Differential expression of calcium channels in sympathetic and parasympathetic preganglionic inputs to neurons in paracervical ganglia of guinea-pigs

Neurons in pelvic ganglia receive nicotinic excitatory post-synaptic potentials (EPSPs) from sacral preganglionic neurons via the pelvic nerve, lumbar preganglionic neurons via the hypogastric nerve or both. We tested the effect of a range of calcium channel antagonists on EPSPs evoked in paracervical ganglia of female guinea-pigs after pelvic or hypogastric nerve stimulation. omega-Conotoxin GVIA (CTX GVIA, 100 nM) or the novel N-type calcium channel antagonist, CTX CVID (100 nM) reduced the amplitude of EPSPs evoked after pelvic nerve stimulation by 50-75% but had no effect on EPSPs evoked by hypogastric nerve stimulation. Combined addition of CTX GVIA and CTX CVID was no more effective than either antagonist alone. EPSPs evoked by stimulating either nerve trunk were not inhibited by the P/Q calcium channel antagonist, omega-agatoxin IVA (100 nM), nor the L-type calcium channel antagonist, nifedipine (30 muM). SNX 482 (300 nM), an antagonist at some R-type calcium channels, inhibited EPSPs after hypogastric nerve stimulation by 20% but had little effect on EPSPs after pelvic nerve stimulation. Amiloride (100 muM) inhibited EPSPs after stimulation of either trunk by 40%, while nickel (100 muM) was ineffective. CTX GVIA or CTX CVID (100 nM) also slowed the rate of action potential repolarization and reduced afterhyperpolarization amplitude in paracervical neurons. Thus, release of transmitter from the terminals of sacral preganglionic neurons is largely dependent on calcium influx through N-type calcium channels, although an unknown calcium channel which is resistant to selective antagonists also contributes to release. Release of transmitter from lumbar preganglionic neurons does not require calcium entry through either conventional N-type calcium channels or the variant CTX CVID-sensitive N-type calcium channel and seems to be mediated largely by a novel calcium channel. (C) 2004 IBRO. Published by Elsevier Ltd. All rights reserved.

Reelin controls position of autonomic neurons in the spinal cord

Mutation of the reeler gene (Reln) disrupts neuronal migration in several brain regions and gives rise to functional deficits such as ataxic gait and trembling in the reeler mutant mouse. Thus, the Reln product, reelin, is thought to control cell–cell interactions critical for cell positioning in the brain. Although an abundance of reelin transcript is found in the embryonic spinal cord [Ikeda, Y. & Terashima, T. (1997) Dev. Dyn. 210, 157–172; Schiffmann, S. N., Bernier, B. & Goffinet, A. M. (1997) Eur. J. Neurosci. 9, 1055–1071], it is generally thought that neuronal migration in the spinal cord is not affected by reelin. Here, however, we show that migration of sympathetic preganglionic neurons in the spinal cord is affected by reelin. This study thus indicates that reelin affects neuronal migration outside of the brain. Moreover, the relationship between reelin and migrating preganglionic neurons suggests that reelin acts as a barrier to neuronal migration.

Segment-specific pattern of sympathetic preganglionic projections in the chicken embryo spinal cord is altered by retinoids

Sympathetic preganglionic neurons exhibit segment-specific projections. Preganglionic neurons located in rostral spinal segments project rostrally within the sympathetic chain, those located in caudal spinal segments project caudally, and those in midthoracic segments project either rostrally or caudally in segmentally graded proportions. Moreover, rostrally and caudally projecting preganglionic neurons are skewed toward the rostral and caudal regions, respectively, of each midthoracic segment. The mechanisms that establish these segment-specific projections are unknown. Here we show that experimental manipulation of retinoid signaling in the chicken embryo alters the segment-specific pattern of sympathetic preganglionic projections and that this effect is mediated by the somitic mesoderm. Application of exogenous retinoic acid to a single rostral thoracic somite decreases the number of rostrally projecting preganglionic neurons at that level. Conversely, disrupting endogenous synthesis of retinoic acid in a single caudal thoracic somite increases the number of rostrally projecting preganglionic neurons at that level. The number of caudally projecting neurons does not change in either case, indicating that the effect is specific for rostrally projecting preganglionic neurons. These results indicate that the sizes of the rostrally and caudally projecting populations may be independently regulated by different factors. Opposing gradients of such factors along the longitudinal axis of the thoracic region of the embryo could be sufficient, in combination, to determine the segment-specific identity of preganglionic projections.

Role of the spinal cord NO/cGMP pathway in the control of arterial pressure and heart rate

The modulatory effect of nitric oxide/cyclic guanosine monophosphate (NO/cGMP) pathway on sympathetic preganglionic neurons still deserves further investigation. The present study was designed to examine the role of the spinal cord NO/cGMP pathway in controlling mean arterial pressure and heart rate. We observed that intrathecal administration of the NO synthase inhibitor N omega-Nitro-L-arginine methyl ester hydrochloride (L-NAME) causes an increase in mean arterial pressure but does not affect heart rate. Intrathecal administration of the soluble guanylyl cyclase inhibitor 1H-[1,2,4] Oxadiazolo[4,3-a] quinoxalin-1-one (ODQ) does not change mean arterial pressure and heart rate. The precursor for NO synthesis, L-arginine, reduces both mean arterial pressure and heart rate while administration of ODQ before L-arginine impaired decreases in mean arterial pressure and heart rate. Administration of the N-methyl-D-aspartate (NMDA) receptor antagonist DL-2-amino-5-phosphonopentanoic acid (AP5) after L-NAME does not affect increases in mean arterial pressure promoted by NO synthase inhibition. Although the hypotensive and bradycardic responses induced by intrathecal administration of L-arginine depend on cGMP, our results indicate that NO acts to tonically inhibit SPNs, independent of either cGMP or NMDA receptors.

Increased sympathetic outflow in juvenile rats submitted to chronic intermittent hypoxia correlates with enhanced expiratory activity

Chronic intermittent hypoxia (CIH) in rats produces changes in the central regulation of cardiovascular and respiratory systems by unknown mechanisms. We hypothesized that CIH (6% O(2) for 40 s, every 9 min, 8 h day(-1)) for 10 days alters the central respiratory modulation of sympathetic activity. After CIH, awake rats (n = 14) exhibited higher levels of mean arterial pressure than controls (101 +/- 3 versus 89 +/- 3 mmHg, n = 15, P < 0.01). Recordings of phrenic, thoracic sympathetic, cervical vagus and abdominal nerves were performed in the in situ working heart-brainstem preparations of control and CIH juvenile rats. The data obtained in CIH rats revealed that: (i) abdominal (Abd) nerves exhibited an additional burst discharge in late expiration; (ii) thoracic sympathetic nerve activity (tSNA) was greater during late expiration than in controls (52 +/- 5 versus 40 +/- 3%; n = 11, P < 0.05; values expressed according to the maximal activity observed during inspiration and the noise level recorded at the end of each experiment), which was not dependent on peripheral chemoreceptors; (iii) the additional late expiratory activity in the Abd nerve correlated with the increased tSNA; (iv) the enhanced late expiratory activity in the Abd nerve unique to CIH rats was accompanied by reduced post-inspiratory activity in cervical vagus nerve compared to controls. The data indicate that CIH rats present an altered pattern of central sympathetic-respiratory coupling, with increased tSNA that correlates with enhanced late expiratory discharge in the Abd nerve. Thus, CIH alters the coupling between the central respiratory generator and sympathetic networks that may contribute to the induced hypertension in this experimental model.

Asymmetrical changes in lumbar sympathetic nerve activity following stimulation of the sciatic nerve in rat

Noxious stimulation of the leg increases hind limb blood flow (HBF) to the ipsilateral side and decreases to the contralateral in rat. Whether or not this asymmetrical response is due to direct control by sympathetic terminals or mediated by other factors such as local metabolism and hormones remains unclear. The aim of this study was to compare responses in lumbar sympathetic nerve activity, evoked by stimulation of the ipsilateral and contralateral sciatic nerve (SN). We also sought to determine the supraspinal mechanisms involved in the observed responses. In anesthetized and paralyzed rats, intermittent electrical stimulation (1 mA, 0.5 Hz) of the contralateral SN evoked a biphasic sympathoexcitation. Following ipsilateral SN stimulation, the response is preceded by an inhibitory potential with a latency of 50 ms (N=26). Both excitatory and inhibitory potentials are abolished following cervical Cl spinal transection (N=6) or bilateral microinjections of muscimol (N=6) in the rostral ventrolateral medulla (RVLM). This evidence is suggestive that both sympathetic potentials are supraspinally mediated in this nucleus. Blockade of RVLM glutamate receptors by microinjection of kynurenic acid (N=4) selectively abolished the excitatory potential elicited by ipsilateral SN stimulation. This study supports the physiological model that activation of hind limb nociceptors evokes a generalized sympathoexcitation, with the exception of the ipsilateral side where there is a withdrawal of sympathetic tone resulting in an increase in HBF. Crown Copyright (C) 2011 Published by Elsevier B.V. All rights reserved.

Neural reflex regulation of arterial pressure in pathophysiological conditions : interplay among the baroreflex, the cardiopulmonary reflexes and the chemoreflex

The maintenance of arterial pressure at levels adequate to perfuse the tissues is a basic requirement for the constancy of the internal environment and survival. The objective of the present review was to provide information about the basic reflex mechanisms that are responsible for the moment-to-moment regulation of the cardiovascular system. We demonstrate that this control is largely provided by the action of arterial and non-arterial reflexes that detect and correct changes in arterial pressure (baroreflex), blood volume or chemical composition (mechano- and chemosensitive cardiopulmonary reflexes), and changes in blood-gas composition (chemoreceptor reflex). The importance of the integration of these cardiovascular reflexes is well understood and it is clear that processing mainly occurs in the nucleus tractus solitarii, although the mechanism is poorly understood. There are several indications that the interactions of baroreflex, chemoreflex and Bezold-Jarisch reflex inputs, and the central nervous system control the activity of autonomic preganglionic neurons through parallel afferent and efferent pathways to achieve cardiovascular homeostasis. It is surprising that so little appears in the literature about the integration of these neural reflexes in cardiovascular function. Thus, our purpose was to review the interplay between peripheral neural reflex mechanisms of arterial blood pressure and blood volume regulation in physiological and pathophysiological states. Special emphasis is placed on the experimental model of arterial hypertension induced by N-nitro-L-arginine methyl ester (L-NAME) in which the interplay of these three reflexes is demonstrable.

Neural reflex regulation of arterial pressure in pathophysiological conditions: interplay among the baroreflex, the cardiopulmonary reflexes and the chemoreflex

The maintenance of arterial pressure at levels adequate to perfuse the tissues is a basic requirement for the constancy of the internal environment and survival. The objective of the present review was to provide information about the basic reflex mechanisms that are responsible for the moment-to-moment regulation of the cardiovascular system. We demonstrate that this control is largely provided by the action of arterial and non-arterial reflexes that detect and correct changes in arterial pressure (baroreflex), blood volume or chemical composition (mechano- and chemosensitive cardiopulmonary reflexes), and changes in blood-gas composition (chemoreceptor reflex). The importance of the integration of these cardiovascular reflexes is well understood and it is clear that processing mainly occurs in the nucleus tractus solitarii, although the mechanism is poorly understood. There are several indications that the interactions of baroreflex, chemoreflex and Bezold-Jarisch reflex inputs, and the central nervous system control the activity of autonomic preganglionic neurons through parallel afferent and efferent pathways to achieve cardiovascular homeostasis. It is surprising that so little appears in the literature about the integration of these neural reflexes in cardiovascular function. Thus, our purpose was to review the interplay between peripheral neural reflex mechanisms of arterial blood pressure and blood volume regulation in physiological and pathophysiological states. Special emphasis is placed on the experimental model of arterial hypertension induced by N-nitro-L-arginine methyl ester (L-NAME) in which the interplay of these three reflexes is demonstrable

Role of the caudal pressor area in the regulation of sympathetic vasomotor tone

It is well known that the ventrolateral medulla contains neurons involved in the tonic and reflex control of the cardiovascular system. Two regions within the ventrolateral medulla were initially identified: the rostral ventrolateral medulla (RVLM) and the caudal ventrolateral medulla (CVLM). Activation of the RVLM raises arterial blood pressure and sympathetic nerve activity, and activation of the CVLM causes opposite effects. The RVLM premotor neurons project directly to sympathetic preganglionic neurons and are involved in the maintenance of resting sympathetic vasomotor tone. A significant proportion of tonic activity in the RVLM sympathetic premotor neurons is driven by neurons located in a third region of the ventrolateral medulla denominated caudal pressor area (CPA). The CPA is a pressor region located at the extreme caudal part of the ventrolateral medulla that appears to have an important role controlling the activity of RVLM neurons. In this brief review, we will address the importance of the ventrolateral medulla neurons for the generation of resting sympathetic tone related to arterial blood pressure control focusing on two regions, the RVLM and the CPA.

Autonomic control of cardiorespiratory interactions in fish, amphibians and reptiles

Control of the heart rate and cardiorespiratory interactions (CRI) is predominantly parasympathetic in all jawed vertebrates, with the sympathetic nervous system having some influence in tetrapods. Respiratory sinus arrhythmia (RSA) has been described as a solely mammalian phenomenon but respiration-related beat-to-beat control of the heart has been described in fish and reptiles. Though they are both important, the relative roles of feed-forward central control and peripheral reflexes in generating CRI vary between groups of fishes and probably between other vertebrates. CRI may relate to two locations for the vagal preganglionic neurons (VPN) and in particular cardiac VPN in the brainstem. This has been described in representatives from all vertebrate groups, though the proportion in each location is variable. Air-breathing fishes, amphibians and reptiles breathe discontinuously and the onset of a bout of breathing is characteristically accompanied by an immediate increase in heart rate plus, in the latter two groups, a left-right shunting of blood through the pulmonary circuit. Both the increase in heart rate and opening of a sphincter on the pulmonary artery are due to withdrawal of vagal tone. An increase in heart rate following a meal in snakes is related to withdrawal of vagal tone plus a non-adrenergic-non-cholinergic effect that may be due to humoral factors released by the gut. Histamine is one candidate for this role.

Clonidina para el Tratamiento del Dolor Oncológico: una Revisión Sistemática de la Literatura

El dolor oncológico representa una de las principales causas de dolor crónico, siendo los opioides la primera línea de manejo, sin embargo 10% de los pacientes requieren estrategias analgésicas multimodales. La eficacia analgésica de la clonidina como coadyuvante ha sido demostrada para diversos modelos de dolor. Sin embargo no hay revisiones sistemáticas que validen su eficacia y seguridad en dolor crónico oncológico. Se realizó una revisión sistemática de la literatura a noviembre 26 de 2012, encontrando 15 trabajos (12 reportes de caso y tres ensayos clínicos controlados), n=138 pacientes. La intervención tuvo una eficacia entre 44,7 y 100%, mostrando mayor beneficio en pacientes con componente de dolor neuropático. La adición de clonidina fue bien tolerada, siendo la sedación y la disminución en tensión arterial y frecuencia cardiaca los efectos secundarios más frecuentes, con relación dosis dependiente, de resolución espontánea y en ninguno de los casos se documentó lesión secundaria en los pacientes. La vía de administración más frecuente fue neuroaxial (intratecal y peridural). La revisión sistemática no fue susceptible de metaanálisis por la heterogeneidad clínica de los estudios. Los resultados obtenidos sugieren que la adición de clonidina puede ser una opción terapeútica eficaz y segura en los pacientes con dolor crónico oncológico severo refractario a opioides a altas dosis asociado o no a infusión neuroaxial de anestésico local, en especial en presencia de componente neuropático. Sin embargo se identificó la necesidad de un mayor número de ensayos clínicos controlados aleatorios que permitan establecer conclusiones definitivas.

Ventrolateral medulla mechanisms involved in cardiorespiratory responses to central chemoreceptor activation in rats

A rise in arterial PCO(2) stimulates breathing and sympathetic activity to the heart and blood vessels. In the present study, we investigated the involvement of the retrotrapezoid nucleus (RTN) and glutamatergic mechanisms in the Botzinger/C1 region (Botz/C1) in these responses. Splanchnic sympathetic nerve discharge (sSND) and phrenic nerve discharge (PND) were recorded in urethane-anesthetized, sino-aortic-denervated, vagotomized, and artificially ventilated rats subjected to hypercapnia (end-expiratory CO(2) from 5% to 10%). Phrenic activity was absent at end-expiratory CO(2) of 4%, and strongly increased when end-expiratory CO(2) reached 10%. Hypercapnia also increased sSND by 103 +/- 7%. Bilateral injections of the GABA-A agonist muscimol (2 mM) into the RTN eliminated the PND and blunted the sSND activation (Delta = +56 +8%) elicited by hypercapnia. Injections of NMDA receptor antagonist AP-5 (100 mM), non-NMDA receptor antagonist 6,7-dinitro-quinoxaline-2,3-dione (DNQX; 100 mM) or metabotropic glutamate receptor antagonist (+/-)-alpha-methyl-4-carboxyphenylglycine (MCPG; 100 mM) bilaterally into the Botz/C1 reduced PND (Delta = +43 +/- 7%, +52 +/- 6% or +56 +/- 11%, respectively). MCPG also reduced sSND (Delta = +41 +/- 7%), whereas AP-5 and DNQX had no effect. In conclusion, the increase in sSND caused by hypercapnia depends on increased activity of the RTN and on metabotropic receptors in the Botz/C1, whereas PND depends on increased RTN activity and both ionotropic and metabotropic receptors in the Botz/C1.

AV3V lesions reduce the pressor response to L-glutamate into the RVLM

Neurons from the rostral ventrolateral medulla (RVLM) directly activate sympathetic preganglionic neurons in the spinal cord. Hypertensive responses and sympathetic activation produced by different stimuli are strongly affected by lesions of the preoptic periventricular tissue surrounding the anteroventral third ventricle (AV3V region). Therefore, in the present study, we investigated the effects of acute (1 day) and chronic (IS days) electrolytic lesions of the AV3V region on the pressor responses produced by injections of the excitatory amino acid L-glutamate into the RVLM of unanesthetized rats. Male Holtzman rats with sham or electrolytic AV3V lesions and a stainless steel cannula. implanted into the RVLM were used. The pressor responses produced by injections of L-glutamate (1, 5 and 10 nmol/100 nl) into the RVLM were reduced 1 day (9 +/- 4, 39 +/- 6 and 37 +/- 4 mm Hg, respectively) and 15 days after AV3V lesions (13 +/- 6, 39 +/- 4 and 43 +/- 4 mm Hg, respectively, vs. sham lesions: 29 +/- 3, 50 +/- 2 and 58 +/- 3 mm Hg, respectively). Injections of L-glutamate into the RVLM in sham or AV3V-lesioned rats produced no significant change in the heart rate (HR). Baroreflex bradycardia and tachycardia produced by iv phenylephrine or sodium nitroprusside, respectively, and the pressor and bradycardic responses to chemoreflex activation with iv potassium cyanide were not modified by AV3V lesions. The results suggest that signals from the AV3V region are important for sympathetic activation induced by L-glutamate into the RVLM. (c) 2006 Elsevier B.V. All rights reserved.

Autonomic control of cardiorespiratory interactions in fish, amphibians and reptiles

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Autonomic control of heart rate is virtually independent of temperature but seems related to the neuroanatomy of the efferent vagal supply to the heart in the bullfrog, Lithobathes catesbeianus

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)