CNS effects of peripherally administered brain peptides.

Acceptance of enkephalins and endorphins into the family of brain peptides involves recognition that these endogenous opiates should share the general properties, including multiple and independent effects, previously described for neuropeptides. Several peptides first isolated by their pituitary-mediated endocrine effects, for example, are known to initiate CNS actions even in hypophysectomized animals. It was reasonable to expect, therefore, that the new opiate peptides would have effects not limited to the centrally induced analgesia by which they were originally identified, but, like the other brain peptides, would have additional CNS actions. Our concept that the multiple actions of peptides can be independent of each other is supported by evidence that even though peripheral administration of the brain opiates is essentially ineffective in producing analgesia, other actions of these peptides, such as changes in behavior, can be observed after administration by this route. Considerable evidence is accumulating in support of this concept of dissociation. The mechanisms by which the central effects of the peptides are exerted after systemic injection remain to be clarified, but analysis of their actions represents a new approach to understanding the performance of the brain. Studies already suggest a possible role of the brain peptides in the diagnosis and treatment of some mental and neurological disorders as well as in optimizing normal CNS functions.     

Endocannabinoids and liver disease. V. endocannabinoids as mediators of vascular and cardiac abnormalities in cirrhosis

Cirrhosis is associated with marked cardiovascular disturbances. These include hyperdynamic circulation characterized by reduced peripheral vascular resistance and mean arterial pressure and increased cardiac output. Despite the baseline increase in cardiac output, ventricular responsiveness to stimuli is blunted. A number of cellular signaling pathways have been shown to contribute to these abnormalities, including central nervous system cardiovascular dysregulation and humoral factors such as nitric oxide. Endogenous and exogenous cannabinoids have significant cardiovascular effects. Recent evidence suggests that increased activity of the endocannabinoid system at multiple levels contributes to development of both cardiac and vascular changes in cirrhosis. This brief review surveys recent in vivo and in vitro findings in an attempt to highlight the areas of agreement and areas of controversy in the field. The endocannabinoid system affects key cardiovascular regulators, including the autonomic nervous system, cardiac muscle, and vascular smooth muscle. The interplay among these modes of action further complicates interpretation of the in vivo findings. The broad range of cardiovascular actions of endocannabinoids provides ample opportunities for pharmacological manipulation. At the same time, it increases the possibility of undesirable side effects, which need to be carefully evaluated in long-term studies.     

Regulation of bone remodeling by the central and peripheral nervous system

The homeostatic nature of bone remodeling has become a notion further supported lately by the demonstration that neuropeptides and their receptors regulate osteoblast and osteoclast function in vivo. Following initial studies reporting the presence of nerves and nerve-derived products within the bone microenvironment and the expression of receptors for these neuropeptides in bone cells, new experimental and mechanistic evidence based on in vivo murine genetic and pharmacologic models recently demonstrated that inputs from the central and peripheral nervous system feed into the already complex regulatory machinery controlling bone remodeling. The function of a number of “osteo-neuromediators” has been characterized, including norepinephrine and the beta2-adrenergic receptor, Neuropeptide Y and the Y1 and Y2 receptors, endocannabinoids and the CB1 and CB2 receptors, as well as dopamine, serotonin and their receptors and transporters, Calcitonin gene-related peptide, and neuronal NOS. This new body of evidence suggests that neurons in the central nervous system integrate clues from the internal and external milieux, such as energy homeostasis, glycemia or reproductive signals, with the regulation of bone remodeling. The next major tasks in this new area of bone biology will be to understand, at the molecular level, the mechanisms by which common central neural systems regulate and integrate these major physiological functions, the relative importance of the central and peripheral actions of neuropeptides present in both compartments and their relationship, and how bone cells signal back to central centers, because the definition of a homeostatic function implies the existence of feedback signals. Together, these findings shed a new light on the complexity of the mechanisms regulating bone remodeling and uncovered new potential therapeutic strategies for the design of bone anabolic treatments. This review summarizes the latest advances in this area, focusing on investigations based on in vivo animal studies.     

The role of sensory neurons in cervical ripening: effects of estrogen and neuropeptides.

Central nervous system nuclei and circuits, such as the medial preoptic, ventromedial and paraventricular nuclei of the hypothalamus, play important roles in reproduction and parturition, and are influenced by estrogen. Peripheral autonomic and sensory neurons also play important roles in pregnancy and parturition. Moreover, the steroid hormone estrogen acts directly, not only on the reproductive tract organs (uterus and cervix), but also on the central and peripheral nerves by regulating expression of various neuronal genes. The peripheral primary afferent neurons innervating the uterine cervix relay mechanical and biochemical sensory information induced by local cervical events and by passage of fetuses, to the spinal cord and supraspinal centers. Consequently, the birth process in mammals is influenced by the combined action of neurons and hormones. Peripheral sensory stimuli, induced physiologically by fetal expulsion or mechanically by vaginocervical stimulation, alter behavior, as well as autonomic and neuroendocrine systems. Recent evidence indicates that primary afferent neurons innervating the cervix, in addition to their sensory effects, likely exert local "efferent" actions on the ripening cervix near term. These efferent effects may involve estrogen-regulated production of such neuropeptides as substance P and calcitonin gene-related peptide in lumbosacral dorsal root ganglia, and their release in the cervix. Collectively, these findings suggest an interrelationship among estrogen, cervix-related sensory neurons, and local cervical events near term.     

A Bond Graph Model of the Cardiovascular System

The study of the autonomic nervous system (ANS) function has shown to provide useful indicators for risk stratification and early detection on a variety of cardiovascular pathologies. However, data gathered during different tests of the ANS are difficult to analyse, mainly due to the complex mechanisms involved in the autonomic regulation of the cardiovascular system (CVS). Although model-based analysis of ANS data has been already proposed as a way to cope with this complexity, only a few models coupling the main elements involved have been presented in the literature. In this paper, a new model of the CVS, representing the ventricles, the circulatory system and the regulation of the CVS activity by the ANS, is presented. The models of the vascular system and the ventricular activity have been developed using the Bond Graph formalism, as it proposes a unified representation for all energetic domains, facilitating the integration of mechanic and hydraulic phenomena. In order to take into account the electro-mechanical behaviour of both ventricles, an electrophysiologic model of the cardiac action potential, represented by a set of ordinary differential equations, has been integrated. The short-term ANS regulation of heart rate, cardiac contractility and peripheral vasoconstriction is represented by means of continuous transfer functions. These models, represented in different continuous formalisms, are coupled by using a multi-formalism simulation library. Results are presented for two different autonomic tests, namely the Tilt Test and the Valsalva Manoeuvre, by comparing real and simulated signals.     

Epoxyeicosanoid signaling in CNS function and disease

Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites of cytochrome P450 epoxygenase enzymes recognized as key players in vascular function and disease, primarily attributed to their potent vasodilator, anti-inflammatory and pro-angiogenic effects. Although EETs’ actions in the central nervous system (CNS) appear to parallel those in peripheral tissue, accumulating evidence suggests that epoxyeicosanoid signaling plays different roles in neural tissue compared to peripheral tissue; roles that reflect distinct CNS functions, cellular makeup and intercellular relationships. This is exhibited at many levels including the expression of EETs-synthetic and -metabolic enzymes in central neurons and glial cells, EETs’ role in neuro-glio-vascular coupling during cortical functional activation, the capacity for interaction between epoxyeicosanoid and neuroactive endocannabinoid signaling pathways, and the regulation of neurohormone and neuropeptide release by endogenous EETs. The ability of several CNS cell types to produce and respond to EETs suggests that epoxyeicosanoid signaling is a key integrator of cell–cell communication in the CNS, coordinating cellular responses across different cell types. Under pathophysiological conditions, such as cerebral ischemia, EETs protect neurons, astroglia and vascular endothelium, thus preserving the integrity of cellular networks unique to and essential for proper CNS function. Recognition of EETs’ intimate involvement in CNS function in addition to their multi-cellular protective profile has inspired the development of therapeutic strategies against CNS diseases such as cerebral ischemia, tumors, and neural pain and inflammation that are based on targeting the cellular actions of EETs or their biosynthetic and metabolizing enzymes. Based upon the emerging importance of epoxyeicosanoids in cellular function and disease unique to neural systems, we propose that the actions of “neuroactive EETs” are best considered separately, and not in aggregate with all other peripheral EETs functions.     

Role of nitric oxide in central sympathetic outflow

The gaseous molecule nitric oxide (NO) plays an important role in cardiovascular homeostasis. It plays this role by its action on both the central and peripheral autonomic nervous systems. In this review, the central role of NO in the regulation of sympathetic outflow and subsequent cardiovascular control is examined. After a brief introduction concerning the location of NO synthase (NOS) containing neurons in the central nervous system (CNS), studies that demonstrate the central effect of NO by systemic administration of NO modulators will be presented. The central effects of NO as assessed by intracerebroventricular, intracisternal, or direct injection within the specific central areas is also discussed. Our studies demonstrating specific medullary and hypothalamic sites involved in sympathetic outflow are summarized. The review will be concluded with a discussion of the role of central NO mechanisms in the altered sympathetic outflow in disease states such as hypertension and heart failure.     

Evolutionary origin of autonomic regulation of physiological activities in vertebrate phyla

Proper regulation of physiological activities is crucial for homeostasis in animals. Autonomic regulation of these activities is most developed in mammals, in which a part of peripheral nervous system, termed the autonomic nervous system plays the dominant role. Circulatory activity and digestive activity in vertebrates change in opposite phases to each other. The stage where circulatory activity is high and digestive activity is low is termed the "fight or flight stage" while the stage where circulatory activity is low and digestive activity is high is termed the "rest and digest stage". It has been thought that the autonomic nervous system originated in early vertebrate phyla and developed to its greatest extent in mammals. In this study, we compared the pattern of change of circulatory and digestive activities in several invertebrates and found that the two stages seen in mammals are also present in a wide variety of animals, including evolutionarily early-diverging invertebrate taxa. From this and other arguments we propose a novel possibility that the basic properties of the autonomic nervous system were established very early in metazoan evolution.     

Autonomic actions of cocaine

The development of our knowledge of the physiological, pharmacological, and biochemical actions of cocaine has in essence occurred in parallel with the development of our knowledge about the function of the autonomic nervous system. Cocaine is a sympathomimetic compound with potent local anesthetic properties. The principal hypothesis accepted to date to explain the sympathomimetic effects of cocaine is that this drug inhibits neuronal monoamine neurotransmitter reuptake by binding to a transporter or uptake site thereby increasing the effective concentration of neurotransmitter at adrenergic receptor sites. Much of the available evidence for this hypothesis has come from studies utilizing in vitro or in situ techniques. There have been relatively fewer studies examining the impact of cocaine on the autonomic nervous system in the intact animal. In addition, few studies have examined the effects of cocaine on central autonomic function. Past studies concerning the mechanism of action of cocaine are reviewed and recent data addressing the cardiovascular, respiratory, and central autonomic effects of cocaine are discussed.     

Neural regulation of the cardiovascular system during exercise

Neural components important in control of the cardiovascular system during exercise can be divided into central nervous system (CNS) components and peripheral components. CNS components would include the cerebral cortex, cerebellum, medullary region of the brain stem, and the spinal cord. Peripheral components would include the efferent limbs of the autonomic nervous system and afferent fibers carrying information to the CNS. The neural pathways involved in the control of cardiovascular system during exercise and the relationship between the various neural components have been actively pursued in the last few years. Several new studies suggest that information arising from the active muscles and the cardiovascular system itself may be important in the control of the cardiovascular system during exercise. The cerebellum may play a modulating role in the cardiovascular response. The information from the peripheral afferent fibers, the cerebellum, and the cerebral cortex is integrated in the brain to result in overall neural control. Exercise training probably modifies the central integration of information and modifies the cardiovascular response to exercise and other stresses.     

Peptidergic inputs to sympathetic preganglionic neurons

This paper presents data showing that the sympathetic autonomic areas of the cat thoracolumbar spinal cord contain nerve terminals and fibres with immunoreactivity for at least seven neuropeptides. The distribution in the intermediolateral cell column of the terminals and fibres which contain enkephalin-, neuropeptide Y-, neurotensin-, substance P-, and neurophysin II-like immunoreactivity (ENK, NPY, NT, SP, and NP2, respectively) suggests that these peptides are involved in more generalized functions of the autonomic nervous system. On the other hand, peaks in density of immunoreactivity at certain levels suggest that different levels of influence of sympathetic preganglionic neurons by the various peptides may occur along the length of the thoracolumbar cord. The distribution of terminals and fibres containing somatostatin- and oxytocin-like immunoreactivity (SS and OXY) suggests that these peptides may be part of specific pathways to particular sympathetic preganglionic neurons. The possible sources of the terminals and fibres containing ENK, NPY, NT, SS, and SP include the spinal cord and supraspinal areas, whereas the source of these structures with OXY and NP2 is most likely supraspinal. The data suggest that coexistence of peptides and interactions between structures containing different neuropeptides occur in the spinal autonomic areas. It is speculated that neuropeptides have an important role to play in the regulation of the cardiovascular division of the autonomic nervous system.     

The potential use of cultured cells to detect non-neuronal targets of neuropeptide action

Although many studies have described the localization and possible neuromodulatory role of neuropeptides little attempt has been made to determine whether glial cells are possible targets of neuropeptides' actions. The use of primary cell cultures derived from neonatal rat central and peripheral nervous system may provide a means of assaying for such effects and gaining a better understanding of glial cells' roles in nervous system function.     

Properties of cardioinhibitory factors produced in shock.

The widespread occurrence of circulating cardioinhibitory factors in many types of circulatory shock and in a variety of mammalian species is impressive. This review summarizes the properties of the nine best-known factors with regard to their occurrence, chemical properties, sites of origin, biological actions, and pharmacological modification. Cardioinhibitory factors appear to play a significant role in the pathogenesis of circulatory shock. There now are pharmacological means available with which to prevent the formation of such factors. With knowledge on the chemistry of cardioinhibitory factors rapidly accumulating, it is anticipated that specific antagonists to the action of these factors will become available in the near future.     

Neurotrophin-3 as an essential signal for the developing nervous system

Rapid advances in characterization of the biological actions mediated by the third member of the neurotrophin family, neurotrophin-3 (NT-3), have been made recently in vitro as well asin situ. These have been made possible by the cloning of the genes for NT-3 and for its transducing receptor tyrosine kinase TrkC. This article will focus on the roles of NT-3 in the nervous system.In situ localization of NT-3 consistent with that of its receptor is manifested at all developmental stages studied and into adulthood. Through TrkC, NT-3 signals a number of trophic effects, ranging from mitogenesis, promotion of survival, or differentiation, depending on the developmental stage of the target cells. The sites of action of NT-3 reside primarily in the peripheral nervous system (PNS), various areas of the central nervous system (CNS), and in the enteric nervous system (ENS). Analyses of the phenotypes of transgenic mice lacking NT-3 or injection of embryos with a blocking antibody have so far revealed the essential role of NT-3 in development of specific populations of the PNS, and in particular of proprioceptive, nodose, and auditory sensory neurons and of sympathetic neurons. The actions of NT-3 also extend to modulation of transmitter release at several types of synapses in the periphery as well as in the adult CNS. In addition, NT-3 may play a role in the development of tissues other than the nervous system, such as the cardiovascular system. Future investigations will widen the understanding of the many roles of NT-3 on both neuronal and nonneuronal cells.     

Autonomic neuropathy in Fabry disease: a prospective study using the Autonomic Symptom Profile and cardiovascular autonomic function tests

Background  

Fabry patients have symptoms and signs compatible with autonomic dysfunction. These symptoms and signs are considered to be due to impairment of the peripheral nervous system, but findings indicative of autonomic neuropathy in other diseases, such as orthostatic intolerance and male sexual dysfunction, are infrequently reported in Fabry disease. The aim of our study was to investigate autonomic symptoms and cardiovascular autonomic function in a large cohort of male and female Fabry patients.     

Nicotinic mechanisms in the autonomic control of organ systems

Most visceral organs are under the control of the autonomic nervous system (ANS). Information on the state and function of these organs is constantly relayed to the central nervous system (CNS) by sensory afferent fibers. The CNS integrates the sensory inputs and sends neural commands back to the organ through the ANS. The autonomic ganglia are the final site for the integration of the message traveling from the CNS. Nicotinic acetylcholine receptors (nAChRs) are the main mediators of fast synaptic transmission in ganglia, and therefore, are key molecules for the processing of neural information in the ANS. This review focuses on the role of nAChRs in the control of organ systems such as heart, gut, and bladder. The autonomic control of these organ systems is discussed in the light of the results obtained from the analysis of mice carrying mutations targeted to nAChR subunits expressed in the ANS.     

Endogenous opiates: 1980

Vast amounts of research have been done that have attempted to delineate the pharmacological and physiological effects of the endogenous opiate peptides. A great deal of knowledge has also been accumulated in a limited time span concerning the types and locations of the opiate receptors and peptides, as well as their functions. In 1980, reports were made concerning the effects of these peptides on analgesia, on tolerance and dependence, on activity, on learning and memory, on schizophrenia and other types of emotional disturbances, and on physiological responses such as eating and drinking, cardiovascular responses, and sexual function. Additional understanding was also gained concerning their interactions with neurotransmitters, other neuropeptides, and hormones. These and other studies published only in 1980 are reviewed in this paper, which is the third of an annual series.     

Cardiovascular actions of l-cysteine and l-cysteine sulfinic acid in the nucleus tractus solitarius of the rat

The sulfur-containing excitatory amino acid (EAA) l-cysteine sulfinic acid (CSA), a neurotransmitter candidate, is endogenously synthesized from l-cysteine (Cys). Exogenous Cys administration into the brain produces cardiovascular effects; these effects likely occur via synaptic stimulation of central nervous system (CNS) neurons that regulate peripheral cardiovascular function. However, the cardiovascular responses produced by CNS Cys administration could result from CSA biosynthesized in synapse. The present study examined the role of CSA in Cys-induced cardiovascular responses within the nucleus tractus solitarius (NTS) of anesthetized rats. The NTS receives input from various visceral afferents that gate autonomic reflexes, including cardiovascular reflexes. Within the NTS, both Cys and CSA microinjections produced decrease responses in arterial blood pressure and heart rate that were similar to those produced by l-glutamate. Co-injection of the ionotropic EAA receptor antagonist kynurenic acid abolished Cys-, but not CSA-, induced cardiovascular responses. This finding suggests that only Cys-induced cardiovascular responses are mediated by kynurenate-sensitive receptors. This study provides the first demonstration that Cys- and CSA-induced cardiovascular responses occur via different mechanisms in the NTS of rats. Further, this study also indicates that Cys-induced cardiovascular responses do not occur via CSA. Thus, within the NTS, endogenous Cys and/or CSA might be involved in cardiovascular regulation.     

Flunarizine and verapamil: Effects on central nervous system and peripheral consequences of cytotoxic hypoxia in rats

Flunarizine is a calcium entry blocking drug possessing antihypoxic activity in animal models of cerebral and peripheral ischemia-anoxia and has clinical usefulness in circulatory disorders of both central and peripheral origin. This report compares the activity of flunarizine and verapamil, another calcium entry blocking drug, on the central nervous system (CNS) and peripheral consequences of cytotoxic hypoxia induced by high and low doses of KCN. The lethal effect of KCN (6 mg/kg, i.p.) in rats was prevented by orally administered flunarizine (ED₅₀ = 12 mg/kg with four-hr pretreatment) but not by verapamil (at oral doses up to 80 mg.kg with one-hr pretreatment). Since the lethal effect of KCN involves failure of respiration at the CNS level, these results suggest that flunarizine protects against the hypoxic effect of the cyanide ion by an action in brain tissue. We found also that the stimulant effect of low intravenous doses (0.5 mg/kg/min) of KCN upon respiration rate was not altered in pentobarbital- and chloralose-anesthetized rats treated with oral doses of flunarizine up to 80 mg/kg (with four hr pretreatment). In contrast, KCN-stimulated respiration rate in pentobarbital anesthetized rats was significantly attenuated by verapamil (20 and 40 mg/kg, p.o. with one hr pretreatment). Since low doses of the cyanide ion render respiration quicker and deeper by an action on chemoreceptive cells in peripheral arteries, the effect of verapamil against the hypoxic effect of KCN is mediated by an action in the periphery. In summary, we have shown that the physiological consequences of cytotoxic hypoxia can be affected by calcium entry blocking drugs having site-specific activities. Based on our results, flunarizine is more effective than verapamil against cellular anoxia involving the CNS.     

The effect of alpha-interferon, cyclosporine A, and radiation-induced immune suppression on morphine-induced hypothermia and tolerance

An interconnection between the immune and the central nervous systems has been suggested by investigators studying the actions of several types of immune modifying agents and procedures upon opiate related phenomena. These studies have included the effects of altering immune system function by administration of either alpha-interferon, cyclosporine or radiation exposure upon naloxone-precipitated opiate withdrawal and upon opioid antinociceptive effects. The present study extends these earlier investigations by examining the effect of immune modulation upon opiate induced hypothermia. The results demonstrate that interferon and cyclosporine have no effects on baseline temperature or morphine induced hypothermia, while irradiation exposure elicits hyperthermia without affecting morphine-induced hypothermia. Finally, neither cyclosporine nor irradiation affect the development of tolerance to morphine induced hypothermia, while a single injection of the immune system modifier interferon was able to prevent the development of such tolerance. These observations suggest that yet another opiate-related phenomenon may be regulated at least in part by the immune system. These results together with our previous findings are further evidence of a link between the immune system and the CNS mediated through the opioid system. In addition, these studies further support our earlier hypothesis that "Interferon" is one of the endogenous substances which serves to prevent the development of tolerance and dependence to endogenous opioids.