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Departments of Physiology and Medicine, University of North Carolina, Chapel Hill, North Carolina 27599
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Chen, Zibin, and Frederic L. Eldridge. Inputs from
upper airway affect firing of respiratory-associated midbrain neurons. J. Appl. Physiol. 83(1): 196-203, 1997.
In 16 decerebrated unanesthetized cats, we studied effects of
neural inputs from upper airway on firing of 62 mesencephalic neurons
that also developed respiratory-associated (RA) rhythmic firing when
respiratory drive was high [Z. Chen, F. L. Eldridge, and P.G.
Wagner. J. Physiol. (Lond.) 437:
305-325, 1991] and on firing of 16 neurons that did not
develop the rhythmic firing (non-RA neurons). Activity in RA neurons
increased after mechanical expansion of pharynx (45% of those tested)
or larynx (68%) and after stimulation of glossopharyngeal (50%) or
superior laryngeal nerves (77%). The increased neuronal firing
occurred despite decreases or abolition of respiratory activity
(expressed in phrenic nerve). Neuronal firing also increased after
mechanical stimulation of nasal mucosa (66%) or by jets
of air directed into the nares (48%) and after light
brushing of nasal skin (~40%). Most stimuli led to decreased firing
in a smaller number of neurons, and some neurons showed no response.
None of the non-RA neurons developed an increase of firing after any of
the stimuli, although one had decreased firing after stimulation of the
superior laryngeal nerve. We conclude that inputs from the upper airway
and nasal skin have independent modulatory effects on the same
mesencephalic neurons that are stimulated by ascending rhythmic RA
input from the medulla. These findings may have relevance to generation
of the sensation of dyspnea.
respiration; mesencephalon; nose; pharynx; larynx; sensation; dyspnea
INTRODUCTION SOME NEURONS IN THE MIDBRAIN (4) and thalamus (5) that
are silent or fire tonically at low levels of respiratory drive develop
increasing firing associated with each respiration at high levels of
respiratory drive, i.e., above a threshold (40-50% of maximum
respiratory activity for midbrain and 70% of maximum for thalamic
neurons). It is unlikely that this rhythmic neuronal firing is
importantly involved in modulation of the motor side of breathing
because the rhythmic firing can be abolished by very small
amounts of an anesthetic agent without significant effect on
respiratory frequency or amplitude of integrated phrenic activity (4).
We showed that inputs from below the
C1 level of the spinal cord and
from the lungs are not necessary for the respiratory-associated (RA)
midbrain and thalamic rhythms to occur, indicating that they arise from
respiratory activity in the medulla. Nevertheless, if the spinal cord
is intact, some of the same neurons with the RA rhythm can also be
activated independently by the chest expansion produced by a ventilator
(4). Finally, we showed that the rhythmic RA neuronal activity can be
decreased by input from vagally mediated pulmonary stretch receptors.
At least part of the effect is by a mechanism that is independent of
the level of medullary respiratory drive (8).
Our findings are consistent with a conclusion that these midbrain and
thalamic neurons reflect input of sensory information about the level
of respiratory activity in the medulla, about events in the chest wall
and respiratory muscles, and about events in the lungs. We have
suggested that these sensory inputs are probably transmitted to the
cortex where they may participate in generation or modulation of the
distressful sensations that are included under the term
"dyspnea."
Sensory inputs that have been suggested to contribute to the various
sensations of dyspnea have included
1) the medullary respiratory drive
itself (as a corollary discharge) (1, 2, 10);
2) input from the chemoreceptors
(2); 3) input from mechanical
receptors in the chest wall (9) and respiratory muscles (12);
4) input from lungs (18, 19); and
5) input from the upper airway (16,
21). If one accepts that the neuronal activities we have studied may be
involved in the generation of dyspnea, then our previous studies
clearly implicate 1 and
3 as causes for the activities to
increase. On the other hand, at least one input from the lungs
(4), the pulmonary stretch
receptors, causes the neuronal firing to decrease (8) and could be
expected to cause dyspnea to decrease (11).
The present study was undertaken to see whether sensory inputs from the
upper airway, including the nose, pharynx, and larynx, also have an
effect on the firing of the mesencephalic neurons that develop the RA
rhythm.
METHODS Animals and Preparations
While the animals were still anesthetized with ether, the skull anterior to the tentorium was removed, and the dura was opened. A supracollicular decerebration was performed by suction removal of the entire forebrain, including the diencephalon. The collicular surface of the midbrain was visualized. Bleeding was controlled by coagulation and local application of Avetine and Gelfoam. Once the forebrain had been removed, no additional anesthesia was given. In two cats, the spinal cord was also transected at the C7 level.
All animals were paralyzed with gallamine triethiodide, 3 mg/kg iv
initially, followed by a continuous infusion at the rate of 3 mg · kg
1 · h1
to maintain paralysis, and they were ventilated with 100%
O2 by using a volume-cycled
ventilator. When it was appropriate to keep end-tidal
PCO2
(PETCO2) and arterial
PCO2 constant, the ventilator could
be servo-controlled by changing its pumping frequency to maintain
PETCO2
within a narrow range around any desired level (17).
Thereafter, the animal was placed in a stereotaxic headholder in the supine position. Carotid sinus nerves were exposed bilaterally and then cut or crushed near the carotid bodies. The cervical vagus nerves were cut distal to the level at which the superior laryngeal nerves joined the vagi. Two small rubber balloons [filled with water to the 1.5-ml uninflated volume (i.e., transmural pressure close to 0) and tied to the ends of lengths of plastic tubing] were inserted separately into 1) the pharynx through the mouth and 2) the larynx through a tracheal incision. The volume of either balloon could be changed by injection or withdrawal of water. The resulting change of pressure in the system, measured by means of a strain gauge, was used as a marker signal.
Ten animals were studied in the prone position. In these, the left
superior laryngeal nerve and C5
root of the phrenic nerve were exposed by a dorsal approach. The latter
was cut, desheathed, and placed on a platinum recording electrode. The
laryngeal nerve was left intact but placed on an electrode for
stimulation. Nerves and electrodes were immersed in a pool of mineral
oil. In these cats, we searched for extracellular activity of
mesencephalic neurons by using stainless steel microelectrodes
[no. 5715 (OD = 0.01 in., 12 M
at 1.000 Hz), A-M Systems,
Everett, WA] by moving the electrode downward from the exposed
dorsal surface of the brain. The settings of the micromanipulator for
stereotaxic zero (3) had been determined before placement of the
animals in the stereotaxic headholder.
Six additional animals were studied in the supine position so that a glossopharyngeal nerve (9th nerve) as well as a superior laryngeal nerve could be exposed and placed on electrodes for stimulation. The stimulation site for the 9th nerve was distal to the insertion of the carotid sinus nerve. These supine animals were raised off the table so that there was room to mount the micromanipulator underneath the exposed brain; thus the microelectrode was moved upward from the brain surface to enter deeper structures (4).
Experimental Protocols
Tidal volume of the ventilator was set at 30-35 ml; and PETCO2 was adjusted to 3-5 Torr above the apneic threshold for rhythmic phrenic activity. After the preparation had become stable, we searched for neuronal activity in the region of the central tegmental field of the mesencephalon. Once a stable, spontaneously firing unit had been found, recordings of its firing and other variables were made and its stereotaxic location noted. In three cats, ventilator-induced movement interfered with stable recording of the neuronal unit, so bilateral pneumothoraxes were performed.We first determined the response of a unit during increased respiratory "drive" (reflected in the level of phrenic activity) that was caused either by continuous stimulation of the carotid sinus nerve (pulse duration, 0.5 ms; 25 Hz; variable voltages, 0.05-2 V) or by increasing PETCO2 (changing the set point of the ventilator's servo controller). As we showed earlier (4), increased respiratory drive causes ~25% of the tested neurons in the mesencephalic central tegmental field (the RA neurons) to develop rhythmic increases of firing rate associated with and following each respiratory burst. The remaining neurons are not affected by respiration (non-RA neurons). Because the RA neurons were main focus of the present study, the effects of sensory inputs from upper airway and face were tested in all such neurons that were found. Nevertheless, we also recorded responses to the same inputs in some non-RA neurons.
Inputs from upper airway and face were produced in a variety of ways. 1) Global stimulation of upper airway was accomplished by blowing air into the nose at a rate sufficient to increase pressure in the airway and cause expansion of the entire upper airway (nasal cavity, naso- and oropharynx, pharynx, and larynx). 2) Mechanical stimulation of the nasal cavity alone was accomplished either by jet of air directed at the mucosa, which could also lead to cooling of the mucosa, or by inserting a pipe cleaner or a rigid piece of plastic into the nasal cavity. 3) Mechanical stimulation of the pharynx or larynx was performed by inflating the balloons that had previously been placed in these cavities with up to 5 ml water. The strengths of the stimuli could be varied by injection of smaller volumes or by changes in speeds of injection. 4) Electrical stimulation of superior laryngeal or 9th nerves was accomplished with trains of pulses of 0.5-ms duration, 50 Hz, and variable voltage (0.05-5 V). 5) Stimulation of nasal skin was performed with a light touch with a cotton swab. An individual cat was not necessarily given all of the various stimuli.
The effects of the various inputs were always studied initially when the level of drive was high and the RA rhythm was present. The neuronal rhythm sometimes made difficult the ready identification of the effects of the different inputs. Therefore, they were usually also studied when respiratory drive had been reduced by lowering PETCO2, which led to the neurons firing only tonically at a low rate or becoming silent. There were no important qualitative differences in the responses of a given neuron to a given input between the two conditions.
Data Processing and Analysis
Phrenic activities were amplified, half-wave rectified, and fed to a voltage-to-frequency (V-f) converter (Vidar 240), the output frequency of which is proportional to the applied voltage. Integration was accomplished by counting the V-f pulses with a digital counter (Hewlett-Packard 3525A) in 0.1-s periods throughout the respiratory cycle. It has been shown that the peak value for each breath is the neural equivalent of tidal volume of breathing (6).Neuronal signals from the mesencephalon were amplified and displayed on an oscilloscope. A window slope/height discriminator (Haer, Brunswick, ME) was used to select spikes from a single neuron; the discriminator then sent standard pulses representing each nerve spike to another oscilloscope and to a recorder. Raw phrenic, raw neuronal activity, femoral arterial pressure, airway PCO2, and stimulation markers were recorded on magnetic tape (Hewlett-Packard 3955D) for later analysis. These variables, as well as integrated phrenic activity and the standard pulses from the discriminator, were also recorded by means of a high-frequency eight-channel analog recorder (Gould TA2000).
The peak level of electrical activity in the phrenic nerve was taken as an index of the level of neural respiratory "drive" in a given cat. However, the absolute activity in a cat depends on a number of technical factors (7), so it cannot be used to make comparisons among cats. To do this, we therefore scaled the phrenic values by assigning a value of 0 to phrenic apneic threshold and a value of 100 to the highest peak phrenic activity level achieved in each cat by any combination of CO2 and carotid sinus nerve stimulation. Other values were scaled on this basis.
We quantified peak phrenic activity on a breath-to-breath basis by means of an on-line computer during the experiment. From analog chart recordings, integrated phrenic activities for each 0.1-s period through the respiratory cycle were measured by means of a digitizing tablet (Jandel) and appropriate software (Sigmascan, Jandel) with the use of an IBM computer. The number of mesencephalic spikes in each 0.1- or 0.5-s period was also counted by means of the digitizer. When it was necessary to visualize clear separation of spikes, the tape recordings were replayed at higher speed on the analog recorder. Neuronal spikes per respiratory cycle or per unit of time were measured. Histograms were constructed from the data. For subsequent analyses of responses to a stimulus, we defined increased firing as at least a transient doubling of spike frequency from its baseline and decreased firing as a halving of spike frequency.
RESULTS
Responses in Neurons Exhibiting RA Rhythm
In the 16 cats, we recorded from 62 neurons in the mesencephalic central tegmental fields that developed a RA rhythm at high levels of respiratory drive. All cats had been vagotomized below the junction of the superior laryngeal nerve to eliminate feedback from lung receptors. All cats had their carotid sinus nerves cut to eliminate feedback from carotid bodies, and two cats also had their spinal cords cut at C7 to eliminate feedback from chest wall and muscles. The findings were not different in these two cats.Such a RA rhythm can be seen in the neuronal recordings of the first
three breaths in Fig. 1A.
Increased neuronal firing is present in the late inspiratory period and
postinspiratory period of each respiration and is typical of that
reported earlier (4). Figure 1A also
shows the effect of mechanical stimulation caused by global expansion
of the whole upper airway (horizontal bar) in one of the cats with a
C7 spinal transection. There is a
prompt increase of firing of the mesencephalic neuron that lasts as
long as the stimulus, a resetting of rhythm, an increased firing during the subsequent RA rhythmic component, and then a poststimulus decrease
of RA firing. In Fig. 1B,
PETCO2 had been lowered, which led to loss of rhythmic phrenic activity and of RA firing of the
neuron. Nevertheless, each of five repeated expansions (bars) of the
upper airway led to prompt firing of the midbrain neuron.
Interestingly, a very small amount of phrenic activity also occurred,
but it was clearly subsequent to the stimulus and the neuronal response
of the midbrain. Of the 13 neurons studied in this way, 11 were found
to increase their firing rate markedly with expansion stimulation of
the upper airway.
We found that stimulation of the nasal mucosa, pharynx (mechanical and 9th nerve), larynx (mechanical and superior laryngeal nerve), and facial skin can modulate the activities of these midbrain RA neurons. About one-half of the neurons responded with an increase of firing rate, but in some there was no effect or a decrease of firing rate (Table 1).
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Mechanical manipulation of nasal mucosa (Table 1) led to increases of neuronal firing (or more complex multiphasic responses as shown in Fig. 2C) in a majority of the neurons but to decreases in a few and to no responses in some. The jet of air led to increased firing in about one-half the neurons, decreased firing in two, and no effect in the remainder. All of the neurons that responded to the air jet with increased activity also responded with increased activity to manipulation of mucosa; however, some of the group that responded to manipulation of the mucosa did not respond to the air jet, perhaps because it was a gentler stimulus. One of the neurons that responded with decreased activity to manipulation of the mucosa had a similar response to the air jet stimulus. Tactile stimulation of nasal skin led to an increase of neuronal firing but was usually accompanied by a decrease of respiration and resetting of rhythm. The responses are summarized in Table 1. Somewhat less than one-half of the RA neurons had increased firing after stimulations of nasal skin, none had decreased firing, and over one-half showed no response to the input. Pharyngeal stimulation. Mechanical stimulation (inflation of balloon in pharynx) and electrical stimulation of the 9th nerve distal to insertion of the carotid sinus nerve led to generally similar responses. These responses included rapidly occurring but modest increases of firing of about one-half of the mesencephalic RA neurons and a concurrent decrease, often complete disappearance, of respiratory (phrenic) activity. Figure 3A shows such a response in a neuron with only a minimum of the rhythmic RA activity. The neuronal response to mechanical pharyngeal stimulation was accompanied by prompt decrease of phrenic activity and resetting of respiratory rhythm. Electrical stimulation of the 9th nerve led to similar responses of the neuronal and respiratory activity. A summary of the responses to pharyngeal inputs and 9th nerve stimulation is provided in Table 1.
Laryngeal stimulation. Mechanical stimulation (balloon inflation) of the larynx led to increases of firing in most mesencephalic neurons tested. The response was accompanied by abolition of phrenic activity as well as resetting of respiratory rhythm (Fig. 3B). Electrical stimulation of the superior laryngeal nerve similarly elicited increased firing of most mesencephalic neurons while abolishing respiratory (phrenic) activity (Fig. 4A). A summary of responses to laryngeal and superior laryngeal nerve stimulation is given in Table 1.
Compared with inputs from other portions of the upper airway, the laryngeal stimulations were most effective in modulating mesencephalic neuronal activity (see Table 1). Therefore, we made several other observations on responses of neurons to laryngeal inputs. Figure 5 shows a mesencephalic neuron that had the RA rhythm at a PETCO2 of 28 Torr and phrenic activity of 47% of maximum. The neuron was then studied when PETCO2 was lowered to below the threshold for rhythmic phrenic activity. Different magnitudes of mechanical stimulation (balloon expansion) of the larynx were given. The smallest (Fig. 5A) had no clear effect on the neuron's activity, but there were increasing effects as the stimulus increased (Fig. 5, B and C). These results are shown in Fig. 5D. Even though the balloon expansion was maintained in Fig. 5, B and C, the increased firing quickly waned (Fig. 5D), indicating adaptation of laryngeal receptors or accommodation of central pathways.
, A;
, B; 
,
C.
Similar findings in this cat (Fig. 6) occurred in another neuron that had been shown to have the RA rhythm. In this case, different rates of balloon expansion with the same volume change (4 ml) were studied. It can be seen that slow expansion (Fig. 6A) had no effect on neuronal firing, but increasing rates of expansion had increasing effects (Fig. 6, B and C). These graded responses are also shown in the plot of Fig. 6D. There is again rapid waning of increased firing even though the stimulus is maintained.
,
A; ,
B; ,
C.
Figure 7 shows two mesencephalic neurons in different cats. The RA rhythms were present at high respiratory drive. In Fig. 7A, both phrenic activity and neuronal activity were zero, but laryngeal input caused a quickly waning burst of neuronal activity at both the onset and cessation of the mechanical laryngeal stimulation. In Fig. 7B, respiratory drive was also below the threshold for rhythmic phrenic activity, but the mesencephalic neuron exhibited tonic firing that was briefly increased by both expansion and deflation of the laryngeal balloon. These findings show that stimulation of laryngeal receptors was responsible for the neuronal responses observed. To determine whether receptor adaptation or central accommodation accounts for the rapid waning of neuronal activity, we studied the responses to electrical stimulation of superior laryngeal nerve and found that a short train (1.5 s) of stimulation led to cessation of phrenic activity and a brief burst of mesencephalic neuronal firing that waned within 5 s (Fig. 4A). When a more prolonged stimulation (10 s) was applied, the induced neuronal firing still waned rapidly, within 5 s, but inhibition of phrenic activity persisted until the end of stimulation (Fig. 4B). This result demonstrated that there is accommodation in the central pathways to the mesencephalic neurons.
Effects of different inputs on same neuron. We were able to record the responses to most of the various inputs used in this study in 27 individual mesencephalic neurons that had been identified as developing a RA rhythm at high respiratory drive. Table 2 shows that 23 of 27 neurons increased their firing in response to upper airway inputs. Among them, 12 neurons were activated by all inputs from nose, pharynx, and larynx. The other neurons had responses to fewer inputs. Three neurons decreased their firing. Only three neurons had no response to any of the stimuli.
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Responses in Neurons Not Exhibiting RA Rhythm
In eight cats, we also studied 14 neurons that did not develop the RA rhythm during high respiratory drive. In contrast to the RA neurons, all except one of the non-RA neurons showed no response to inputs from upper airway or face. The only responsive non-RA neuron, the firing of which was decreased after electrical stimulation of superior laryngeal nerve, also responded to carotid sinus nerve stimulation with decrease of firing.DISCUSSION
Our findings demonstrate again that it is relatively easy in unanesthetized decerebrate animals to document the development in mesencephalic neurons of rhythmic firing that appears to be driven, with a relatively long latency (~0.5-1 s), by medullary inspiratory activity when it exceeds a threshold of ~50% of its maximum. We have proposed (4, 5) that this rhythmic activity of the mesencephalic as well as thalamic neurons reflects transmission toward the cortex of sensory signals of about the magnitude of neural respiratory drive in the medulla and that this information may be involved in generating the sensation of breathlessness.
Neural inputs from receptors in nose, pharynx, and larynx have complex effects. Acting in the medulla, they produce reflex effects on pattern and timing of respiration and are probably important in stabilizing the upper airway. From a sensory standpoint, they are certainly involved in the mediation of the conscious sensations of touch, pressure, temperature, irritation, and pain (20). We had shown that two other respiratory-related neural inputs, one from the thorax (4) and the other from the lungs (8), independently [i.e., not through an effect on the respiratory controller's activity and with relatively short latency (~0.1-0.2 s)] modulate the midbrain and thalamic neurons that develop the RA rhythm. Therefore, we thought it possible that upper airway inputs, proposed to have roles in modulation of breathlessness (15, 16), might also affect these neurons. The purpose of the present study was to test this hypothesis in mesencephalic neurons.
The present study shows that about one-half of the mesencephalic neurons exhibiting the RA rhythm were also affected by inputs from nose, nasal skin, pharynx, and larynx (see Table 1). The effects of the inputs were complex (see Table 2). We found that most midbrain neurons that developed a RA rhythm (23 of 27 studied with all upper airway inputs) responded to at least one of the inputs with increased firing. On the other hand, we studied 14 neurons in the same area of the mesencephalon that did not develop the RA rhythm during hypercapnia or carotid sinus nerve stimulation, and we found no facilitatory responses to any of the inputs. Only one of the non-RA neurons showed a response, a decrease of firing with electrical stimulation of the superior laryngeal nerve. Our results suggest, therefore, that the upper airway inputs preferentially modulate the neurons that develop the RA rhythm during increased medullary respiratory drive.
We are confident that inputs other than those from the upper airway were not responsible for our findings. PETCO2 was kept constant by means of a servocontrolled ventilator. The carotid sinus nerves were cut so that input from the carotid bodies was eliminated. Input from the lungs was ablated by cutting the vagi in the neck. Input from the thorax was abolished in two tested cats by transection of the spinal cord at C7; the findings in these cats were not different from in those with intact spinal cords.
Because the magnitude of the rhythmic activity in the mesencephalic neurons is related to the level of medullary respiratory drive, one would expect that any change of the latter would lead to a change of the RA activity in the neuron. We believe this is not the mechanism behind our findings for the following reasons. 1) The latency of the responses to the upper airway inputs was relatively short (0.1-0.2 s; see Figs. 1, 2, 4, 5, and 7), whereas latency of the response to the respiratory burst has been shown to be, as noted above and in Chen et al. (4), relatively long (see Fig. 1A). 2) In the below-threshold state, when respiratory activity was zero, inputs from the upper airway still caused short-latency firing of mesencephalic neurons (see Figs. 1B and 5-7). 3) When respiratory activity was above apneic threshold, an input that caused an increased firing of a neuron usually also led to a decrease of respiratory activity, i.e., a dissociation between activity of the neuron (increased) and central neural respiratory drive (decreased, reflected by a loss of phrenic activity and resetting of respiratory rhythm; see Figs. 2A, 3, and 4). Therefore, we suggest that the neuronal responses to the airway inputs are by independent pathways not involving the medullary respiratory controller.
One can raise the question as to how closely the stimuli used in this study mimic natural ones. None, of course, resemble those that would be expected during normal quiet breathing. On the other hand, the mechanical stimuli are those that might occur in pathophysiological conditions such as irritation, cooling, and obstruction of the upper airway (13). Electrical stimulation of the 9th and superior laryngeal nerves is nonspecific. Nevertheless, it is of interest that these stimuli had effects on mesencephalic neuronal activity and respiration similar to those of the mechanical stimulations of pharynx and larynx.
In conclusion, findings in this and our previous reports show that 1) some mesencephalic neurons develop a rhythmic firing pattern associated with the respiratory burst from the medulla; 2) the same neurons are activated independently by spinally mediated input from the chest wall and/or respiratory muscles; 3) their firing is decreased or abolished independently by vagally mediated input from pulmonary stretch receptors; and 4) they can be independently modulated by inputs from various parts of the upper airway. The neurons studied here are thus clearly multimodal in that they receive inputs from various parts of the respiratory apparatus.
We suggest that the neurons play an important role in the integration and transmission to higher brain of sensory information about breathing. We have proposed that this information ultimately participates in the generation and modulation of the sensation of breathlessness or dyspnea at the cortical level. We have shown that the RA and chest wall information reaches thalamic neurons in a form similar to that in the midbrain (5). However, it is not necessary that there be a specific "dyspnea" pathway. Perhaps a more likely possibility is that neurons more diffusely located in the reticular formation of midbrain and thalamus are involved in the process of gathering respiratory information from medulla and peripheral receptors and transmitting it onward. That the process is not just a nonspecific arousal is suggested by the finding that inputs from vagal stretch receptors inhibit the rhythmic firing of the midbrain RA neurons (8), a finding consistent with the relief of dyspnea found in quadriplegics after increased expansion of the lungs (11).
Facial inputs (cold air) are reported to decrease dyspnea (14). The problem in relating such findings to ours, where facial input (mechanical) stimulated the midbrain neurons, is that such inputs also have an inhibitory effect on medullary respiratory drive, which might secondarily reduce input to the midbrain neurons. Although it is not certain that inputs from upper airways and face are capable per se of producing the sensation of dyspnea, our studies suggest that they could modulate it in complex ways.
ACKNOWLEDGEMENTS
We thank Lynn Houser for excellent technical assistance.
FOOTNOTES
Address for reprint requests: Z. Chen, Dept. of Physiology, CB7545, Univ. of North Carolina, Chapel Hill, NC 27599.
Received 18 April 1996; accepted in final form 14 March 1997.
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