Central Sympathetic System Research Articles

Central sympathetic network for thermoregulatory responses to psychological stress

In mammals, many types of psychological stressors elicit a variety of sympathoexcitatory responses paralleling the classic fight-or-flight response to a threat to survival, including increased body temperature via brown adipose tissue thermogenesis and cutaneous vasoconstriction, and increased skeletal muscle blood flow via tachycardia and visceral vasoconstriction. Although these responses are usually supportive for stress coping, aberrant sympathetic responses to stress can lead to clinical issues in psychosomatic medicine. Sympathetic stress responses are mediated mostly by sympathetic premotor drives from the rostral medullary raphe region (rMR) and partly by those from the rostral ventrolateral medulla (RVLM). Hypothalamomedullary descending pathways from the dorsomedial hypothalamus (DMH) to the rMR and RVLM mediate important, stress-driven sympathoexcitatory transmission to the premotor neurons to drive the thermal and cardiovascular responses. The DMH also likely sends an excitatory input to the paraventricular hypothalamic nucleus to stimulate stress hormone release. Neurons in the DMH receive a stress-related excitation from the dorsal peduncular cortex and dorsal tenia tecta (DP/DTT) in the ventromedial prefrontal cortex. By connecting the corticolimbic emotion circuit to the central sympathetic and somatic motor systems, the DP/DTT → DMH pathway plays as the primary mediator of the psychosomatic signaling that drives a variety of sympathetic and behavioral stress responses. These brain regions together with other stress-related regions constitute a central neural network for physiological stress responses. This network model is relevant to understanding the central mechanisms by which stress and emotions affect autonomic regulations of homeostasis and to developing new therapeutic strategies for various stress-related disorders.

Fetal Undernutrition Programming, Sympathetic Nerve Activity, and Arterial Hypertension Development.

A wealth of evidence showed that low birth weight is associated with environmental disruption during gestation, triggering embryotic or fetal adaptations and increasing the susceptibility of progeny to non-communicable diseases, including metabolic and cardiovascular diseases, obesity, and arterial hypertension. In addition, dietary disturbance during pregnancy in animal models has highlighted mechanisms that involve the genesis of arterial hypertension, particularly severe maternal low-protein intake (LP). Functional studies demonstrated that maternal low-protein intake leads to the renal decrease of sodium excretion and the dysfunction of the renin-angiotensin-aldosterone system signaling of LP offspring. The antinatriuretic effect is accentuated by a reduced number of nephron units and glomerulosclerosis, which are critical in establishing arterial hypertension phenotype. Also, in this way, studies have shown that the overactivity of the central and peripheral sympathetic nervous system occurs due to reduced sensory (afferent) renal nerve activity. As a result of this reciprocal and abnormal renorenal reflex, there is an enhanced tubule sodium proximal sodium reabsorption, which, at least in part, contributes directly to arterial hypertension development in some of the programmed models. A recent study has observed that significant changes in adrenal medulla secretion could be involved in the pathophysiological process of increasing blood pressure. Thus, this review aims to compile studies that link the central and peripheral sympathetic system activity mechanisms on water and salt handle and blood pressure control in the maternal protein-restricted offspring. Besides, these pathophysiological mechanisms mainly may involve the modulation of neurokinins and catecholamines pathways.

Cerebrospinal fluid 5-HIAA concentrations correlate with cardiac uptake of 123I-MIBG during myocardial scintigraphy in drug naïve Parkinson's disease.

We examined the correlations between cerebrospinal fluid (CSF) concentrations of homovanillic acid (HVA) and 5-hydroxyindole acetic acid (5-HIAA) and imaging assessment scores, using 123I-Ioflupane SPECT and 123I-MIBG myocardial scintigraphy in 23 drug naïve PD patients. The CSF 5-HIAA concentration correlated with the H/M ratio of the delayed image (r = 0.458, p < 0.05) and the washout rate (r = - 0.642, p < 0.01) of 123I-MIBG myocardial scintigraphy. These correlations suggest some unclarified pathophysiological links between the central serotonergic and cardiac sympathetic systems.

Neuropeptides in the posterodorsal medial amygdala modulate central cardiovascular reflex responses in awake male rats.

The rat posterodorsal medial amygdala (MePD) links emotionally charged sensory stimuli to social behavior, and is part of the supramedullary control of the cardiovascular system. We studied the effects of microinjections of neuroactive peptides markedly found in the MePD, namely oxytocin (OT, 10 ng and 25 pg; n=6/group), somatostatin (SST, 1 and 0.05 μM; n=8 and 5, respectively), and angiotensin II (Ang II, 50 pmol and 50 fmol; n=7/group), on basal cardiovascular activity and on baroreflex- and chemoreflex-mediated responses in awake adult male rats. Power spectral and symbolic analyses were applied to pulse interval and systolic arterial pressure series to identify centrally mediated sympathetic/parasympathetic components in the heart rate variability (HRV) and arterial pressure variability (APV). No microinjected substance affected basal parameters. On the other hand, compared with the control data (saline, 0.3 µL; n=7), OT (10 ng) decreased mean AP (MAP50) after baroreflex stimulation and increased both the mean AP response after chemoreflex activation and the high-frequency component of the HRV. OT (25 pg) increased overall HRV but did not affect any parameter of the symbolic analysis. SST (1 μM) decreased MAP50, and SST (0.05 μM) enhanced the sympathovagal cardiac index. Both doses of SST increased HRV and its low-frequency component. Ang II (50 pmol) increased HRV and reduced the two unlike variations pattern of the symbolic analysis (P<0.05 in all cases). These results demonstrate neuropeptidergic actions in the MePD for both the increase in the range of the cardiovascular reflex responses and the involvement of the central sympathetic and parasympathetic systems on HRV and APV.

Effects of renal denervation on the development of post-myocardial infarction heart failure and cardiac autonomic nervous system in rats

Prior studies indicated that radiofrequency renal denervation (RD)had beneficial effects on post-myocardial infarction (MI) heart failure(HF) in rats[1–3]. In this studywe aimedtoassessits effects on cardiacautonomic nervous system (CANS) which might be one of the mostimportant mechanisms of RD's therapeutic effect on post-MI HF anddetermine the best timing for RD.One hundred Wistar rats were randomly assigned intofiveexperimental groups: MI group (n = 20), RD group (n = 20),MI-1d + RD group (RD performed one day post-MI, n = 20),MI-4w + RD group (RD performed four weeks post-MI, n = 20),andNgroup(controlgroup, n = 20).MIwasproducedthroughligationof the anterior descending artery. RD was performed through strippingof the renal nerves. The experimental design and implementation wereconducted in accordance with animal welfare guidelines.Eight weeks post-MI, significant improvements were observed inboth MI-1d + RD and MI-4w + RD groups compared to the MIgroup, that include (1) improved left ventricular (LV) function andhemodynamics with increased water and sodium excretion;(2) decreased plasma and renal tissue norepinephrine levelswhile tissue norepinephrine content increased in myocardium;(3) increased β1-receptor in myocardium and improved heartratevariability;and(4)decreasedplasmarenin,angiotensinII,aldoste-rone,BNPandendothelinlevels.Moretherapeuticeffectswerefoundinthe MI-1d + RD group than the MI-4w + RD group (see Table 1 andFig. 1).Firstly, our study showed that RD attenuated the remodeling ofCANS and modulated its activities. RD leads to preservation of β1receptors content along with the β1 mRNA expression in non-infarcted cardiac tissue in this HF model (Fig. 1). This correlated withan improvement in heart function and cardiac remodeling. HRV is asensitive marker for the CANS [4]. RD led to a slower HR and higherSDNN in both intervention groups (See Table 1). The increase in SDNNindicates that cardiac sympathetic over-activation was suppressed andvagal activity was enhanced with the result of stabilizing cardiacelectrical activity, decreasing malignant arrhythmias, thereby reducingthe incidence of sudden death.Secondly, we found that RD blocked both peripheral and centralRAAS and sympathetic nervous system (SNS) at the same time. Andthis may answer the question how RD exerted effect on CANS. In ourstudy RD restores renin, angiotensin II, and aldosterone to near-normal levels. This not only explains the increase in sodium and waterexcretion, but also confirms that RD blocks renal RAAS via blockage ofthe efferent renal sympathetic nerves which is consistent with ourprevious study [2]. Studies have shown that angiotensin II not onlyactivates the central and peripheral SNS, function as part of a positivefeedback cycle between RAAS and the SNS, but also activates the localRAAS of other organs, notably the heart [5]. Our study also showedthat the plasma NE level in MI-1d + RD and MI-4w + RD groupsdecreased significantly, which reflects an overall reduction ofsympathetic activity, and especially represents reduction of centralsympathetic activity. This result maybe in part due to blockade of therenal sympathetic afferent pathway by RD. Furthermore, previousstudies have shown that during HF, the tissue NE levels of both theheart and kidney are decreased due to depletion, decreased reuptakeand increased spillover. The decrease of the tissue NE level causedfeedback activation of the central sympathetic system [6].Thus,increased tissue NE level may alleviate the activation of the centralsympathetic system, which was reflected by our data (Fig. 1).Many studies have shown that central RAAS stimulates the central

Sympathetic Activity in Dahl Salt-Sensitive Hypertension - Why is a Nitric Oxide-Induced Inhibitory System Up-Regulated in the Sympathetic Center?

In essential hypertension, peripheral sympathetic nerve activity is generally thought to be increased regardless of salt sensitivity or insensitivity. Recent reports suggest that the cause may be abnormal central nervous system enhancement. However, other several reports have shown that a central sympathetic inhibitory system, the neuronal nitric oxide synthase system, may be strongly enhanced in salt-sensitive hypertensive Dahl rats, an animal model of salt-sensitive hypertension. These two facts lead to questions what happens finally in peripheral sympathetic activity and what is the relationship between sympathetic nerves and hypertension. In this review, we will show evidences for enhancement of central sympathetic inhibitory system, putative cause for up-regulation of central neuronal nitric oxide synthase system, and a role of its function, then lastly we consider the relationship between hypertension and sympathetic nerves in a rat model, with a focus on salt-sensitive hypertension.

A peripherally administered, centrally acting angiotensin II AT 2 antagonist selectively increases brain AT 1 receptors and decreases brain tyrosine hydroxylase transcription, pituitary vasopressin and ACTH

The physiological actions of brain Angiotensin II AT 2 receptors and their relationship to Angiotensin II AT 1 receptors remain controversial. To further clarify their role, we determined to what extent systemic administration of an AT 2 receptor antagonist affected AT 2 receptor binding within the brain and the expression of AT 1 receptors. For this purpose, we subcutaneously administered the AT 2 receptor antagonist PD123319 (1 mg/kg/day) to adult male rats for two weeks via osmotic minipumps. We also studied the content of pituitary adrenocorticotropic hormone and vasopressin, representative of hypothalamic–pituitary–adrenal axis activation, and the tyrosine hydroxylase gene expression in the locus coeruleus as a measure of central norepinephrine function. We found significant decreases in AT 2 receptor binding in brain areas inside the blood brain barrier, the inferior olive and the locus coeruleus. AT 2 receptor blockade increased AT 1 receptor binding and mRNA expression not only in the subfornical organ and the median eminence, situated outside the blood brain barrier, but also in the hypothalamic paraventricular nucleus, located inside the blood brain barrier. These changes paralleled decreased expression of tyrosine hydroxylase mRNA in the locus coeruleus and decreased pituitary adrenocorticotropic and vasopressin content. Our results demonstrate that sustained peripheral administration of an AT 2 antagonist decreases binding to brain AT 2 receptors, indicating that this drug is a useful tool for the study of their central role. AT 2 receptor activity inhibition up-regulates AT 1 receptor expression in specific brain areas. Blockade of brain AT 2 receptors is compatible with enhanced hypothalamic–pituitary–adrenal axis and decreased central sympathetic system activity.

Salivary α-Amylase Levels after Yohimbine Challenge in Healthy Men

We and others have previously shown that standardized psychosocial stress significantly increases salivary alpha-amylase (sAA), but it remains unclear whether sAA reflects autonomic nervous system activation. The aim of this study was to assess cardiovascular effects and sAA and catecholamine secretion after iv injection of yohimbine. We conducted a randomized double-blind placebo-controlled study at an academic research unit. Thirteen healthy males (aged 20-28 yr) were examined. Participants received iv injection of yohimbine (0.4 microg/kg) or placebo (0.9% NaCl). Eight saliva and blood samples were taken before and after injection for the assessment of salivary flow rate and sAA and catecholamine concentrations. In addition, blood pressure, mood, and anxiety were assessed repeatedly. Yohimbine induced increases of sAA activity and output in comparison to placebo (P = 0.034). Blood pressure (P < 0.001), salivary flow rate (P = 0.007), and catecholamines (P < 0.001) were also significantly increased. No significant correlations between alpha-amylase parameters and catecholamines were observed. The results indicate that yohimbine administration activates not only autonomic parameters but also sAA via adrenergic mechanisms, suggesting that sAA might be an indirect indicator of the central sympathetic system.

Correspondence between the time course of cerebral vasospasm and the level of cerebral dopamine-β-hydroxylase in rabbits

The aim of the study was to explore whether the biphasic time course of the vasospastic response following experimental subarachnoid hemorrhage is associated with any concomitant changes in the amount of cerebral dopamine β-hydroxylase in the noradrenergic central nervous system. A single-hemorrhage animal model was used. Rabbits were sacrificed from day 1 to day 8 after subarachnoid hemorrhage. Intimal corrugation of the basilar artery and the amount of cerebral dopamine β-hydroxylase in the hypothalamus and brain stem were measured each day. Vasospastic changes occurred in the biphasic manner following subarachnoid hemorrhage. More profound vasospastic corrugation occurred in the acute phase, followed by a slightly less intense corrugation in the chronic phase (between days 5 and 8 after the subarachnoid hemorrhage). Simultaneously, a clear concomitant biphasic time course developed in the form of an increased amount of dopamine-β-hydroxylase in the noradrenergic nervous system of the rabbit hypothalamus and brain stem during the acute and chronic phases after the subarachnoid hemorrhage. Statistically significant correlation between basilar artery corrugation and the amount of dopamine β-hydroxylase was found. These results suggest the possible role of the central sympathetic system in the pathogenesis of vasospasm. At the same time, this study demonstrates the chronological similarity of the vasospastic development after subarachnoid hemorrhage in the animal experimental model with the human time course of vasospasm.

Thermography imaging during static and controlled thermoregulation in complex regional pain syndrome type 1: diagnostic value and involvement of the central sympathetic system

BackgroundComplex Regional Pain Syndrome type 1 (CRPS1) is a clinical diagnosis based on criteria describing symptoms of the disease.The main aim of the present study was to compare the sensitivity and specificity of calculation methods used to assess thermographic images (infrared imaging) obtained during temperature provocation. The secondary objective was to obtain information about the involvement of the sympathetic system in CRPS1.MethodsWe studied 12 patients in whom CRPS1 was diagnosed according to the criteria of Bruehl. High and low whole body cooling and warming induced and reduced sympathetic vasoconstrictor activity. The degree of vasoconstrictor activity in both hands was monitored using a videothermograph. The sensitivity and specificity of the calculation methods used to assess the thermographic images were calculated.ResultsThe temperature difference between the hands in the CRPS patients increases significantly when the sympathetic system is provoked. At both the maximum and minimum vasoconstriction no significant differences were found in fingertip temperatures between both hands.ConclusionThe majority of CRPS1 patients do not show maximal obtainable temperature differences between the involved and contralateral extremity at room temperature (static measurement). During cold and warm temperature challenges this temperature difference increases significantly. As a result a higher sensitivity and specificity could be achieved in the diagnosis of CRPS1. These findings suggest that the sympathetic efferent system is involved in CRPS1.

Modulated hemodynamic response to clonidine in bile duct-ligated rats: The role of nitric oxide

Despite the well-known involvement of the peripheral sympathetic abnormalities in the development of cardiovascular complications of cholestasis, the role of the central sympathetic system is still elusive. The goal of this study was to evaluate the effects of central sympathetic tone reduction, through clonidine administration, on hemodynamic parameters of 7-day bile duct-ligated rats. The contributions of nitric oxide and endogenous opioids were also examined by acute intravenous (10 min before clonidine) or chronic daily subcutaneous administrations of N(ω)-nitro- l-arginine methyl ester ( l-NAME, 3 mg/kg) or naltrexone (20 mg/kg). Seven days after bile duct ligation or sham operation, animals were anesthetized with sodium pentobarbital. After hemodynamic stabilization, clonidine (10 μg/kg) was injected intravenously, which elicited an initial hypertension (the peripheral effect) followed by persistent hypotension and bradycardia (the central effects). Cholestatic rats demonstrated significant basal bradycardia ( P < 0.001) and hypotension ( P < 0.05), which were corrected by chronic naltrexone but not l-NAME treatment. While the peripheral effect of clonidine was blunted, the central effects were exaggerated in cholestatic rats ( P < 0.01). Acute l-NAME treatment accentuated the hypertensive phase in sham-operated and cholestatic rats ( P < 0.05). However, the difference between the two groups was preserved ( P < 0.01). This treatment attenuated the central effects in both sham-operated and cholestatic rats to the same level ( P < 0.001). Chronic l-NAME treatment resulted in exaggeration of the peripheral response in cholestatic and central responses in sham-operated rats ( P < 0.05), and abolished the difference between the groups. Naltrexone treatment had no significant effect on either the central or the peripheral responses to clonidine. This study shows that both central and peripheral hemodynamic responses to clonidine are altered in cholestasis. It also provides evidence that nitric oxide contributes to the development of these abnormalities.

The HPA and immune axes in stress: The involvement of the serotonergic system

The impact of acute and chronic stress on the hypothalamic-pituitary-adrenal (HPA) axis is reviewed and evidence presented that corticotrophin releasing factor (CRF) is the stress neurotransmitter which plays an important role in the activation of the central sympathetic and serotonergic systems. The activity of CRF is expressed through specific receptors (CRF 1 and 2) that are antagonistic in their actions and widely distributed in the limbic regions of the brain, as well as in the hypothalamus, and on immune cells. The mechanism whereby chronic stress, via the CRF induced activation of the dorsal raphe nucleus, can induce a change in the serotonergic system, involves an increase in the 5HT2A and a decrease in the 5HT1A receptor mediated function. Such changes contribute to the onset of anxiety and depression. In addition, the hypersecretion of glucocorticoids that is associated with chronic stress and depression desensitises the central glucocorticoid receptors to the negative feedback inhibition of the HPA axis. This indirectly results in the further activation of the HPA axis. The rise in pro-inflammatory cytokines that usually accompanies the chronic stress response results in a further stimulation of the HPA axis thereby adding to the stress response. While CRF would appear to play a pivotal role, evidence is provided that simultaneous changes in the serotonergic and noradrenergic systems, combined with the activation of peripheral and central macrophages that increase the pro-inflammatory cytokine concentrations in the brain and blood, also play a critical role in predisposing to anxiety and depression. Neurodegenerative changes in the brain that frequently occur in the elderly patient with major depression, could result from the activation of indoleaminedioxygenase (IDO), a widely distributed enzyme that converts tryptophan via the kynenine pathway to for the neurotoxic end product quinolinic acid.

Angiotensin II AT1 receptor antagonists inhibit the angiotensin‐CRF‐AVP axis and are potentially useful for the treatment of stress‐related and mood disorders

AbstractThe corticotropin‐releasing factor (CRF), arginine‐vasopressin (AVP), atrial natriuretic peptide (ANP), and Angiotensin II (Ang II) interact, regulating the central sympathetic system, the hypothalamic‐pituitary‐adrenal (HPA) axis, and the central behavioral mechanisms involved in the response to stress and the development of mood disorders. Non‐peptidic, orally active AVP V1, V3, or CRF1 receptor antagonists reduce anxiety in animals. ANP is anxiolytic when administered to rodents and humans with anxiety disorders. These compounds are being developed for the therapy of anxiety and depression, but their clinical efficacy has not yet been established.Brain Ang II, a physiological ANP antagonist, promotes CRF and AVP release and stimulates the peripheral and central sympathetic systems. The degree of Ang II AT1 receptor stimulation determines the response to stress. An orally active, non‐peptidic Ang II AT1 receptor antagonist blocks CRF and AVP release during stress, prevents the sympathoadrenal and hormonal stress reaction, the cortical CRF1 and benzodiazepine receptor alterations, facilitates the effects of ANP, prevents stress‐induced gastric ulcerations, and is anxiolytic in rodents. CRF, AVP, ANP, and the sympathetic system are intimately linked parts of a fundamental regulatory mechanism controlled by the brain Ang II system through AT1 receptor stimulation, and should be studied together. Selective, safe antagonists of Ang II AT1 receptors, with central effects after oral administration, have been actively used for the treatment of hypertension and should be considered also as potential anti‐stress, anti‐anxiety, and antidepressant compounds with properties similar or superior to the CRF and AVP antagonists or the ANP agonists under development. Drug Dev. Res. 65:237–269, 2005. © Published 2005 Wiley‐Liss, Inc.

Brain neuronal nitric oxide synthase neuron-mediated sympathoinhibition is enhanced in hypertensive Dahl rats

To elucidate the role of central neurons containing neuronal nitric oxide synthase (nNOS neurons) in the sympathetic nervous system in hypertensive Dahl salt-sensitive (DS) rats. Dahl rats were fed either a regular-salt (0.4% NaCl) or high-salt (8% NaCl) diet for 4 weeks. The effect of intracerebroventricular administration of S-methyl-L-thiocitrulline, a selective nNOS inhibitor, on renal sympathetic nerve activity was examined in chronically instrumented conscious DS rats. The activity and protein amount of brain nNOS was evaluated by enzyme assay and western blot analysis. The distribution and number of nNOS neurons in the brainstem were examined immunohistochemically in hypertensive and normotensive DS rats. S-methyl-L-thiocitrulline induced a larger increase in tonic renal sympathetic nerve activity generated before baroreflex-mediated inhibition in hypertensive DS rats than normotensive DS rats. Hypertensive DS rats showed increased nNOS activity in the brainstem, but not in the diencephalon or cerebellum. High nNOS activity was confirmed by an increase in the amount of nNOS protein. nNOS Neurons were localized in several nuclei throughout the brainstem; the dorsolateral periaqueductal gray, pedunculopontine tegmental nucleus, dorsal raphe nucleus, laterodorsal tegmental nucleus, lateral parabrachial nucleus, rostral ventrolateral medulla, nucleus tractus solitarius and raphe magnus. The number of nNOS neurons in these nuclei, except for the two raphes, was significantly greater in hypertensive than in normotensive DS rats. These findings suggest that central nNOS-mediated sympathoinhibition may be enhanced in salt-sensitive hypertensive Dahl rats. The upregulated nNOS-mediated inhibition may occur in the central sympathetic control system generated before baroreflex-mediated inhibition.

Effects of centrally acting antihypertensive drugs on the microcirculation of spontaneously hypertensive rats.

We investigated the acute effects of centrally acting antihypertensive drugs on the microcirculation of pentobarbital-anesthetized spontaneously hypertensive rats (SHR). The effects of the sympatho-inhibitory agents clonidine and rilmenidine, known to activate both alpha2-adrenoceptors and nonadrenergic I1-imidazoline binding sites (I1BS) in the central nervous system, were compared to those of dicyclopropylmethyl-(4,5-dimethyl-4,5-dihydro-3H-pyrrol-2-yl)-amine hydrochloride (LNP 509), which selectively binds to the I1BS. Terminal mesenteric arterioles were observed by intravital microscopy. Activation of the central sympathetic system with L-glutamate (125 microg, ic) induced marked vasoconstriction of the mesenteric microcirculation (27 +/- 3%; N = 6, P < 0.05). In contrast, the marked hypotensive and bradycardic effects elicited by intracisternal injection of clonidine (1 microg), rilmenidine (7 microg) and LNP 509 (60 microg) were accompanied by significant increases in arteriolar diameter (12 +/- 1, 25 +/- 10 and 21 +/- 4%, respectively; N = 6, P < 0.05). The vasodilating effects of rilmenidine and LNP 509 were two-fold higher than those of clonidine, although they induced an identical hypotensive effect. Central sympathetic inhibition elicited by baclofen (1 microg, ic), a GABA B receptor agonist, also resulted in vasodilation of the SHR microvessels. The acute administration of clonidine, rilmenidine and LNP 509 also induced a significant decrease of cardiac output, whereas a decrease in systemic vascular resistance was observed only after rilmenidine and LNP 509. We conclude that the normalization of blood pressure in SHR induced by centrally acting antihypertensive agents is paralleled by important vasodilation of the mesenteric microcirculation. This effect is more pronounced with substances acting preferentially (rilmenidine) or exclusively (LNP 509) upon I1BS than with those presenting important alpha2-adrenergic activity (clonidine).

The Wake-Promoting Hypocretin–Orexin Neurons Are in an Intrinsic State of Membrane Depolarization

Wakefulness depends on the activity of hypocretin-orexin neurons because their lesion results in narcolepsy. How these neurons maintain their activity to promote wakefulness is not known. Here, by recording for the first time from hypocretin-orexin neurons and comparing their properties with those of neurons expressing melanin-concentrating hormone, we show that hypocretin-orexin neurons are in an intrinsic state of membrane depolarization that promotes their spontaneous activity. We propose that wakefulness and associated energy expenditure thus depend on that property, which allows the hypocretin-orexin neurons to maintain a tonic excitatory influence on the central arousal and peripheral sympathetic systems.

Stress, norepinephrine and depression.

Experimental and clinical evidence implicates stress as a major predisposing factor in depression and other severe psychiatric disorders. In this review, evidence is presented to show how the impact of stress on the central sympathetic system leads to changes in the endocrine, immune and neurotransmitter axes which underlie the main clinical symptoms of depression. Thus it can be shown that the noradrenergic system is dysfunctional in depression, a situation which reflects the chronic hypersecretion of glucocorticoids and inflammatory mediators within the brain in addition to an enhanced activity of the locus ceruleus. With regard to the actions of antidepressants in modulating the stress response and alleviating depression it is now evident that, irrespective of the presumed specificity of the antidepressants for the noradrenergic or serotonergic systems, they all normalize noradrenergic function. This action is due partly to the regulation of tyrosine hydroxylase activity in the locus ceruleus but also enhances neuronal sprouting which counteracts the neurodegenerative effects of chronic stress.

Factors explaining variance in perceived pain in women with fibromyalgia.

BackgroundWe hypothesized that a substantial proportion of the subjectively experienced variance in pain in fibromyalgia patients would be explained by psychological factors alone, but that a combined model, including neuroendocrine and autonomic factors, would give the most parsimonious explanation of variance in pain.MethodsPsychometric assessment included McGill Pain Questionnaire, General Health Questionnaire, Hospital Anxiety and Depression Rating Scale, Eysenck personality Inventory, Neuroticism and Lie subscales, Toronto Alexithymia Scale, and Multidimensional Health Locus of Control Scale and was performed in 42 female patients with fibromyalgia and 48 female age matched random sample population controls. A subgroup of the original sample (22 fibromyalgia patients and 13 controls) underwent a pharmacological challenge test with buspirone to assess autonomic and adrenocortical reactivity to serotonergic challenge.ResultsAlthough fibromyalgia patients scored high on neuroticism, anxiety, depression and general distress, only a minor part of variance in pain was explained by psychological factors alone. High pain score was associated with high neuroticism, low baseline cortisol level and small drop in systolic blood pressure after buspirone challenge test. This model explained 41.5% of total pain in fibromyalgia patients. In population controls, psychological factors alone were significant predictors for variance in pain.ConclusionFibromyalgia patients may have reduced reactivity in the central sympathetic system or perturbations in the sympathetic-parasympathetic balance. This study shows that a biopsychosocial model, including psychological factors as well as factors related to perturbations of the autonomic nervous system and hypothalamic-pituitary-adrenal axis, is needed to explain perceived pain in fibromyalgia patients.

Mineralocorticoids, salt and high blood pressure

Essential hypertensive patients often respond to treatments mitigating mineralocorticoid action, even though circulating levels of these steroids are within normal ranges. In addition to the kidney, mineralocorticoid or Type I receptors are found in the brain and vascular smooth muscle where they mediate effects associated with several forms of experimental hypertension. Studies in which discrete anatomic or functional areas of the brain have been ablated demonstrate that the periventricular areas of the hypothalamus and the central sympathetic and baroreceptor systems are crucial for the development of hypertension in the renoprival, DOCA salt, and Dahl salt-sensitive rat. Intracerebroventricular (icv) infusion of aldosterone in both rats and dogs at doses that do not raise serum levels above normal produce hypertension. The hypertension produced by systemic mineralocorticoid excess, adrenal regeneration, and icv or oral administration of glycyrrhetinic acid or carbenoxolone in genetically normotensive rats and by dietary salt in the Dahl salt-sensitive rat is inhibited by the icv infusion of a mineralocorticoid receptor antagonist or a Na + channel-selective amiloride analog. Recent data demonstrate the extraadrenal synthesis of steroids in aortic endothelial cells, smooth muscle cells and the brain. The role of the extraadrenal synthesis of steroids raises new avenues for research into the causes of hypertension.

Sympathetic skin response.

The sympathetic skin response (SSR) is the potential generated by sweat in response to different stimuli. This potential has a waveform that habituates with closely repeated stimuli and a latency of 1.3-1.5 s at the hand and 1.9-2.1 s at the foot. It has been used to study the peripheral sympathetic system in peripheral nerve diseases. The response is absent in many cases of peripheral neuropathy, often in the presence of autonomic symptoms. SSR has also been used to study a few diseases that may affect the central sympathetic system. This review outlines the history, physiopathogenesis, and analysis of SSR as well as general techniques used in its study. The reported association of SSR with peripheral and central nervous system diseases is also presented.