Muscimol dialysis in the rostral ventral medulla reduced the CO(2) response in awake and sleeping piglets.

Some victims of sudden infant death syndrome have arcuate nucleus abnormalities. The arcuate nucleus may be homologous with ventral medullary structures in the cat known to be involved in the control of breathing and the response to systemic hypercapnia. We refer to putative arcuate homologues in the piglet collectively as the rostral ventral medulla (RVM). We inhibited the RVM in awake and sleeping, chronically instrumented piglets by microdialysis of the GABA(A) receptor agonist muscimol. Muscimol dialysis (10 and 40 mM) had no effect on eupnea but caused a significant reduction in the response to hypercapnia during both wakefulness (34.8 +/- 8.7 and 30.7 +/- 10.1%, respectively) and sleep (36.7 +/- 6.7 and 49.5 +/- 8.9%, respectively). The effect of muscimol on the CO(2) response was entirely via a reduction in tidal volume and appeared to be greater during non-rapid-eye-movement sleep. We conclude that the piglet RVM contains neurons of importance in the response to systemic CO(2) during both wakefulness and non-rapid-eye-movement sleep. We hypothesize that dysfunction of homologous regions in the human infant could lead to impaired ability to respond to hypercapnia, particularly during sleep, which could potentially be involved in the pathogenesis of sudden infant death syndrome.     

Prolongation of the laryngeal chemoreflex after inhibition of the rostral ventral medulla in piglets: a role in SIDS?

We tested the hypothesis that inhibition of neurons within the rostral ventral medulla (RVM) would prolong the laryngeal chemoreflex (LCR), a putative stimulus in the sudden infant death syndrome (SIDS). We studied the LCR in 19 piglets, age 3-16 days, by injecting 0.05 ml of saline or water into the larynx during wakefulness, non-rapid eye movement (NREM) sleep, and REM sleep, before and after 1 or 10 mM muscimol dialysis in the RVM. Muscimol prolonged the LCR (P < 0.05), and the prolongation was greater when the LCR was stimulated with water compared with saline (P < 0.02). The LCR was longer during NREM sleep than during wakefulness and longest during REM sleep (REM compared with wakefulness). Muscimol had no effect on the likelihood of arousal from sleep after LCR stimulation. We conclude that the RVM provides a tonic facilitatory drive to ventilation that limits the duration of the LCR, and loss of this drive may contribute to the SIDS when combined with stimuli that inhibit respiration.     

Fluorescence location of RVLM kainate microinjections that alter the control of breathing

Kainic acid (4.7 mM) applied to the rostral ventrolateral medulla (RVLM) surface decreases phrenic output, CO2 sensitivity, and blood pressure in chloralose-urethan-anesthetized, vagotomized, paralyzed, glomectomized, servoventilated cats. In this study using the same preparation, bilateral 50- to 100-nl kainate injections just below the RVLM surface better localized these responses topographically. The physiological responses to unilateral 10-nl kainate injections were then correlated with anatomic location determined by fluorescent microbeads (0.5 micron diam). Many sites were associated with no effect, a few rostral and caudal sites with increased phrenic activity, and cluster of sites with decreased phrenic activity often to apnea, decreased CO2 sensitivity, and decreased responses to carotid sinus nerve stimulation. Blood pressure was unaffected. These sites, within 400 microns of the surface, were ventral to the facial nucleus, ventrolateral to the nucleus paragigantocellularis lateralis, caudal to the superior olive, and rostral to the retrofacial nucleus. They appeared to be within the recently described retrotrapezoid nucleus, which contains cells with respiratory-related activity and projections to the dorsal and ventral respiratory groups. Cells within this site appear able to provide tonic input to respiration and to affect peripheral and central chemoreception.     

Retrofacial lesions: effects on CO2-sensitive phrenic and sympathetic nerve activity.

We made unilateral chemical (10- or 50-nl microinjections; 4.7 mM kainic acid) or electrolytic (5-15 mA; 15 s) lesions in a region of the rostral ventrolateral medulla (VLM) caudal to the retrotrapezoid nucleus in 10 decerebrate, paralyzed, vagotomized, and servo-ventilated cats. The lesions were 3.0-4.2 mm lateral to the midline, within 2 mm caudal to the facial nucleus, and within 2.5 mm of the VLM surface. Four control injections (mock cerebrospinal fluid and fluorescent beads alone) produced small and inconsistent effects over 3-5 h. The predominant effect of the lesions was a significant decrease in baseline integrated phrenic nerve amplitude (PNA) (apnea in 2 cases), total respiratory cycle duration, and the response to increased CO2 (slope < 15% of control in 3 cases). The respiratory-related peak amplitude of the integrated sympathetic signal, blood pressure, and the sympathetic nerve activity response to CO2 were also decreased after the majority of lesions. Not all lesions produced all effects, and some lesions resulted in increased PNA and respiratory cycle duration. The lesioned region appears functionally to represent a caudal extension of the retrotrapezoid nucleus containing neurons necessary for normal baseline PNA and CO2 sensitivity. In addition, it contains neurons involved in the determination of resting respiratory frequency and normal sympathetic activity and blood pressure. The pattern of mixed responses among animals suggests that a heterogeneity of function is present within a relatively small VLM region.     

Preganglionic neurons of the sphenopalatine ganglia reside in the dorsal facial area of the medulla in cats

Stimulation of the sphenopalatine ganglion (SPG), a parasympathetic ganglion of the facial nerve, or the dorsal facial area (DFA), an area in the lateral tegmental field just dorsal to the facial nucleus, induces an increase in blood flow of the common carotid artery (CCA). This study attempted to clarify the anatomical and functional relationships between the SPG and the DFA, and to demonstrate putative serotonergic (5-HT) and substance P (SP) innervations to the neurons of the DFA in regulation of the CCA blood flow in cats. Horseradish peroxidase (HRP), a retrograde tracer, was injected in the SPG. All HRP-labeled neurons were distributed in the reticular areas dorsal and lateral to the superior olivary nucleus and the facial nucleus, extending from the caudal half of the superior olivary nucleus to the rostral 3/4 of the facial nucleus on the HRP-injected side. They were grouped into five clusters, namely lateral circumference of the superior olivary nucleus, dorsal circumference of the superior olivary nucleus, lateral circumference of the facial nucleus, dorsal circumference of the facial nucleus, and the DFA. The percentage of HRP-neurons in each cluster was 0.5 +/- 0.1% (mean +/- S.E., n=6), 15.2 +/- 1.9%, 23.7 +/- 0.9%, 52.5 +/- 1.7%, and 8.3 +/- 0.7%, respectively. Glutamate stimulation of the DFA (at 5.0 to 7.0 mm rostral to the obex, 2.8 to 4.0 mm lateral to the midline, and 2.5 to 3.5 mm ventral to the dorsal surface of the medulla), but not other areas, resulted in the increased CCA blood flow. The 5HT- and SP-immunoreactive nerve terminals abutted on the ChAT-immunoreactive cell body (preganglionic neurons) in the DFA. In conclusion, parasympathetic preganglionic neurons in the DFA project fibers to the SPG, are innervated by 5HT- and SP-like nerve terminals, and are responsible for regulation of the CCA blood flow. They may be also important in regulation of the cerebral blood flow.     

Glycine at hypoglossal motor nucleus: genioglossus activity, CO(2) responses, and the additive effects of GABA.

There is evidence for glycine and GABA(A)-receptor-mediated inhibition of hypoglossal motoneurons in vitro. However, comparable studies have not been performed in vivo, and the interactions of such mechanisms with integrative reflex respiratory control have also not been determined. This study tests the hypotheses that glycine at the hypoglossal motor nucleus (HMN) will suppress genioglossus (GG) muscle activity, even in the presence of hypercapnic respiratory stimulation, and the effects of glycine will be blocked by strychnine. We also determined whether coapplication of glycine and muscimol (GABA(A)- receptor agonist) to the HMN is additive in suppressing GG activity. Twenty-four urethane-anesthetized, tracheotomized, and vagotomized rats were studied. Diaphragm and GG activities, the electroencephalogram, and blood pressure were recorded. Microdialysis probes were implanted into the HMN for delivery of artificial cerebrospinal fluid (control), glycine (0.0001-10 mM), or muscimol (0.1 microM). Increasing glycine at the HMN produced graded suppression of GG activity (P < 0.001), although the GG still responded to stimulation with 7% inspired CO(2) (P = 0.002). Strychnine (0.1 mM) reversed the glycine-mediated suppression of GG activity, whereas combined glycine and muscimol were additive in GG muscle suppression. It remains to be determined whether the recruitment of such glycine and GABA mechanisms explains the periods of major GG suppression in behaviors such as rapid eye movement sleep.     

Drug-Induced Changes in Blood Pressure Lead to Changes in Extracellular Concentrations of Epinephrine, Dihydroxyphenylacetic Acid, and 5-Hydroxyindoleacetic Acid in the Rostral Ventrolateral Medulla of the Rat

Neurochemical changes in the extracellular fluid of the rostral ventrolateral medulla (RVLM) were produced by changes in arterial blood pressure. Blood pressure was raised or lowered with systemic infusions of phenylephrine or nitroprusside and neurochemicals were recovered from RVLM by in vivo microdialysis. A dialysis probe 300 microns in diameter and 500 microns in length was stereotaxically implanted in the RVLM of the urethane-anesthetized rat. Sterile physiological Ringer's solution was perfused at a rate of 1.5 microliter/min. The perfusate was collected under ice-cold conditions every 15 min for the assay of epinephrine, dihydroxyphenylacetic acid (DOPAC), 5-hydroxyindoleacetic acid (5-HIAA), ascorbic acid, and uric acid. After stable baseline neurochemical concentrations were achieved, animals were infused with phenylephrine or nitroprusside intravenously to raise or lower the blood pressure. Increasing blood pressure 50 mm Hg above the baseline value by phenylephrine led to a significant reduction in heart rate and a reduction in extracellular epinephrine and DOPAC concentrations. The 5-HIAA concentration was increased during the hypertensive drug infusion. There were no changes in the concentrations of ascorbic acid or uric acid. Hypotension produced by nitroprusside (-20 mm Hg) led to neurochemical changes which were the reciprocal of those seen during hypertension. During hypotension, heart rate increased as did the extracellular fluid epinephrine concentration. The 5-HIAA concentration fell with hypotension and remained depressed following the nitroprusside infusion. Ascorbic acid and uric acid concentrations did not change during hypotension but ascorbic acid did increase after the nitroprusside infusion stopped. These data provide direct evidence that epinephrine release in RVLM is linked to changes in systemic blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Paraventricular oxytocin neurons are involved in neural modulation of breathing.

In this study, we determined the projections of oxytocin-containing neurons of the paraventricular nucleus (PVN) to phrenic nuclei and to the rostral ventrolateral medullary (RVLM) region, which is known to be involved in respiratory rhythm generation. Studies were also designed to determine oxytocin-receptor expression within the RVLM and the physiological effects of their activation on respiratory drive and arterial blood pressure. Oxytocin immunohistochemistry combined with cholera toxin B, a retrograde tracer, showed that a subpopulation of oxytocin-containing parvocellular neurons in the dorsal and medial ventral regions of the PVN projects to phrenic nuclei. Similarly, a subpopulation of pseudorabies virus-labeled neurons in the PVN coexpressed oxytocin after injection of pseudorabies virus, a transynaptic retrograde marker, into the costal region of the diaphragm. A subpopulation of oxytocin expressing neurons was also found to project to the RVLM. Activation of this site by microinjection of oxytocin into the RVLM (0.2 nmol/200 nl) significantly increased diaphragm electromyographic activity and frequency discharge (P < 0.05). In addition, oxytocin increased blood pressure and heart rate (P < 0.05). These data indicate that oxytocin participates in the regulation of respiratory and cardiovascular activity, partly via projections to the RVLM and phrenic nuclei.     

Intramedullary projections of the rostral nucleus of the solitary tract in the rat: gustatory influences on autonomic output

The efferent connections of the rostral nucleus of the solitary tract (NTS) in the rat were studied by anterograde transport of Phaseolus vulgaris leucoagglutinin. Rostral to the injection site, fibers travel through the rostral parvocellular reticular formation and deflect medially or laterally around the motor trigeminal nucleus, giving off few terminals in these nuclei and terminate in the parabrachial nucleus. Moderate projections to the peritrigeminal zone, including the intertrigeminal nucleus and the dorsal subcoeruleus nucleus, were observed. Caudally to the injection site, dense innervations from the rostral nucleus of the solitary tract were detected in the parvocellular reticular formation ventral and caudal to the injection site and in the intermediate and ventral medullary reticular formation. The rostral central and ventral subdivisions of the NTS up to the level where the nucleus of the solitary tract abuts the fourth ventricle and the hypoglossal nucleus, receive moderate input from the rostral nucleus of the solitary tract. In general, the projections from the rostral nucleus of the solitary tract were bilateral with an ipsilateral predominance. The caudal part of the nucleus of the solitary tract, the dorsal motor nucleus of the vagus and the facial nucleus were not labeled. It is concluded that medullary rNTS projections participate in oral motor behavior and autonomic control of abdominal organs.     

刺激三叉神经核团各亚核引起呼吸效应的比较

实验家兔31只,在手术麻醉恢复后分别有对照地观察电流,谷氨酸钠,利多卡因作用于三叉神经起始核、终止核和脊束核的不同平面时对呼吸的影响。因兔的三叉神经脊束核呈纵向长条形,故对脊束核分别选其头端(A,2.3mm)中点(AP,0mm)和尾端(P,1.9mm)三个点刺激和观察。引导并记录膈神经放电及其积分曲线,呼出气CO_2分压曲线和血压曲线。用RM-6000型多道生理记录仪记录。 结果表明,电刺激和微量注射谷氨酸钠于脊束核和终止核,有明显加强呼吸的作用,但以同样的刺激作用于起始核,呼吸增强作用相对要小得多。微量注射利多卡因于起始核和终止核使呼吸减弱,但注射于脊束核,使呼吸加强,其原因有待进一步研究。本工作的结论是对三叉神经脊束核和终止核的刺激可以引起明显的呼吸改变。     

Two regions in the isolated brainstem of the frog that modulate respiratory-related activity

Using microinjection techniques, we have explored the isolated, complete midline sectioned brainstem of the frog (Rana catesbeiana) to identify regions that influence the endogenous respiratory-related motor activity. Ten-nanoliter injections of lidocaine (1%), GABA (100 mM) and glutamate (10 and 100 mM) into discrete regions of the rostral and the caudal brainstem produced different effects on the phasic neural discharge. In the rostral site lidocaine, GABA and glutamate injections altered neural burst frequency with little or no effect on burst amplitude. In the caudal site, responses to lidocaine and GABA injections consisted primarily of decreases in neural burst amplitude, often, but not always associated with minor decreases in burst frequency. In this same region, the response to glutamate was characterized by a temporary interruption of the rhythmic neural burst activity. The largest responses to substance injection in both regions were obtained at sites ranging between 200 and 500 m from the ventral surface, in the ventral medullary reticular formation. The results reveal the existence of two areas in the frog brainstem that influence respiratory motor output, one related to the respiratory burst frequency and the other related to the amplitude of the motor output.Abbreviations V trigeminal nerve - VI abducens nerve - VII facial nerve - VIII auditory nerve - X vagal nerve - H hypoglossal nerve - VRG ventral respiratory group - NTS nucleus of the solitary tract     

Cells of origin of the branches of the facial nerve: a retrograde HRP study in the rabbit

The origin of different branches of the facial nerve in the rabbit was determined by using retrograde transport of HRP. Either the proximal stump of specific nerves was exposed to HRP after transection, or an injection of the tracer was made into particular muscles innervated by a branch of the facial nerve. A clear somatotopic pattern was observed. Those branches which innervate the rostral facial musculature arise from cells located in the lateral and intermediate portions of the nuclear complex. Orbital musculature is supplied by neurons in the dorsal portion of the complex, with the more rostral orbital muscles receiving input from more laterally located cells while the caudal orbital region receives innervation from more medial regions of the dorsal facial nucleus. The rostral portion of the ear also receives innervation from cells located in the dorsomedial part of the nucleus, but the caudal aspect of the ear is supplied exclusively by cells located in medial regions. The cervical platysma, the platysma of the lower jaw, and the deep muscles (i.e., digastric and stylohyoid) receive input from cells topographically arranged in the middle and ventral portions of the nuclear complex. It is proposed that the topographic relationship between the facial nucleus and branches of the facial nerve reflects the embryological derivation of the facial muscles. Those muscles that develop from the embryonic sphincter colli profundus layer are innervated by lateral and dorsomedial portions of the nuclear complex. The muscles derived from the embryonic platysma layer, including the deep musculature, receive their input from mid to ventral regions of the nuclear complex.     

CCK—8、M—ENK免疫反应结构在猫延髓吻侧腹侧区的分布

用免疫组化 ABC 技术,观察了八肽缩胆囊素(CCK—8),甲硫氨酸脑啡肽(M—ENK)免疫反应(IR)结构在猫延髓吻侧腹侧区的分布。结果表明:CCK—8—IR 细胞分内、外两群:内侧群细胞分布于巨细胞网状核(NGc)、旁巨细胞外侧核(PGL)以及下橄榄核背外侧的网状结构,从吻侧向尾侧逐渐减少;外侧群细胞分布于外侧网状核(LRN)及其背内侧网状结构,从吻侧向尾侧逐渐增多。在中缝苍白核(Rpa)、中缝大核(Rm)仅见少量 CCK—8—IR 细胞。察见 CCK—8—IR纤维主要有3种:粗、细和终末前纤维。CCK—8—IR 纤维在面后核、疑核以及二核紧邻的网状结构最为密集;在 PGL 密度中等;在 NGc、LRN、Rpa 和 Rm 稀疏分布。M—ENK—IR 细胞和纤维分布于 Rpa、Rm、NGc、PGL 和 LRN,此外在面后核、疑核以及二核紧邻的网状结构可见较密集的纤维。     

Elevated body temperature enhances the laryngeal chemoreflex in decerebrate piglets.

Hyperthermia and reflex apnea may both contribute to sudden infant death syndrome (SIDS). Therefore, we investigated the effect of increased body temperature on the inhibition of breathing produced by water injected into the larynx, which elicits the laryngeal chemoreflex (LCR). We studied decerebrated, vagotomized, neonatal piglets aged 3-15 days. Blood pressure, end-tidal CO(2), body temperature, and phrenic nerve activity were recorded. To elicit the LCR, we infused 0.1 ml of distilled water through a polyethylene tube passed through the nose and positioned just rostral to the larynx. Three to five LCR trials were performed with the piglet at normal body temperature. The animal's core body temperature was raised by approximately 2.5 degrees C, and three to five LCR trials were performed before the animal was cooled, and three to five LCR trials were repeated. The respiratory inhibition associated with the LCR was substantially prolonged when body temperature was elevated. Thus elevated body temperature may contribute to the pathogenesis of SIDS by increasing the inhibitory effects of the LCR.     

Parabrachial neurons mediate dorsal periaqueductal gray evoked respiratory responses in the rat.

The neural substrates mediating autonomic components of the behavioral defense response reside in the periaqueductal gray (PAG). The cardiovascular components of the defense response evoked from the dorsal PAG (DPAG) have been well described and are dependent, in part, on the integrity of neurons in the region of the parabrachial nucleus as well as the rostral ventrolateral medulla. Descending pathways mediating the ventilatory response associated with activation of DPAG neurons are unknown. The present study was undertaken to test the hypothesis that parabrachial area neurons are also involved in mediating the respiratory response to DPAG stimulation. In urethane-anesthetized, spontaneously breathing rats, electrical stimulation of the DPAG significantly increased respiratory rate, arterial pressure, and heart rate. Changes in respiratory frequency were associated with significant decreases in inspiratory and expiratory durations. After bilateral inhibition of neurons in the lateral parabrachial nucleus (LPBN) region with 5 mM muscimol (n = 6), DPAG-evoked increases in respiration and heart rate were attenuated by 90 +/- 6 and 72 +/- 13%, respectively. The pressor response evoked by DPAG stimulation, however, was attenuated by only 57 +/- 6%. Bilateral blockade of glutamate receptors with 20 mM kynurenic acid (n = 6) in the LPBN also markedly attenuated DPAG-evoked increases in respiration and heart rate (65 +/- 15 and 53 +/- 9% reduction, respectively) but only modestly changed the DPAG-evoked pressor response (34 +/- 16% reduction). These results demonstrate that LPBN neurons play a significant role in the DPAG-mediated respiratory component of behavioral defense responses. This finding supports previous work demonstrating that the dorsolateral pons plays a significant role in mediating most physiological adjustments associated with activation of the DPAG.     

Eating-Induced Dopamine Release from Mesolimbic Neurons Is Mediated by NMDA Receptors in the Ventral Tegmental Area: A Dual-Probe Microdialysis Study

Abstract: This study was aimed at identifying the neuronal pathways that mediate the eating-induced increase in the release of dopamine in the nucleus accumbens of the rat brain. For that purpose, a microdialysis probe was implanted in the ventral tegmental area and a second probe was placed in the ipsilateral nucleus accumbens. Receptor-specific compounds acting on GABA_A (40 µ M muscimol; 50 µ M bicuculline), GABA_B (50 µ M baclofen), acetylcholine (50 µ M carbachol), NMDA [30 µ M (±)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP)], and non-NMDA [300 µ M 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)] receptors were infused into the ventral tegmental area by retrograde dialysis, whereas extracellular dopamine was recorded in the ipsilateral nucleus accumbens. Intrategmental infusion of muscimol or baclofen decreased extracellular dopamine in the ipsilateral nucleus accumbens; CPP and CNQX were without effect, and bicuculline and carbachol increased dopamine release. During infusion of the various compounds, food-deprived rats were allowed to eat for 10 min. The infusions of muscimol, bicuculline, baclofen, carbachol, and CNQX did not prevent the eating-induced increase in extracellular dopamine in the nucleus accumbens. However, during intrategmental infusion of CPP, the eating-induced increase in extracellular dopamine in the nucleus accumbens was suppressed. These results indicate that a glutamatergic projection to the ventral tegmental area mediates, via an NMDA receptor, the eating-induced increase in dopamine release from mesolimbic dopamine neurons.     

Descending pathways mediating cardiovascular response from dorsomedial hypothalamic nucleus

Physiological and anatomic methods were used to determine whether neurons in the rostral ventrolateral medulla (RVLM), nucleus tractus solitarius (NTS), or hypothalamic paraventricular nucleus (PVN) mediate the cardiovascular response evoked from the dorsomedial hypothalamic nucleus (DMH), which is believed to play a key role in mediating responses to stress. In urethane-anesthetized rats, activation of neurons in the DMH by microinjection of bicuculline resulted in a large increase in arterial pressure, heart rate, and renal sympathetic nerve activity. The pressor and sympathoexcitatory responses, but not the tachycardic response, were greatly reduced after bilateral muscimol injections into the RVLM even when baseline arterial pressure was maintained at a constant level. These responses were not reduced by muscimol injections into the PVN or NTS. Retrograde tracing experiments identified many neurons in the DMH that projected directly to the RVLM. The results indicate that the vasomotor and cardiac components of the response evoked from the DMH are mediated by pathways that are dependent and independent, respectively, of neurons in the RVLM.     

Effect of Endothelin on Vasomotor and Respiratory Neurons in the Rostral Ventrolateral Medulla in Rats

1. We have previously shown that intracisternal administration of endothelin-1 (ET-1) elicited cardiorespiratory responses acting on the ventral surface of the medulla oblongata (VSM) subjacent to the rostral ventrolateral medulla (RVLM). In this study, we examined whether vasomotor and respiratory neurons in RVLM participate in above-mentioned responses and whether those neurons respond to direct iontophoretic application of ET-1 and/or an ET-A receptor antagonist, FR139317.2. Unit activity of vasomotor, respiratory, or nociceptive neurons in RVLM was recorded together with arterial blood pressure (AP) and heart rate (HR) in urethane-anesthetized Sprague-Dawley rats.3. Intracisternal administration or topical application of ET-1 (0.1–1 pmol) to VSM caused excitation of the majority of vasomotor neurons (15/18) and respiratory neurons (10/11) but not in nociceptive neurons (0/7). Changes in neuronal activity were in similar time course with corresponding changes in AP and HR. Iontophoretic application of ET-1 to the vicinity of recording neuron caused excitation in 19 of 21 vasomotor neurons without affecting AP nor HR. Remaining two neurons were insensitive to ET-1. FR139317 did not affect basal activity of the vasomotor neurons but inhibited ET-1-evoked excitation. Twenty-four of 40 respiratory neurons were excited and 13 were inhibited by iontophoretic application of ET-1. Five of ET-1-excited respiratory neurons were inhibited by FR139317 alone while six of ET-1-inhibited neurons were not affected by FR139317 alone. In both cases, FR139317 inhibited the effect of simultaneously applied ET-1. Iontophoretic application of ET-1 excited only one out of 10 nociceptive neurons so far tested.4. These results support the view that intracisternally administered ET-1 alters activity of vasomotor and respiratory neurons in the RVLM, at least in part by acting directly on neurons themselves and hence causes systemic cardiorespiratory changes. Majority of vasomotor and respiratory neurons should express ET-A receptors and some respiratory neurons are under tonic excitatory control by ET-1.     

Role of the RVM in Descending Pain Regulation Originating from the Cerebrospinal Fluid-Contacting Nucleus

Evidence has suggested that cerebrospinal fluid-contacting nucleus (CSF-contacting nucleus) is correlated with the development and recurrence of pain. A recent research showed that the CSF-contacting nucleus acts as a component of the descending 5-hydroxytryptamine (5-HT) system and plays a role in descending pain inhibition. However, limited studies are conducted to investigate the relationship between the CSF-contacting nucleus and pain. In present study, we explored the effect of CSF-contacting nucleus on nociceptive behaviors in both normal and neuropathic rats via targeted ablation of the CSF-contacting nucleus in the brainstem, using cholera toxin subunit B-saporin (CB-SAP), a cytotoxin coupled to cholera toxin subunit B. The CB-SAP-treated rats showed aggravated thermal hyperalgesia and mechanical allodynia. Also, results from immunohistochemical experiments showed that rostral ventromedial medulla (RVM) received fiber projection from the CSF-contacting nucleus, which disappeared after ablation of the CSF-contacting nucleus, and the CB-SAP treated rats showed downregulation of c-Fos expression in the RVM as compared with the rats receiving i.c.v. injection of phosphate buffer saline (PBS). A significant downregulation of 5-HT-labeled neurons and tryptophan hydroxylase 2 (TPH2) as the marker of 5-HT cells in the RVM, and 5-HT expression in spinal dorsal horn in both normal and chronic constriction injury (CCI) rats after i.c.v. injection of CB-SAP was observed. These results suggested that RVM may be involved in descending pain modulation originating from the CSF-contacting nucleus.     

Cardiac and respiratory activity at arousal from sleep under controlled ventilation conditions.

Arousal from sleep is associated with elevated cardiac and respiratory activity. It is unclear whether this occurs because of homeostatic mechanisms or a reflex activation response associated with arousal. Cardiorespiratory activity was measured during spontaneous arousals from sleep in subjects breathing passively on a ventilator. Under such conditions, homeostatic mechanisms are eliminated. Ventilation, end-tidal PCO2, mask pressure, diaphragmatic electromyograph, heart rate, and blood pressure were measured in four normal subjects under two conditions: assisted ventilation and a normal ventilation control condition. In the control condition, there was a normal, sleep-related fall in ventilation and rise in end-tidal PCO2. Subsequently, at an arousal, there was an increase in respiratory and cardiac activity. In the ventilator condition, a vigorous cardiorespiratory response to a spontaneous arousal from sleep remained. These results indicate that sleep-related respiratory stimuli are not necessary for the occurrence of elevated cardiorespiratory activity at an arousal from sleep and are consistent with the hypothesis that such activity is at least in part due to a reflex activation response.