Responses of bulbospinal and laryngeal respiratory neurons to hypercapnia and hypoxia

The purpose was to evaluate activities of medullary respiratory neurons during equivalent changes in phrenic discharge resulting from hypercapnia and hypoxia. Decerebrate, cerebellectomized, paralyzed, and ventilated cats were used. Vagi were sectioned at left midcervical and right intrathoracic levels caudal to the origin of right recurrent laryngeal nerve. Activities of phrenic nerve and single respiratory neurons were monitored. Neurons exhibiting antidromic action potentials following stimulations of the spinal cord and recurrent laryngeal nerve were designated, respectively, bulbospinal or laryngeal. The remaining neurons were not antidromically activated. Hypercapnia caused significant augmentations of discharge frequencies for all neuronal groups. Many of these neurons had no change or declines of activity in hypoxia. We conclude that central chemoreceptor afferent influences are ubiquitous, but excitatory influences from carotid chemoreceptors are more limited in distribution among medullary respiratory neurons. Hypoxia will increase activities of neurons that receive sufficient excitatory peripheral chemoreceptor afferents to overcome direct depression by brain stem hypoxia. The possibility that responses of respiratory muscles to hypoxia are programmed within the medulla is discussed.     

Influence of respiratory network drive on phrenic motor output evoked by activation of cat pre-Botzinger complex

We have previously demonstrated that microinjection of dl-homocysteic acid (DLH), a glutamate analog, into the pre-B?tzinger complex (pre-B?tC) can produce either phasic or tonic excitation of phrenic nerve discharge during hyperoxic normocapnia. Breathing, however, is influenced by input from both central and peripheral chemoreceptor activation. This influence of increased respiratory network drive on pre-B?tC-induced modulation of phrenic motor output is unclear. Therefore, these experiments were designed to examine the effects of chemical stimulation of neurons (DLH; 10 mM; 10-20 nl) in the pre-B?tC during hyperoxic modulation of CO2 (i.e., hypercapnia and hypocapnia) and during normocapnic hypoxia in chloralose-anesthetized, vagotomized, mechanically ventilated cats. For these experiments, sites were selected in which unilateral microinjection of DLH into the pre-B?tC during baseline conditions of hyperoxic normocapnia [arterial PCO2 (PaCO2) = 37-43 mmHg; n = 22] produced a tonic (nonphasic) excitation of phrenic nerve discharge. During hypercapnia (PaCO2 = 59.7 +/- 2.8 mmHg; n = 17), similar microinjection produced excitation in which phasic respiratory bursts were superimposed on varying levels of tonic discharge. These DLH-induced phasic respiratory bursts had an increased frequency compared with the preinjection baseline frequency (P < 0.01). In contrast, during hypocapnia (PaCO2 = 29.4 +/- 1.5 mmHg; n = 11), microinjection of DLH produced nonphasic tonic excitation of phrenic nerve discharge that was less robust than the initial (normocapnic) response (i.e., decreased amplitude). During normocapnic hypoxia (PaCO2 = 38.5 +/- 3.7; arterial Po2 = 38.4 +/- 4.4; n = 8) microinjection of DLH produced phrenic excitation similar to that seen during hypercapnia (i.e., increased frequency of phasic respiratory bursts superimposed on tonic discharge). These findings demonstrate that phrenic motor activity evoked by chemical stimulation of the pre-B?tC is influenced by and integrates with modulation of respiratory network drive mediated by input from central and peripheral chemoreceptors.     

Characterization of respiratory-modulated activities of hypoglossal motoneurons

In decerebrate, vagotomized, paralyzed, and ventilated cats, activities of the phrenic nerve and single hypoglossal nerve fibers were monitored. The great majority of hypoglossal neuronal activities were inspiratory (I), discharging during a period approximating that of phrenic. Many were not active at normocapnia but were recruited in hypercapnia or hypoxia. Once recruited, discharge frequencies, which rose quickly to near maximal levels in early to midinspiration, significantly increased with further augmentations of drive. Also, the onset of activities became progressively earlier, compared with phrenic discharge, in hypercapnia or hypoxia. Smaller numbers of hypoglossal fiber activities, having inspiratory-expiratory (I-E), expiratory (E), expiratory-inspiratory (E-I), or tonic discharge patterns, were also recorded. Activities of E, I-E, and those I fibers that became I-E in high drive may underlie the early burst of expiratory activity of the hypoglossal nerve. It is concluded that the firing and recruitment patterns of hypoglossal neurons differ from those of phrenic motoneurons. However, responses to chemoreceptor stimuli are similar among the two neuronal groups.     

Respiratory-related hypoglossal nerve activity: influence of anesthetics

In decerebrate, vagotomized, paralyzed, and ventilated cats, phrenic and respiratory-related hypoglossal discharges were evident at normocapnic normoxia or hyperoxia. Both increased progressively in hypercapnia or hypoxia. With increasing drive, onset of inspiratory hypoglossal activity began earlier relative to phrenic onset; an early expiratory hypoglossal burst was also observed. Following subanesthetic doses of chloralose, halothane, ketamine, or pentobarbital, hypoglossal activity was depressed much more than phrenic discharge. In moderate hypercapnia or hypoxia, phrenic activity increased more than hypoglossal, whereas, at high drive, the latter rose more sharply in some cats. Electromyograms of the diaphragm and genioglossus were recorded in intact awake cats to determine if their responses and those of decerebrates are comparable. Respiratory-related genioglossal discharge was evident in normocapnia. We conclude that anesthesia suppresses hypoglossal motor activities much more than those of the bulbospinal-phrenic system. Data for decerebrate cats and unanesthetized cats or humans provide no evidence of a differential distribution of chemoreceptor afferents on hypoglossal and bulbospinal-phrenic neurons, as suggested by results in anesthetized animals.     

Hypoxic and hypercapnic drives to breathe generate equivalent levels of air hunger in humans.

Anecdotal observations suggest that hypoxia does not elicit dyspnea. An opposing view is that any stimulus to medullary respiratory centers generates dyspnea via "corollary discharge" to higher centers; absence of dyspnea during low inspired Po(2) may result from increased ventilation and hypocapnia. We hypothesized that, with fixed ventilation, hypoxia and hypercapnia generate equal dyspnea when matched by ventilatory drive. Steady-state levels of hypoxic normocapnia (end-tidal Po(2) = 60-40 Torr) and hypercapnic hyperoxia (end-tidal Pco(2) = 40-50 Torr) were induced in naive subjects when they were free breathing and during fixed mechanical ventilation. In a separate experiment, normocapnic hypoxia and normoxic hypercapnia, "matched" by ventilation in free-breathing trials, were presented to experienced subjects breathing with constrained rate and tidal volume. "Air hunger" was rated every 30 s on a visual analog scale. Air hunger-Pet(O(2)) curves rose sharply at Pet(O(2)) <50 Torr. Air hunger was not different between matched stimuli (P > 0.05). Hypercapnia had unpleasant nonrespiratory effects but was otherwise perceptually indistinguishable from hypoxia. We conclude that hypoxia and hypercapnia have equal potency for air hunger when matched by ventilatory drive. Air hunger may, therefore, arise via brain stem respiratory drive.     

Role of the carotid bodies in chemosensory ventilatory responses in the anesthetized mouse.

We examined the effects of carotid body denervation on ventilatory responses to normoxia (21% O2 in N2 for 240 s), hypoxic hypoxia (10 and 15% O2 in N2 for 90 and 120 s, respectively), and hyperoxic hypercapnia (5% CO2 in O2 for 240 s) in the spontaneously breathing urethane-anesthetized mouse. Respiratory measurements were made with a whole body, single-chamber plethysmograph before and after cutting both carotid sinus nerves. Baseline measurements in air showed that carotid body denervation was accompanied by lower minute ventilation with a reduction in respiratory frequency. On the basis of measurements with an open-circuit system, no significant differences in O2 consumption or CO2 production before and after chemodenervation were found. During both levels of hypoxia, animals with intact sinus nerves had increased respiratory frequency, tidal volume, and minute ventilation; however, after chemodenervation, animals experienced a drop in respiratory frequency and ventilatory depression. Tidal volume responses during 15% hypoxia were similar before and after carotid body denervation; during 10% hypoxia in chemodenervated animals, there was a sudden increase in tidal volume with an increase in the rate of inspiration, suggesting that gasping occurred. During hyperoxic hypercapnia, ventilatory responses were lower with a smaller tidal volume after chemodenervation than before. We conclude that the carotid bodies are essential for maintaining ventilation during eupnea, hypoxia, and hypercapnia in the anesthetized mouse.     

Posterior cricoarytenoid activity in normal adults during involuntary and voluntary hyperventilation

The effect of isocapnic hypoxia and hyperoxic hypercapnia on the electrical activity of the posterior cricoarytenoid (PCA) muscle was determined in eight normal adult humans by use of standard rebreathing techniques and was compared with PCA activity during voluntary hyperventilation performed under isocapnic and hypocapnic conditions. PCA activity was recorded with intramuscular hooked-wire electrodes implanted through a fiberoptic nasopharyngoscope. During quiet breathing in all subjects, the PCA was phasically active on inspiration and tonically active throughout the respiratory cycle. At comparable increments in respiratory output, hypercapnia, hypoxia, and voluntary hyperventilation appeared to be associated with similar increases in phasic or tonic PCA activity. During quiet breathing, the onset of phasic PCA activity usually occurred before inspiratory airflow and extended beyond the start of expiratory airflow. The duration of phasic PCA preactivation and postinspiratory phasic PCA activity remained unchanged during progressive hypercapnia and progressive hypoxia. The results, in combination with recent findings for vocal cord adductors, suggest that vocal cord position throughout the respiratory cycle during hyperpnea is actively controlled by simultaneously acting and antagonistic intrinsic laryngeal muscles.     

Respiratory activities of intralaryngeal branches of the recurrent laryngeal nerve

To distinguish experimentally between motor nerve activity destined for vocal cord abductor muscles and that bound for muscles that adduct the cords, we recorded efferent activities of intralaryngeal branches of the recurrent laryngeal nerve (RLN) in decerebrate, vagotomized, paralyzed, ventilated cats. Activities of the whole RLN and phrenic nerve were also recorded. Nerve activities were assessed at several steady-state end-tidal O2 and CO2 concentrations. The nerve to the thyroarytenoid (TA) muscle, a vocal cord adductor, was only slightly active under base-line (normocapnic, hyperoxic) conditions but in most cats developed strong activity during expiration in hypocapnia or hypoxia. In severe hypocapnia, phasic expiratory TA activity persisted even during phrenic apnea, indicating continuing activity of the respiratory rhythm generator. The nerve to the posterior cricoarytenoid (PCA) muscle, the vocal cord abductor, was always active in inspiration but often showed expiratory activity as well. This expiratory activity was usually enhanced by hypercapnia and often inhibited by hypoxia. The results are consistent with previous electromyographic findings and emphasize the importance of distinguishing abductor from adductor activity in studies of laryngeal control.     

Role of substance P in hypercapnic excitation of carotid chemoreceptors

Experiments were performed on 17 anesthetized, paralyzed, and artificially ventilated cats to evaluate the importance of substance P-like peptide (SP) on the carotid body responses to CO2. Single or paucifiber carotid chemoreceptor activity was recorded from the peripheral end of the cut carotid sinus nerve. In eight of the cats the influence of SP on hyperoxic hypercapnic responses was studied. While the animals breathed 100% O2, intracarotid infusion of SP (1 microgram.kg-1.min-1, 3 min) increased chemoreceptor activity by +4.8 +/- 0.3 impulses/s. After SP infusion, inhalation of CO2 in O2 caused a rapid increase in activity that reached a peak and then adapted to a lower level, whereas similar levels of CO2 before SP caused only a gradual increase in carotid body discharge rate without any overshoot in response. Furthermore SP significantly increased the magnitude and slope of the CO2 response. In the other nine cats the effect of intracarotid infusion of an SP antagonist, [D-Pro2,D-Trp7,9] SP (10-15 micrograms.kg-1.min-1), on carotid body responses to 1) hyperoxic hypercapnia (7% CO2-93% O2), 2) isocapnic hypoxia (11% O2-89% N2), and 3) hypoxic hypercapnia (11% O2-7% CO2-82% N2) was examined. SP antagonist had no effect on carotid body response to hyperoxic hypercapnia but significantly attenuated the chemoreceptor excitation caused by isocapnic hypoxia and hypoxic hypercapnia. These results suggest that 1) SP may play an important role in carotid body responses to hypoxia but not to CO2, and 2) the mechanisms of stimulation of the carotid body by hypercapnia and by hypoxia differ.     

Effects of antidromic activity in gustatory nerve fibers on taste disc cells of the frog tongue

Summary Antidromic electrical stimulation of the lingual branch of the glossopharyngeal (IX) nerve of the frog was carried out while recording intracellular potentials of taste disc cells.Antidromic activation of sensory fibers resulted in depolarization of cells of the upper layer of the disc and most commonly in hyperpolarization of the cells in the lower layer. These changes in potential exhibited latencies greater than 1 s (Fig. 3), and thus cannot be due to electrotonic effects of action potentials in terminals of IX nerve fibers, which have much shorter conduction times. These cell potentials also showed summation, adaptation and post-stimulus rebound (Figs. 3, 4).Depending upon the chemical stimulus used, antidromic activity produced either depression or enhancement of gustatory fiber discharge in response to taste stimuli (Fig. 5).Alteration of the resting membrane potential by current injection did not significantly modify the antidromically evoked potentials (Fig. 8), whereas chemical stimulation of the tongue did (Fig. 7), indicating that these potential changes are not the result of passive electrical processes.These experimental results indicate that the membrane potential of taste disc cells can be modified by antidromic activity in their afferent nerves. This mechanism may be responsible for peripheral interactions among gustatory units of the frog tongue.The research was supported in part by NIH grant NS-09168.     

Invited review: Neural network plasticity in respiratory control.

Respiratory network plasticity is a modification in respiratory control that persists longer than the stimuli that evoke it or that changes the behavior produced by the network. Different durations and patterns of hypoxia can induce different types of respiratory memories. Lateral pontine neurons are required for decreases in respiratory frequency that follow brief hypoxia. Changes in synchrony and firing rates of ventrolateral and midline medullary neurons may contribute to the long-term facilitation of breathing after brief intermittent hypoxia. Long-term changes in central respiratory motor control may occur after spinal cord injury, and the brain stem network implicated in the production of the respiratory rhythm could be reconfigured to produce the cough motor pattern. Preliminary analysis suggests that elements of brain stem respiratory neural networks respond differently to hypoxia and hypercapnia and interact with areas involved in cardiovascular control. Plasticity or alterations in these networks may contribute to the chronic upregulation of sympathetic nerve activity and hypertension in sleep apnea syndrome and may also be involved in sudden infant death syndrome.     

Arousal and cardiopulmonary responses to hyperoxic hypercapnia in lambs

Experiments were done to investigate the arousal and cardiopulmonary responses to hyperoxic hypercapnia in 8 lambs. Each lamb was anaesthetized and instrumented for recordings of electrocorticogram, electro-oculogram, nuchal and diaphragm electromyograms and measurements of arterial blood pressure and haemoglobin oxygen saturation. No sooner than 3 days after surgery, measurements were made in quiet sleep and active sleep during control periods when the animal was breathing 21% oxygen and during experimental periods of hyperoxic hypercapnia when the animal was breathing 10% carbon dioxide and 30% oxygen. Hyperoxic hypercapnia was terminated during each epoch by returning the inspired gas mixture to 21% oxygen once the animal aroused from sleep. Arousal occurred from both sleep states during hyperoxic hypercapnia but was delayed in active sleep compared to quiet sleep (active sleep 58 +/- 17 s; quiet sleep 21 +/- 10 s; mean +/- 1SD). There were no significant changes in heart rate or blood pressure during hyperoxic hypercapnia before arousal. However, respiratory rate and diaphragm electrical activity did increase during hyperoxic hypercapnia before arousal. Thus, our data provide evidence that hypercapnia can initiate arousal from sleep in young lambs. The mechanisms responsible for this response are yet to be determined.     

Differential responses of expiratory muscles to chemical stimuli in awake dogs

We assessed respiratory muscle response patterns to chemoreceptor stimuli (hypercapnia, hypoxia, normocapnic hypoxia, almitrine, and almitrine + CO2) in six awake dogs. Mean electromyogram (EMG) activities were measured in the crural (CR) diaphragm, triangularis sterni (TS), and transversus abdominis (TA). Hypercapnia and normocapnic hypoxia caused mild to marked hyperpnea [2-5 times control inspiratory flow (VI)] and increased activity in CR diaphragm, TS, and TA. When hypocapnia was permitted to develop during hypoxia and almitrine-induced moderate hyperpnea, CR diaphragm activity increased, whereas TS and TA activities usually did not change or were reduced below control. Over time in hypercapnia, CR diaphragm, TS, and TA were augmented and maintained at these levels over many minutes; with hypoxic hyperventilation CR diaphragm, TS, and TA were first augmented but then CR diaphragm remained augmented while TS and, less consistently, TA were inhibited over time. Marked hyperpnea (4-5 times control) due to carotid body stimulation increased TA and TS EMG activity despite an accompanying hypocapnia. We conclude that in the intact awake dog 1) carotid body stimulation augments the activity of both inspiratory and expiratory muscles; 2) hypocapnia overrides the augmenting effect of carotid body stimulation on expiratory muscles during moderate hyperpnea, usually resulting in either no change or inhibition; 3) at higher levels of hyperpnea both chemoreceptor stimulation and stimulatory effects secondary to a high ventilatory output favor expiratory muscle activation; these effects override any inhibitory effects of a coincident hypocapnia; and 4) expiratory muscles of the rib cage/abdomen may be augmented/inhibited independently of one another.     

Effects of hypoxia and hypercapnia on geniohyoid contractility and endurance

Sleep apnea and other respiratory diseases produce hypoxemia and hypercapnia, factors that adversely affect skeletal muscle performance. To examine the effects of these chemical alterations on force production by an upper airway dilator muscle, the contractile and endurance characteristics of the geniohyoid muscle were examined in situ during severe hypoxia (arterial PO2 less than 40 Torr), mild hypoxia (PO2 45-65 Torr), and hypercapnia (PCO2 55-80 Torr) and compared with hyperoxic-normocapnic conditions in anesthetized cats. Muscles were studied at optimal length, and contractile force was assessed in response to supramaximal electrical stimulation of the hypoglossal nerve (n = 7 cats) or geniohyoid muscle (n = 2 cats). There were no significant changes in the twitch kinetics or force-frequency curve of the geniohyoid muscle during hypoxia or hypercapnia. However, the endurance of the geniohyoid, as reflected in the fatigue index (ratio of force at 2 min to initial force in response to 40-Hz stimulation at a duty cycle 0.33), was significantly reduced by severe hypoxia but not by hypercapnia or mild hypoxia. In addition, the downward shift in the force-frequency curve after the repetitive stimulation protocol was greater during hypoxia than hyperoxia, especially at higher frequencies. In conclusion, the ability of the geniohyoid muscle to maintain force output during high levels of activation is adversely affected by severe hypoxia but not mild hypoxia or hypercapnia. However, none of these chemical perturbations affected muscle contractility acutely.     

Analysis of postinspiratory activity of phrenic motoneurons with chemical and vagal reflexes

We examined the effects of chemical and reflex drives on the postinspiratory inspiratory activity (PIIA) of phrenic motoneurons using a single-fiber technique. Action potentials from "single" fibers were recorded from the C5 phrenic root together with contralateral mass phrenic activity (also from C5) in anesthetized, paralyzed, and artificially ventilated cats with intact vagus and carotid sinus nerves. Nerve fibers were classified as "early" or "late" based on their onset of discharge in relation to mass phrenic activity during hyperoxic ventilation. Only the early fibers displayed PIIA but not the late fibers, even when their activity began earlier in inspiration with increased chemical drives. Isocapnic hypoxia increased, whereas hyperoxic hypercapnia shortened the duration of PIIA. Pulmonary stretch and "irritant" receptors inhibited PIIA. Hypercapnia and stimulation of peripheral chemoreceptors by lobeline excited both early and late units to the same extent, but hypoxic ventilation had a less marked excitatory effect on late fiber activity. Irritant receptor activation increased the activity of early more than late fibers. Hyperoxic hyperventilation eliminated late phrenic fiber activity, whereas early fibers became tonically active. Bilateral vagotomy abolished this sustained discharge in eight of nine early units, suggesting the importance of vagal afferents in producing tonic firing during hyperventilation. These results suggest that early and late phrenic fibers have different responses to chemical stimuli and to vagally mediated reflexes; late units do not discharge in postinspiratory period, whereas early fibers do; the PIIA is not affected in the same way by various chemical and vagal inputs; and early units that exhibit PIIA display tonic activity with hyperoxic hypocapnia.     

Influence of pulmonary inflations on discharge of pontile respiratory neurons

The purpose of this study was to characterize the influence of pulmonary inflations on the discharge patterns of rostral pontile respiratory neurons. Decerebrate and paralyzed cats were ventilated with a servo-respirator which produced patterns of pulmonary inflation, assessed by tracheal pressure, which paralleled alterations in integrated activity of the phrenic nerve. Neurons with respiratory-modulated neuronal activities were recorded in the pneumotaxic region of the nucleus parabrachialis medialis and Kolliker-Fuse nucleus, as well as in the trigeminal motor nucleus. Approximately equal numbers of neurons had phasic and tonic respiratory-modulated discharge patterns. The discharge patterns of most neurons were not qualitatively altered when pulmonary inflation was prevented. However, withholding inflation did cause the recruitment of some respiratory-modulated neuronal activities. Similar findings were obtained in normocapnia and hypercapnia. Results support the concept that the discharge of neurons in the pneumotaxic region may exert phasic, as well as tonic, influences on ventilatory activity.     

Maintenance of gasping and restoration of eupnea after hypoxia is impaired following blockers of alpha1-adrenergic receptors and serotonin 5-HT2 receptors.

In severe hypoxia or ischemia, normal eupneic breathing fails and is replaced by gasping. Gasping serves as part of a process of autoresuscitation by which eupnea is reestablished. Medullary neurons, having a burster, pacemaker discharge, underlie gasping. Conductance through persistent sodium channels is essential for the burster discharge. This conductance is modulated by norepinephrine, acting on alpha 1-adrenergic receptors, and serotonin, acting on 5-HT2 receptors. We hypothesized that blockers of 5-HT2 receptors and alpha 1-adrenergic receptors would alter autoresuscitation. The in situ perfused preparation of the juvenile rat was used. Integrated phrenic discharge was switched from an incrementing pattern, akin to eupnea, to the decrementing pattern comparable to gasping in hypoxic hypercapnia. With a restoration of hyperoxic normocapnia, rhythmic, incrementing phrenic discharge returned within 10 s in most preparations. Following addition of blockers of alpha 1-adrenergic receptors (WB-4101, 0.0625-0.500 microM) and/or blockers of 5-HT2 (ketanserin, 1.25-10 microM) or multiple 5-HT receptors (methysergide, 3.0-10 microM) to the perfusate, incrementing phrenic discharge continued. Fictive gasping was still induced, although it ceased after significantly fewer decrementing bursts than in preparations than received no blockers. Moreover, the time for recovery of rhythmic activity was significantly prolonged. This prolongation was in excess of 100 s in all preparations that received both WB-4101 (above 0.125 microM) and methysergide (above 2.5 microM). We conclude that activation of adrenergic and 5-HT2 receptors is important to sustain gasping and to restore rhythmic respiratory activity after hypoxia-induced depression.     

海马区锥体神经元轴突高频电刺激对胞体的影响

目的 深部脑刺激（deep brain stimulation,DBS）利用持续的电脉冲高频刺激（high-frequency stimulation,HFS）调控神经元的活动，可望用于治疗更多脑疾病。为了深入了解HFS的作用机制，促进DBS的发展，本文研究轴突HFS在引起轴突阻滞期间神经元胞体的改变。方法 在麻醉大鼠海马CA1区的锥体神经元轴突上施加脉冲频率为100 Hz的1 min逆向高频刺激（antidromic high-frequency stimulation,A-HFS）。为了研究胞体的响应，利用线性垂直排列的多通道微电极阵列，记录刺激位点上游CA1区锥体神经元胞体附近各结构分层上的诱发电位，包括A-HFS脉冲诱发的逆向群峰电位（antidromic population spike,APS）以及A-HFS期间施加的顺向测试脉冲诱发的顺向群峰电位（orthodromic population spike,OPS），并计算诱发电位的电流源密度（current-source density,CSD），用于分析A-HFS期间锥体神经元胞体附近动作电位的生成和传导。结果 锥体神经...     

Influence of the ventral surface of the medulla on tracheal responses to CO2

These studies investigated the role of the intermediate area of the ventral surface of the medulla (VMS) in the tracheal constriction produced by hypercapnia. Experiments were performed in chloralose-anesthetized, paralyzed, and artificially ventilated cats. Airway responses were assessed from pressure changes in a bypassed segment of the rostral cervical trachea. Hyperoxic hypercapnia increased tracheal pressure and phrenic nerve activity. Intravenous atropine pretreatment or vagotomy abolished the changes in tracheal pressure without affecting phrenic nerve discharge. Rapid cooling of the intermediate area reversed the tracheal constriction produced by hypercapnia. Graded cooling produced a progressive reduction in the changes in maximal tracheal pressure and phrenic nerve discharge responses caused by hypercapnia. Cooling the intermediate area to 20 degrees C significantly elevated the CO2 thresholds of both responses. These findings demonstrate that structures near the intermediate area of the VMS play a role in the neural cholinergic responses of the tracheal segment to CO2. It is possible that neurons or fibers in intermediate area influence the motor nuclei innervating the trachea. Alternatively, airway tone may be linked to respiratory motor activity so that medullary interventions that influence respiratory motor activity also alter bronchomotor tone.     

Mu-opioid receptor agonist effects on medullary respiratory neurons in the cat: evidence for involvement in certain types of ventilatory disturbances

Mu-opioid receptor agonists depress tidal volume, decrease chest wall compliance, and increase upper airway resistance. In this study, potential neuronal sites and mechanisms responsible for the disturbances were investigated, dose-response relationships were established, and it was determined whether general anesthesia plays a role. Effects of micro-opioid agonists on membrane properties and discharges of respiratory bulbospinal, vagal, and propriobulbar neurons and phrenic nerve activity were measured in pentobarbital-anesthetized and unanesthetized decerebrate cats. In all types of respiratory neurons tested, threshold intravenous doses of the micro-opioid agonist fentanyl slowed discharge frequency and prolonged duration without altering peak discharge intensity. Larger doses postsynaptically depressed discharges of inspiratory bulbospinal and inspiratory propriobulbar neurons that might account for depression of tidal volume. Iontophoresis of the micro-opioid agonist DAMGO also depressed the intensity of inspiratory bulbospinal neuron discharges. Fentanyl given intravenously prolonged discharges leading to tonic firing of bulbospinal expiratory neurons in association with reduced hyperpolarizing synaptic drive potentials, perhaps explaining decreased inspiratory phase chest wall compliance. Lowest effective doses of fentanyl had similar effects on vagal postinspiratory (laryngeal adductor) motoneurons, whereas in vagal laryngeal abductor and pharyngeal constrictor motoneurons, depression of depolarizing synaptic drive potentials led to sparse, very-low-frequency discharges. Such effects on three types of vagal motoneurons might explain tonic vocal fold closure and pharyngeal obstruction of airflow. Measurements of membrane potential and input resistance suggest the effects on bulbospinal Aug-E neurons and vagal motoneurons are mediated presynaptically. Opioid effects on the respiratory neurons were similar in anesthetized and decerebrate preparations.