ANTEROVENTRAL WALL OF THE THIRD VENTRICLE AND DORSAL LAMINA TERMINALIS: HEADQUARTERS FOR CONTROL OF BODY FLUID HOMEOSTASIS?

1. The subfornical organ, median preoptic nucleus and the organum vasculosum of the lamina terminalis (OVLT) are a series of structures situated in the anterior wall of the third ventricle and form the lamina terminalis. The OVLT and ventral part of the median preoptic nucleus are part of a region known as the anteroventral third ventricle region.
2. Data from many laboratories, using techniques ranging from lesions, electrophysiology, neuropharmacology, Fos expression, immunohistochemistry and receptor localization, indicate that the tissue in the lamina terminalis plays a major role in many aspects of body fluid and electrolyte balance.
3. The subfornical organ and OVLT lack the blood-brain barrier and detect alterations in plasma tonicity and the concentrations of circulating hormones such as angiotensin II and possibly atrial natriuretic peptide and relaxin.
4. This information is then integrated within the lamina terminalis (probably in the median preoptic nucleus) with neural signals from other brain regions. The neural output from the lamina terminalis is distributed to a number of effector sites including the paraventricular (both parvo- and magno-cellular parts) and supraoptic nuclei and influences vasopressin secretion, water drinking, salt intake, renin secretion, renal sodium excretion and cardiovascular regulation.     

Circumventricular Organs: Gateways to the Brain Multisynaptic Neuronal Pathways From The Submandibular And Sublingual Glands To The Lamina Terminalis In The Rat: A Model For The Role Of The Lamina Terminalis In The Control Of Osmo- And Thermoregulatory Behaviour

1. The putative regulatory role of the lamina terminalis in the central control of salivation was investigated in the rat using the viral‐tracing technique and Fos‐immunohistochemistry. 2. Neurons situated in the lamina terminalis, such as the vascular organ of the lamina terminalis (OVLT), median preoptic nucleus (MnPO) and subfornical organ (SFO), were retrogradely labelled after pseudorabies virus injections into the submandibular or sublingual gland. 3. Viral tracing combined with glandular denervation showed that lamina terminalis structures sent efferents, in particular, to the parasympathetic side of submandibular gland innervation. 4. Saliva lost under heat stress has severe implications for the body fluid economy of rats and a key to the understanding of the central regulation of heat‐induced salivation may be the integrative role of the lamina terminalis processing thermoregulatory and osmoregulatory information.     

Thermoregulatory role of periventricular tissue surrounding the anteroventral third ventricle (AV3V) during acute heat stress in the rat

1. Thermoregulatory effector mechanisms are strongly influenced by hydration status. Dehydration delays the onset of evaporative heat loss and the redistribution of cardiac output in response to elevations in core temperature, yet very little is known about how and where thermal and non-thermal information is integrated. 2. The anteroventral third ventricular (AV3V) region encompasses several distinct neural structures, including the organum vasculosum of the lamina terminalis, the median preoptic nucleus, the preoptic periventricular nucleus and the medial aspects of the medial preoptic nucleus. In addition to its well-documented role in body fluid and cardiovascular homeostasis, recent anatomical and in vitro evidence has indicated the AV3V region may also be pivotal in the integration of thermal and osmotic information. 3. Electrolytic lesions of the AV3V region produce a markedly reduced thermal tolerance in rats. Elevations in mean arterial pressure, heart rate and mesenteric resistance were all attenuated in the AV3V-lesioned animals in response to a heat stress; however, hindquarter resistance was unaffected. Heat-induced salivation was also attenuated, severely reducing the ability of rats to lose heat via evaporation. 4. The AV3V region clearly has a functional role in thermoregulation, as well as cardiovascular and body fluid homeostasis. These data add further support to the hypothesis that thermal and non-thermal information may be integrated within this region.     

Circumventricular Organs: Gateways to the Brain Approaches For Gene Delivery To The Subfornical Organ And Magnocellular Neurons

1. The subfornical organ (SFO), the magnocellular neurons in supraoptic (SON) and paraventricular (PVN) nuclei and the neurohypophysis (NH) constitute an important neuroendocrine axis for the maintenance of cardiovascular and body fluid homeostasis in mammals. The SFO lacks a blood–brain barrier and is an important target for the effects of circulating angiotensin II on thirst. The SON and PVN, which receive projections from the SFO, synthesize the peptide vasopressin, which is stored in the NH nerve terminals and is released into the circulation under conditions of hypovolaemia and hyperosmolality. 2. Although neuropharmacological methods are still of fundamental importance for the understanding of the central nervous system (CNS), the techniques of gene transfer to the CNS that have been developed recently provide a new means to study and influence neural function. A key vector for delivering reporter or functional genes to the brain has been replication‐deficient adenovirus, because it is safer, can be generated in high titres, can transfect non‐dividing cells and can be retrogradely transported from nerve terminals to somata. 3. In the present review, we describe new approaches that have been developed to transfer genes to the SFO, SON, PVN and NH cells both in vitro and in vivo. We have defined the adenoviral concentrations required to optimize gene expression without causing cytotoxicity and an inflammatory response in the target cells. Gene transfer is an important tool to reveal mechanisms of SFO and SON control of cardiovascular homeostasis and may provide a therapeutic approach for prevention and/or treatment of pathophysiologies, such as arterial hypertension and genetic diabetes insipidus.     

BLOCKADE OF ANGIOTENSIN CONVERTING ENZYME IN CIRCUMVENTRICULAR ORGANS OF THE BRAIN AFTER ORAL LISINOPRIL ADMINISTRATION DEMONSTRATED BY QUANTITATIVE IN VITRO AUTORADIOGRAPHY

1. To elucidate the central effect of lisinopril, a new angiotensin converting enzyme (ACE) inhibitor, ACE localization and levels were followed in the brain of Sprague-Dawley rats by quantitative in vitro autoradiography after administration of the drug. 2. Following acute lisinopril (10 mg/kg p.o.) treatment, serum ACE activity was acutely reduced, but returned to normal by 24 h. 3. Levels of ACE in most parts of the brain, including the basal ganglia and choroid plexus of all ventricles were not affected by lisinopril. Lisinopril inhibited brain ACE in the subfornical organ and organum vasculosum of the lamina terminalis, circumventricular organs, where the blood brain barrier is deficient. These regions are rich in ACE and angiotensin II receptors, and are known targets for angiotensin II-induced effects on fluid, electrolyte and blood pressure homeostasis. 4. These observations indicate that quantitative in vitro autoradiography is a powerful method to study the access of drugs to the central nervous system. 5. This study shows that blood brain barrier plays an important role in limiting the penetration of lisinopril into the central nervous system. The circumventricular organs may be important targets for ACE inhibitors.     

Neural pathways from the lamina terminalis influencing cardiovascular and body fluid homeostasis

1. The lamina terminalis, a region of the brain with a high concentration of angiotensin AT1 receptors, consists of three distinct nuclei, the median preoptic nucleus, the subfornical organ and organum vasculosum of the lamina terminalis (OVLT). These latter two regions lack a blood-brain and detect changes in plasma angiotensin (Ang) II concentration and osmolality. 2. Efferent neural pathways from the lamina terminalis to the hypothalamic paraventricular and supraoptic nuclei mediate vasopressin secretion in response to plasma hypertonicity and increased circulating levels of AngII. 3. Studies using the neurotropic virus pseudorabies, which undergoes retrograde transynaptic neuronal transport following injection into peripheral sites, show that neurons in the lamina terminalis have efferent polysynaptic neural connections to the peripheral sympathetic nervous system. Some of these neurons have been shown to have polysynaptic connections to the kidney and to express AT1 receptor mRNA. We propose that circulating AngII acts at AT1 receptors in the subfornical organ and OVLT to influence the sympathetic nervous system. It is likely that the neural pathway subserving this influence involves a synapse in the hypothalamic paraventricular nucleus. 4. The lamina terminalis may exert an inhibitory osmoregulatory influence on renin secretion by the kidney. This osmoregulatory influence may be mediated by inhibition of renal sympathetic nerve activity and appears to involve a central angiotensinergic synapse. 5. The lamina terminalis exerts an osmoregulatory influence on renal sodium excretion that is independent of the renal nerves and is probably hormonally mediated.     

COMPARATIVE NEUROANATOMY OF ANGIOTENSIN II RECEPTOR LOCALIZATION IN THE MAMMALIAN HYPOTHALAMUS

1. The distribution of angiotensin II (AII) receptor binding sites in the hypothalamus of rat, rabbit, sheep and human was determined by in vitro autoradiography using 125I-[Sar1,Ile8]-AII as radioligand. 2. High receptor binding levels were observed in the continuum of tissue comprising the anterior wall of the third ventricle, including the subfornical organ, the median pre-optic nucleus and the organum vasculosum of the lamina terminalis. 3. High levels of binding sites were also found in the paraventricular and supra-optic nuclei, the median eminence and the arcuate nucleus. 4. These findings demonstrate sites in the hypothalamus of rat, rabbit, sheep and human where AII could exert its known actions on fluid and electrolyte balance, pituitary hormone release and cardiovascular function.     

ACTIONS OF ANGIOTENSIN IN THE SUBFORNICAL ORGAN AND AREA POSTREMA: IMPLICATIONS FOR LONG TERM CONTROL OF AUTONOMIC OUTPUT

1. Considerable physiological and anatomical evidence indicates that circulating angiotensin II (AngII), plays important roles in the long-term regulation of autonomic output as a result of actions in two circumventricular structures, the subfornical organ (SFO) and area postrema (AP). 2. Extracellular recordings have demonstrated excitatory actions of AngII on neurons from both of these structures which are ATi receptor mediated, maintained when cells are placed in synaptic isolation, and are dose dependent. Interestingly SFO neurons appear to be an order of magnitude more sensitive to AngII than those in AP. 3. Recent calcium imaging studies have demonstrated that AngII induces increases in intracellular calcium in both SFO and AP neurons. Whole cell patch recordings have also begun to provide important information suggesting that AngII actions may modulate voltage activated ion channels in these two structures to elicit its observed actions on circumventricular organs (CVO) neurons at the blood-brain interface. 4. Through these actions circulating AngII is thus able to influence efferent projections from these CVO which in turn influence the output of hypothalamic cells projecting to the posterior pituitary (vasopressin secretion), nucleus tractus soli-tarius (NTS), and intermediolateral cell column of the spinal cord (to influence sympathetic preganglionics), and medullary neurons in the NTS.     

Central osmoregulatory influences on thermoregulation

1. Many mammals maintain a constant core body temperature in the face of a heat load by using evaporative cooling responses, such as sweating, panting and spreading of saliva. These cooling mechanisms incur a body fluid deficit if the fluid lost as sweat, saliva or respiratory moisture is not replaced by the ingestion of water; body fluid hypertonicity and hypovolaemia result. 2. Evidence in several mammals shows that, as they become dehydrated, evaporative cooling mechanisms such as sweating and panting are inhibited so that further fluid loss from the body is reduced. As a result, core temperature in the dehydrated animal is maintained at a higher than normal level. 3. Increasing the osmotic pressure of plasma has an inhibitory effect on panting and sweating in mammals. It has been proposed that osmoreceptors mediate these inhibitory influences of plasma hypertonicity on sweating and panting. 4. The suppression of panting in dehydrated sheep is mediated by cerebral osmoreceptors that are probably located in the lamina terminalis. We speculate that osmoreceptors in the lamina terminalis may also influence thermoregulatory sweating. 5. When dehydrated animals drink water, sweating and panting resume rapidly before water has been absorbed from the gut. It is likely that the act of drinking initiates a reflex that can override the osmoreceptor inhibition of panting, resulting in core temperature falling back quickly to a normal level.     

Forebrain osmotic regulation of the sympathetic nervous system

1. Accumulating evidence in both humans and animals indicates that acute increases in plasma osmolality elevate sympathetic nerve activity (SNA). In addition, plasma hyperosmolality (or hypernatraemia) can produce sustained increases in SNA and arterial blood pressure (ABP) through stimulation of forebrain osmoreceptors. 2. Although an abundance of information exists regarding the osmoregulatory circuits for thirst and secretion of antidiuretic hormone, much less is known about those pathways and synaptic mechanisms linking osmotic perturbations and SNA. To date, the available evidence suggests that osmosensitive sites within the forebrain lamina terminalis, such as the organum vasculosum of the lamina terminalis, are key elements that link plasma hypertonicity to elevated SNA. 3. The major efferent target of osmosensitive regions in the forebrain lamina terminalis is the hypothalamic paraventricular nucleus (PVH). Evidence from a number of studies indicates that the PVH contributes to both acute and chronic osmotically driven increases in SNA. In turn, PVH neurons increase SNA through a direct vasopressinergic spinal pathway and/or a glutamatergic pathway to bulbospinal sympathetic neurons of the rostral ventrolateral medulla. 4. Future studies are needed to: (i) define the contribution of various osmosensitive regions of the forebrain lamina terminalis to acute and chronic osmotically driven increases in SNA; (ii) identify the cellular mechanisms and neural circuitry linking plasma osmolality and SNA; and (iii) define whether such mechanisms contribute to elevated SNA in salt-sensitive hypertension.     

TOWARD AN INTEGRATIVE APPROACH IN THE ANALYSIS OF DEPENDENCY PROBLEMS

This article takes some preliminary steps towards an integrated analysis of dependency problems e.g., long-term tranquillizer use, alcohol dependence, problematic use of narcotics. It argues for the need to outline important theoretical, epistemological, and methodological prerequisites in the analysis of the complex dynamic developmental processes involved in dependency problems. The dynamic process leading to dependence can be studied by the aid of an artificial science neural network approach in combination with a mixed method strategy including a clarification of a combination of different epistemological positions. It is intended that the empirical output of this complex strategy will provide a starting point for a new theoretical analysis which, in turn, will lead to new and more relevant input variables in the neural network approach that will help us to extend our knowledge of the dynamic processes leading to dependency. [Translations are provided in the International Abstracts Section of this issue.]     

Apelin in the control of body fluid homeostasis and cardiovascular functions

The discovery of apelin, an endogenous ligand of the orphan APJ receptor is an important advance for fundamental research and clinical medicine. Apelin and its receptor have a wide tissue distribution not only in the brain but also in peripheral organs including kidney, heart, vessels, and adipose tissue. Apelin is implicated in many physiological and pathophysiological processes such as the regulation of body fluid homeostasis, cardiovascular functions, glucose homeostasis, cell proliferation, and angiogenesis. This review focuses on, i) the various signaling cascades evoked upon stimulation of the apelin receptor by the different molecular forms of apelin found in vivo, ii) the distribution of apelin and its receptor in the brain and the cardiovascular system, iii) the opposing actions of vasopressin and apelin in the regulation of water balance at the central and kidney levels, and on the cardiovascular system regarding regulation of arterial blood pressure, vascular tone, and cardiac function.     

GABAergic modulation of the ANG II-induced drinking response in the rat medial preoptic nucleus

The present study was designed to examine the participation of gamma-aminobutyric acid (GABA) receptor mechanisms in the medial preoptic nucleus (MPO) in the drinking response caused by angiotensin II (ANG II) activation of the subfornical organ (SFO) in the awake rat. Local administration of ANG II (5 pmol, 50 nl) into the SFO elicited drinking. The water intake induced was significantly attenuated by previous injections (50 nl) into the MPO of the GABA(A) agonist muscimol (0.5, 5 and 50 pmol), but not by the GABA(B) agonist baclofen (0.5, 5 and 50 pmol) or vehicle, into the MPO. On the other hand, the ANG II-induced water intake was significantly enhanced by previous injections (50 nl) into the MPO of the GABA(A) antagonist bicuculline (0.5 and 5 pmol), but not the GABA(B) antagonist phaclofen (0.05, 0.5 and 5 pmol). Muscimol (50 nmol) injected into the MPO significantly reduced the water intake elicited by intracellular fluid depletion (i.e., hypertonic saline: 2 M, 2 ml/kg bw ip), whereas bicuculline (5 pmol) was without effect. These results show the involvement of the GABAergic system within the MPO in the dipsogenic responses induced by ANG II acting at the SFO and intracellular fluid depletion, and suggest that the system may serve to attenuate the ANG II-induced dipsogenic response through GABA(A) receptors.     

ROLE OF NITRIC OXIDE IN THE CONTROL OF THE RENAL MEDULLARY CIRCULATION

1. Nitric oxide (NO) has been implicated as an important controller in the short- and long-term regulation of arterial pressure. Studies performed in our laboratory have demonstrated that chronic intravenous administration of the NO synthase inhibitor N^G-nitro-L-arginine methyl ester (L-NAME) selectively decreases renal medullary blood flow, causes sodium and water retention and leads to hypertension. 2. To determine the importance of the renal medullary effects in this model of hypertension, further studies were conducted to examine the influence of selective stimulation or inhibition of renal medullary NO on whole kidney function and cardiovascular homeostasis. With the use of a unique catheter to directly infuse into the renal medullary interstitial space, stimulation (bradykinin or acetylcholine) or inhibition (L-NAME) of renal medullary NO selectively increased or decreased renal medullary blood flow. 3. The changes in medullary flow in these experiments were associated with parallel changes in sodium and water excretion independent of alterations in renal cortical blood flow or glomerular filtration rate. 4. Studies were then undertaken to examine the long-term effects of selective NO inhibition in the renal medulla on cardiovascular homeostasis. Chronic infusion of L-NAME directly into the renal medullary interstitial space of uninephrectomized Sprague-Dawley rats led to a selective decrease in renal medullary blood flow that was sustained throughout the 5 day L-NAME infusion period. The decrease in medullary blood flow was associated with retention of sodium and the development of hypertension and the effects were reversible. 5. The data reviewed indicate that NO in the renal medulla has a powerful influence on fluid and electrolyte homeostasis and the control of blood pressure.     

Low Non-NMDA Receptor Current Density as Possible Protection Mechanism from Neurotoxicity of Circulating Glutamate on Subfornical Organ Neurons in Rats

The subfornical organ (SFO) is one of circumventricular organs characterized by the lack of a normal blood brain barrier. The SFO neurons are exposed to circulating glutamate (60~100 µM), which may cause excitotoxicity in the central nervous system. However, it remains unclear how SFO neurons are protected from excitotoxicity caused by circulating glutamate. In this study, we compared the glutamate-induced whole cell currents in SFO neurons to those in hippocampal CA1 neurons using the patch clamp technique in brain slice. Glutamate (100 µM) induced an inward current in both SFO and hippocampal CA1 neurons. The density of glutamate-induced current in SFO neurons was significantly smaller than that in hippocampal CA1 neurons (0.55 vs. 2.07 pA/pF, p<0.05). To further identify the subtype of the glutamate receptors involved, the whole cell currents induced by selective agonists were then compared. The current densities induced by AMPA (0.45 pA/pF) and kainate (0.83 pA/pF), non-NMDA glutamate receptor agonists in SFO neurons were also smaller than those in hippocampal CA1 neurons (2.44 pA/pF for AMPA, p<0.05; 2.34 pA/pF for kainate, p< 0.05). However, the current density by NMDA in SFO neurons was not significantly different from that of hippocampal CA1 neurons (1.58 vs. 1.47 pA/pF, p>0.05). These results demonstrate that glutamate-mediated action through non-NMDA glutamate receptors in SFO neurons is smaller than that of hippocampal CA1 neurons, suggesting a possible protection mechanism from excitotoxicity by circulating glutamate in SFO neurons.     

Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: TRANSGENIC RATS: TOOLS TO STUDY THE FUNCTION OF THE RENIN-ANGIOTENSIN SYSTEM

• 1 The development of the transgenic technology for the rat allowed the evaluation of gene functions in the cardiovascular system in vivo. New insights have been gained particularly in the functions of the renin-angiotensin system (RAS), as most transgenic rat models established so far carry genes of this system.
• 2 TGR(mREN2)27 is a rat harbouring the mouse Ren-2 gene and exhibiting fulminant hypertension. The plasma RAS in this animal is down-regulated; however, the tissue-specific production of angiotensin II is activated (e.g. in the adrenal gland, the brain and the vessel wall). The physiological consequences of this activation, which finally leads to hypertension, can be studied in TGR(mREN2)27, rendering it a valuable tool in the functional analysis of tissue RAS.
• 3 TGR(hREN) and TGR(hAOGEN) carry the human genes for renin and angiotensinogen, respectively. In these animals the species-specific interaction of the two proteins and the expression pattern of the genes can be studied. Furthermore, these animals can be used to test renin-inhibitory drugs for use in antihypertensive therapy.
• 4 Further refinement of transgenic methodology (e.g. by the development of gene targeting in rats), should enhance our understanding of the functions of the RAS in cardiovascular regulation.

     

Highly activated c-fos expression in specific brain regions (ependyma, circumventricular organs, choroid plexus) of histidine decarboxylase deficient mice in response to formalin-induced acute pain

Activation of different brain regions for acute pain-related stress induced by a single subcutaneous injection of 4% formalin was investigated in histidine decarboxylase-deficient mice. Besides pain- and stress-related brain areas and the tuberomamillary neurons, strong Fos activation and c-fos mRNA expression were found in distinct brain regions and cell types, which have not been activated in wild type control mice. These structures include the circumventricular organs (organum vasculosum of the lamina terminalis, subfornical organ, area postrema), some of the ependymal cells along the wall of the ventricles, tanycytes in the third ventricle's ependyma and the median eminence, as well as in the epithelial cells of the choroid plexus in the lateral, third and fourth ventricles. All of these areas and cell types are known as compartments of the brain-blood-cerebrospinal fluid interface. The present observations provide strong evidence that an acute stressor, formalin-evoked painful stimulus elicits rapid alterations in the activity of neuroglial elements of histidine decarboxylase-deficient mice that are directly involved in the communication between the brain and the cerebrospinal fluid space.     

Cytochrome P450 2B (CYP2B)-mediated activation of methyl-parathion in rat brain extracts.

The role of cytochrome P450 (CYP) and the CYP isoform involved in the activation of the widely used pesticide methyl-parathion (MePA) were investigated in rat brain extracts by measuring the effect of different CYP inhibitors on acetylcholinesterase (AChE) inhibition by MePA. Brain extracts provide a useful tool to study the activation mechanisms of organophosphorus compounds (OP) since they contain both the activating enzyme(s) and the molecular target for OP toxicity. As expected, in incubations of rat brain extract supplemented with NADPH, AChE activity was non-competitively inhibited by the presence of MePA, indicating that MePA was activated to its reactive metabolite methyl-paraoxon (MePO). Indeed, Vmax(app) decreased from 13.4 to 8.7 micromol thionitrobenzoic acid (TNB)/min per mg protein. MePA activation by rat brain extracts, as measured by the AChE inhibition produced by the presence of the pesticide in the incubation, was fully prevented by previously bubbling the incubation mix with CO, by the presence of monoclonal anti-rat CYP2B1/2B2 antibodies and by the addition of phenobarbital (PB), a CYP2B substrate. Interestingly, MePA showed a greater affinity for CYP2B than PB. CYP1A1 antibodies showed no effect on MePA activation. The presence of cytochrome P450 2B (CYP2B) in the rat brain extracts was confirmed by immunoblotting. These results demonstrate indisputably the responsibility of CYP2B in MePA activation in the rat brain in vitro, suggesting that metabolic activation of OP compounds in situ might be crucial for their organ specific toxicity to the central nervous system also in vivo.     

REGIONAL BRAIN ACTIVATION IN HUMANS DURING RESPIRATORY AND BLOOD PRESSURE CHALLENGES

1. The aim of the present study was to determine the brain sites mediating aspects of respiratory and cardiovascular control in adult humans using non-invasive functional magnetic resonance (/MRI) procedures, thereby avoiding the spatial and temporal sampling limitations associated with classic neural assessment techniques. 2. We examined activity changes across the entire brain following application of respiratory loads and upon induction of blood pressure and heart rate alterations. Magnetic resonance signals were visualized with a 1.5Tesla scanner in healthy volunteers (22-52 years of age) using procedures that optimally assess changes in brain tissue microcirculation. Images were collected during a Valsalva manoeuvre, inspiratory loading, hypercapnia, cold pressor challenges to the hand and forehead and during intervening baseline states. 3. Image values from experimental conditions were compared with corresponding baseline values on a pixel-by-pixel basis to identify brain regions in which the experimental conditions produced physiological activation. 4. Ventilatory and pressor challenges elicited significant changes in regional image signal intensity in areas within the orbital cortex, amygdala, hypothalamus and hippocampus. Cerebellar, medullary and pontine areas were also recruited. However, while particular brain regions were only activated during specific stimuli, other regional signal changes occurred with multiple experimental manipulations. 5. The findings indicate that respiratory and cardiac challenges elicit discrete activity changes over multiple brain sites. Activated regions include structures not often related to respiratory or cardiovascular regulation, such as the cerebellum; a prominent role for limbic forebrain structures in mediating the response is also suggested. The f MRI visualization procedures may greatly assist in the determination of neural structures that mediate respiratory and cardiovascular control in humans.     

Effects of morphine on central catecholamine turnover,blood pressure and heart rate in the rat

Summary In the unanaesthetized rat morphine caused increased dopamine (DA) turnover, unchanged or possibly increased central noradrenaline (NA) turnover (utilization), hypertension and tachycardia. In the anaesthetized rat, brain DA turnover was not affected, whereas the NA-turnover was decelerated, particularly in some brain regions, e.g. cerebral cortex and medulla oblongata, and hypotension and bradycardia was obtained. Both biochemical and cardiovascular effects of morphine were antagonized by naloxone. A very small dose of morphine (1 mg/kg) caused tachycardia also in the anaesthetized rat. Decerebration just inferior to the inferior colliculus abolished the cardiovascular, excitatory effects of morphine in the conscious rat, but left the circulatory, depressant actions of the drug unchanged.The morphine-induced cardiovascular effects, particularly the hypotension and bradycardia in the anaesthetized animal, are suggested to be related to, or mediated by, the effects of the drug on brain NA-mechanisms, especially in view of several similarities between morphine and the antihypertensive -adrenergic agonist clonidine. Whereas higher brain structures appear important in the excitatory, circulatory effects of morphine, structures below the decerebration level, e.g. medulla oblongata, appear primarily involved in the hypotension and bradycardia obtained in the anaesthetized animal. Possibly, morphine has a diphasic dose-response curve with respect to cardiovascular function and, by inference, on brain noradrenergic mechanisms.