnetic resonance imaging. We observed occipital deactivation at test consistent with perceptually based implicit learning, and lateral temporal cortex deactivation reflecting implicit acquisition of the category's semantic nature. Medial temporal lobe (MTL) activation during exposure and test suggested involvement of explicit memory as well. Behavioral performance of Alzheimer's disease (AD) patients and healthy seniors was also assessed, and AD performance was correlated with gray matter volume using voxel-based morphometry. AD patients showed learning, consistent with preserved implicit memory, and confirming that AD patients' implicit memory is not limited to abstract patterns. However, patients were somewhat impaired relative to healthy seniors. Occipital and lateral temporal cortical volume correlated with successful AD patient performance, and thus overlapped with young adults' areas of deactivation. Patients' severe MTL atrophy precluded involvement of this region. AD patients thus appear to engage a cortically based implicit memory mechanism, whereas their relative deficit on this task may reflect their MTL disease. These findings suggest that implicit and explicit memory systems collaborate in neurologically intact individuals performing an ostensibly implicit memory task.     

Estradiol and plasminogen activator secretion by cultured rat Sertoli cells in response to melanocyte-stimulating hormones

Pro-opiomelanocortin-derived peptides, alpha-MSH and beta-endorphin, are synthesized and secreted by Leydig cells, and are believed to have paracrine effects on Sertoli cells in the testis. Peptides with MSH activity stimulate adenylate cyclase and cAMP accumulation in Sertoli cell-enriched cultures. The purpose of the present study was to determine whether such peptides would affect Sertoli cell parameters, such as aromatase and plasminogen activator activities, that are known to be regulated by cAMP. alpha-MSH stimulated aromatase activity in Sertoli cell-enriched cultures prepared from 10-day-old rats and this effect was potentiated by methyl isobutylxanthine (MIX). The combination of alpha-MSH plus MIX was not as potent as FSH. alpha-MSH, des-acetyl-alpha-MSH, beta-MSH, ACTH(1-13), and ACTH(1-24) stimulated aromatase activity to a similar extent, suggesting that Sertoli cells do not distinguish between the activities of these peptides. alpha-MSH potentiated the action of dbcAMP and forskolin on Sertoli cell aromatase, but unexpectedly had no effect on the action of either half-maximal or maximal doses of FSH. The regulation of plasminogen activator was examined next; urokinase was markedly suppressed by FSH in 10-day-old Sertoli cells. Although neither alpha-MSH nor MIX alone had an effect on urokinase secretion, in combination they were as effective as FSH. In 10-day-old Sertoli cells each of these peptides had little or no effect on tissue plasminogen activator.(ABSTRACT TRUNCATED AT 250 WORDS)     

Abnormalities in the hypothalamic-pituitary-adrenocortical axis in patients with chronic renal failure

The recently described human corticotropin-releasing factor was administered to eight patients with chronic renal failure in order to assess hypothalamic-pituitary-adrenocortical (HPA) function. Acute administration of corticotropin-releasing factor lead to a diminished increase of the basally elevated levels of ACTH and beta-endorphin immunoreactivity in patients on chronic hemodialysis. Basal plasma cortisol concentration was normal in end-stage renal disease; however, considering the corresponding elevated ACTH concentrations, cortisol levels were inadequately low. Thus, the hypothalamus as well as the adrenal gland seems to contribute to the alterations in HPA function observed in patients with chronic renal failure; involvement of the pituitary gland and effects of metabolic alterations cannot be ruled out.     

Effects of total intravenous anesthesia with propofol on immuno-endocrine changes during surgical stress

Endocrine factors and cytokines are crucial to host responses to stress and infection. Because surgery is a major stressful condition, it is necessary to understand the influence of specific anesthetic procedures on immune-endocrine responses. The purpose of this study was to compare total intravenous anesthesia with propofol with conventional inhalational anesthesia on circulating cortisol, adrenocorticotropic hormone (ACTH), prolactin, alpha-melanocyte-stimulating hormone (αMSH), and the cytokine, interleukin-6 (IL-6) in healthy patients undergoing tubal ligation. The results show that circulating cortisol was significantly suppressed ous propofol completely abolished the response of circulating cortisol to surgery. Because ACTH responses to surgery were similar in the two groups, the inhibition likely occurred directly on the adrenal glands. This study is the first to report the effects of anesthesia on circulating αMSH, which was decreased significantly after induction with both anesthetic techniques and was still depressed at 90 min in the propofol patients. Other aspects of immune-endocrine responses to surgery were similar irrespective of anesthetic type, which further suggests a specific suppression of adrenal function by propofol.     

Arginine vasopressin in vasodilatory shock: effects on metabolism and beyond

PURPOSE OF REVIEW: To describe the effects of arginine vasopressin other than its vasoconstrictive and antidiuretic potential in vasodilatory shock. RECENT FINDINGS: Arginine vasopressin influences substrate metabolism by stimulation of hepatic glucose release, gluconeogenesis, ureogenesis and fatty acid esterification. Although arginine vasopressin is a secretagogue of different hormones, only prolactin increases during arginine vasopressin therapy. Plasmatic and cellular coagulation are affected by arginine vasopressin, resulting in thrombocyte aggregation. Therefore, platelet count typically decreases following arginine vasopressin infusion in critically ill patients. In addition, arginine vasopressin reduces bile flow and may increase bilirubin concentrations. Despite its potential to decrease serum sodium, no change in electrolytes was observed in critically ill patients receiving arginine vasopressin. Although arginine vasopressin is an endogenous antipyretic, body temperature is not decreased by central venous arginine vasopressin infusion. In addition, arginine vasopressin modulates immune function through V1 receptors. Compared with norepinephrine, arginine vasopressin may have protective effects on endothelial function. Net arginine vasopressin effects on gastrointestinal motility seem to be inhibitory and are dose dependent. SUMMARY: Except for its antidiuretic and vasoconstrictive actions, the effects of arginine vasopressin in patients with vasodilatory shock have so far only been partially examined. Potential influences of arginine vasopressin on metabolism and immune, liver and mitochondrial function remain to be assessed in future studies.     

Immunocytochemical localization of bioregulatory peptides in marmoset testes.

Immunocytochemical localization of neuropeptides (beta-endorphin, substance P, arginine vasopressin, oxytocin), pituitary hormones (adrenocorticotropin, prolactin, growth hormone, follicle stimulating hormone (FSH), gonadal inhibin, gastrin, and human chorionic gonadotrophin (hCG)) was carried out in marmoset testis during development. Both intensity of immunostaining and distribution of these peptides in testicular compartments viz. seminiferous tubules and Leydig cells changed dramatically during development. In vitro biosynthesis of inhibin and FSH was increased by hCG, whereas prolactin (5 micrograms) and prostatic inhibin peptide suppressed the synthesis of these hormones.     

Peripheral beta-endorphin and pain modulation.

Beta-endorphin is a peptide with morphine-like effects produced primarily in the anterior lobe of the pituitary gland. After its cleavage from the parent molecule, proopiomelanocortin, beta-endorphin is circulated via the blood stream to interact with specific opioid receptors located throughout the body. The peptide produces analgesia by inhibiting the firing of peripheral somatosensory fibers. It also affects other senses, such as vision, hearing, and smell. Whereas the ability to increase beta-endorphin secretion during times of surgical stress is positively correlated with amelioration of pain, the administration of exogenous opioids, such as fentanyl, reduces plasma beta-endorphin. Decreased beta-endorphin concentrations may play a role in trigeminal neuralgia, migraine headache, and rheumatoid arthritis.     

Hormonal and metabolic responses to cardiac surgery with sufentanil-oxygen anaesthesia

The effects of sufentanil, 10 and 20 micrograms kg-1 on the hormonal and metabolic responses to coronary artery surgery were compared in 20 patients. The most important finding was that the changes in circulating beta-endorphin, ACTH, cortisol, GH, glucose, lactate and glycerol concentrations during and after cardiac surgery were similar with both doses of sufentanil. Although sufentanil prevented a significant increase in plasma beta-endorphin, ACTH and cortisol values until 6 h after cardiopulmonary bypass (CPB), a significant increase in GH secretion occurred with the onset of CPB. Plasma insulin concentrations declined significantly after 30 min CPB, but recovered after 60 min CPB with the restoration of normothermia. Blood glucose values did not change during surgery before CPB, but started to rise with the onset of CPB and continued to increase significantly in the postoperative period. Changes in blood lactate and plasma glycerol concentrations primarily reflected the load of CPB and the effects of heparin, respectively. The results show that increasing the dose of sufentanil up to 20 micrograms kg-1 does not result in better suppression of the endocrine and metabolic changes associated with cardiac surgery.