Vol. 275, Issue 4, R1013-R1024, October 1998
Differential suppression of upper airway motor activity during
carbachol-induced, REM sleep-like atonia
Victor
Fenik1,2,
Richard O.
Davies1,2,
Allan I.
Pack2, and
Leszek
Kubin1,2
1 Department of Animal Biology,
School of Veterinary Medicine,
and 2 Center for Sleep and
Respiratory Neurobiology, School of Medicine, University of
Pennsylvania, Philadelphia, Pennsylvania 19104
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ABSTRACT |
Microinjections of carbachol into the
pontine tegmentum of decerebrate cats have been used to study the
mechanisms underlying the suppression of postural and respiratory
motoneuronal activity during the resulting rapid eye movement (REM)
sleep-like atonia. During REM sleep, distinct respiratory muscles are
differentially affected; e.g., the activity of the diaphragm shows
little suppression, whereas the activity of some upper airway muscles
is quite strong. To determine the pattern of the carbachol-induced
changes in the activity of different groups of upper airway
motoneurons, we simultaneously recorded the efferent activity of the
recurrent laryngeal nerve (RL), pharyngeal branch of the vagus nerve
(Phar), and genioglossal branch of the hypoglossal (XII) and phrenic
(Phr) nerves in 12 decerebrate, paralyzed, vagotomized, and
artificially ventilated cats. Pontine carbachol caused a stereotyped
suppression of the spontaneous activity that was significantly larger
in Phar expiratory (to 8.3% of control) and XII inspiratory
motoneurons (to 15%) than in Phr inspiratory (to 87%), RL inspiratory
(to 79%), or RL expiratory motoneurons (to 72%). The suppression in
upper airway motor output was significantly greater than the depression
caused by a level of hypocapnia that reduced Phr activity as much as carbachol. We conclude that pontine carbachol evokes a stereotyped pattern of suppression of upper airway motor activity. Because carbachol evokes a state having many neurophysiological characteristics similar to those of REM sleep, it is likely that pontine cholinoceptive neurons have similar effects on the activity of upper airway
motoneurons during both states.
cough; laryngeal motoneurons; obstructive sleep apnea; pharyngeal
motoneurons; respiratory drive
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INTRODUCTION |
SLEEP, PARTICULARLY the rapid eye movement (REM) stage,
exerts profound effects on the control of all skeletal muscles. One of
the major signs of REM sleep is a strong suppression of postural muscle
tone. In parallel with this postural atonia, there are decreases in the
tone of both respiratory pump and upper airway muscles, the changes in
upper airway muscle activity frequently being large and leading to
airway narrowing and, in predisposed individuals, to sleep-disordered
breathing (5, 21, 38, 47). The suppression of upper airway activity is
not uniform, with the decrease of activity in most pharyngeal dilators
being greater than in laryngeal muscles (9, 10, 21, 40).
To study the changes in upper airway muscle activity that accompany REM
sleep and the neuronal mechanisms underlying these changes, we adapted
the carbachol model of REM sleep (see Refs. 15, 25, 42, and 45 for
reviews). Microinjections of carbachol, a cholinergic agonist, into the
pontine tegmentum of chronically instrumented, behaving cats evoke a
state having many characteristics similar to those of REM sleep and
consistently evoke a generalized postural atonia. The similarities
between the effects of carbachol in behaving cats and REM sleep were
summarized recently in reviews by Baghdoyan (see Table 1 in Ref. 2) and
Lydic (see Table 1 in Ref. 25). Important for the present studies, in
acutely decerebrated cats, intracellular recordings from lumbar
motoneurons show that injections of carbachol into the pons induce an
atonia with state-specific inhibitory postsynaptic potentials that
closely resemble those recorded during REM sleep in chronic cats (31).
In acutely decerebrate cats, carbachol also evokes eye movements (44)
and a reduction of the firing of brain stem serotonergic raphe neurons,
similar to that during REM sleep (48). Thus pontine carbachol
injections can be used in acutely decerebrate cats to produce, at
controlled times, a depression of motor output that is similar to the
atonia of REM sleep. Consequently, this preparation provides an
opportunity to study the central neuronal mechanisms that underlie the
REM sleep-like depression of motor activity with the use of
neurophysiological and neuropharmacological techniques whose
application in chronic animal studies is difficult to implement.
We previously studied the effects that microinjections of carbachol
into the pons of decerebrate cats have on selected respiratory motoneuronal outputs and found a stereotyped, differential suppression of the motoneurons to respiratory pump muscles, with the following increasing order of the magnitude of suppression: diaphragm < inspiratory intercostals < expiratory intercostals (13, 44). In
addition, we studied the motoneuronal activity of one pharyngeal dilator muscle, the genioglossus, whose carbachol-induced suppression was very profound (to 10% of control) (13). This and observations of
the activity of selected upper airway muscles during REM sleep in
humans (20, 23, 40, 47) and experimental animals (10, 27, 41) showed
that large differences exist in the magnitude of suppression among
distinct upper airway muscles. However, a clear pattern of those
changes is difficult to discern based on the existing body of evidence.
Because the pharynx is the region most vulnerable to airway obstruction
during sleep (9, 21, 38, 40), we hypothesized that the
carbachol-induced suppression of activity would be stronger in
pharyngeal than in laryngeal motoneuronal groups. The specific aim of
the study was to test this hypothesis by simultaneously measuring the
carbachol-induced changes in the motor activity of selected nerves
innervating these structures. We used paralyzed, vagotomized, and
artificially ventilated decerebrate cats to ensure that the
carbachol-induced changes in neuronal activity were due solely to the
activation of central cholinoceptive mechanisms in the pons and were
not confounded by peripheral feedbacks.
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METHODS |
Animal preparation.
The results reported are from experiments on 12 cats of either sex
(2.5-3.8 kg) preanesthetized with ketamine (100 mg im) and
diazepam (2 mg im), intubated, anesthetized with halothane (0.2-1.0%), and decerebrated at a precollicular level (14). Anesthesia was then discontinued. The procedures used to minimize animal discomfort, for anesthesia, for decerebration, and for all
subsequent preparations of the animal and recording were approved by
the Institutional Animal Care and Use Committee of the University of
Pennsylvania. The surgical methods and recording techniques have been
described in detail previously (13). Recordings began ~9 h after the
injection of ketamine-diazepam and 7 h after the decerebration
(half-life of diazepam in the cat is ~5 h; thus residual effects of
drug were present throughout experiment).
A femoral artery and vein were catheterized for blood pressure
recording and drug administration, respectively. The
C5 branch of the phrenic nerve
(Phr), a dorsal motor branch of C4
and the recurrent laryngeal nerve (RL) on the right side, and the main genioglossal branch of the hypoglossal nerve (XII) and the pharyngeal branch of the vagus nerve (Phar) on the left side were prepared for
recording. The left vagus nerve was cut in the midcervical region, and
the right vagus was cut in the thorax, caudal to the origin of the RL.
For pontine microinjections, the bony tentorium was removed and the
dura was reflected to expose the anterior cerebellar vermis. The
animals were paralyzed with gallamine triethiodide (initial dose of 10 mg iv followed by a continuous infusion of 5 mg · kg
1 · h1)
and artificially ventilated at a rate of 16-20
breaths/min with elevated inspired
O2 levels (30-50%). The
partial pressure of inspired CO2
(PICO2) was set
at ~3% to obtain a stable respiratory modulation of nerve activity
(end-tidal CO2 of 4.0-4.5%; Godard Capnograph). Within a given experiment, the
O2 and
CO2 were kept constant, except
when specific changes in CO2 were
produced. The mean arterial blood pressure was monitored continuously
and was always >80 mmHg. Rectal temperature was maintained at
37-38.5°C by a servocontrolled heating pad.
The dissected nerves were placed on bipolar electrodes and immersed in
mineral oil pools. The neural activities were amplified (Grass P511,
bandwidth 30-3,000 Hz; Grass Instruments, Quincy, MA) and fed to
analog moving averagers (CWE, MA-821; 200 ms time constant). The moving
averages of the nerves, together with blood pressure and an event
marker, were continuously monitored throughout the experiment on a
chart recorder (Gould TA2000; Gould, Glen Burnie, MD). The raw nerve
activities, event marker, tracheal pressure, end-tidal
CO2 level, and blood pressure were
recorded on a digital tape recorder (Cygnus Technology CDAT-16,
bandwidth 0-2,500 Hz) for further analysis. In five experiments,
the activity in one of the nerves was absent or, for
technical reasons, not suitable for analysis (Table
1).
Glass micropipettes (tip diameters 20-30 µm) were used for
microinjection of solutions of carbachol (10 mM in 0.9% NaCl; Sigma, St. Louis, MO) or atropine sulfate (10 mM in 0.9% NaCl; Sigma). Pontamine sky blue (2%) was added to the carbachol solution to mark
the microinjection site. The drugs were injected with pressure pulses
(NeuroPhore, BH-2), and the volumes ejected were determined by
measuring the movement of the meniscus with a pocket microscope. The
injected volumes of carbachol solution were 60-280 nl,
corresponding to 0.11-0.51 µg; those for atropine were
100-250 nl, corresponding to 0.7-1.76 µg. In a previous
study using this approach, there was no response to an injection of the
vehicle alone (13).
At the end of the experiment, the animal was perfused with 10%
Formalin in saline and the brain stem was removed for subsequent sectioning and histological verification of the microinjection sites.
Experimental protocol.
After a stable control recording had been obtained, carbachol was
injected into the pontine tegmentum on the right side, aiming for
stereotaxic coordinates P3.5, H
4.0, and L2.0 (13). After a
latent period, a characteristic decrease in nerve activity occurred followed by a steady state. Atropine was then used to cause a recovery
from the effects of carbachol. In the cat, within the time frame of an
acute experiment, one can produce only two responses to carbachol, one
from each side of the pons (13). We made 18 carbachol injections in 12 animals: 12 first injections and 6 second injections. The data from
each carbachol injection were considered as a separate test. In Fig. 4,
we indicate which data sets are from animals with two carbachol
injections and whether the given set is from the first or second
injection.
After 10 of the carbachol injections (7 animals, with 7 first
injections and 3 second), atropine was microinjected into the pons and
caused a recovery from the effect of carbachol. For the atropine
microinjections, the carbachol pipette was removed and replaced with
one containing atropine, positioned at the same coordinates. In six of
the seven animals in which the first injection of carbachol was
followed by a pontine microinjection of atropine that caused a full
recovery of activity, a second carbachol microinjection was made in a
symmetrical site on the left side, using the postatropine conditions as
a control. In the remaining animal, the effect of the first injection
of carbachol was reversed by a pontine microinjection followed by an
intravenous injection of atropine (1 mg/animal) and no second injection
of carbachol was made. For the remaining carbachol injections (5 animals, with 5 first injections and 3 second injections), atropine was
injected intravenously rather than in the pons to fully antagonize the
effects of the second carbachol injection.
In three animals, the PICO2
was reduced by turning off the inspired
CO2 to reduce the amplitudes of
the recorded nerve activities. When the amplitude of the phrenic
activity equaled the phrenic amplitude present after the
carbachol-induced suppression, the pattern of the resulting decreases
in upper airway nerve activity was compared with that produced by
carbachol. The CO2 level was then
restored to control value.
Data analysis.
All analyses were performed off line using a personal computer-based
data acquisition and analysis system (EGAA, RC Electronics) and
graphics and statistics software (SigmaPlot and SigmaStat, Jandel).
From the moving average of the phrenic neurogram, we determined the
onset of each inspiration and expiration during the period that was
analyzed; these were used to calculate the respiratory rate and the
duration of inspiration (TI)
and expiration (TE). The mean
amplitude of the peak inspiratory and/or expiratory activity of
each nerve was measured from the moving average
1) during the control period,
2) during the period of maximum
suppression of activity after the carbachol injection,
3) after the recovery produced by
atropine, and 4) after decreasing
the PICO2. Cycle-triggered
averaging of nerve activity was performed during steady-state periods
using the onset of expiration as a trigger. The baseline of the moving
average of the nerve activities was established from those segments of
the recording when there were no spikes during a part of the
respiratory cycle, as verified by observation of the raw nerve
activity. For each experiment, measurements of the various parameters
of the responses were normalized relative to the mean control values
immediately before each carbachol microinjection. The mean number of
respiratory cycles analyzed to derive the average steady-state control
values was 51 ± 7.0 (range of 10-134 cycles, determined by
available duration of data on tape).
Two-tailed Student's paired or unpaired
t-tests with Bonferroni correction
were used for statistical comparisons. Differences were considered
significant when P < 0.05. The
variability of the means is expressed by the standard error throughout
this report.
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RESULTS |
Patterns of spontaneous activity under control conditions.
In addition to the Phr and Phar, whose activities were recorded in all
animals, stable respiratory-modulated activity having a consistent
pattern in control conditions was recorded in the RL in 9, and XII in
10, of the 12 animals. The upper airway nerve activities had a stable
pattern in each animal, but, across different animals, some components
were consistently present, whereas others were variable. Only those
components consistently present were analyzed. Table 1 summarizes the
details of the patterns seen in each animal and nerve.
The main component of RL activity had an inspiratory augmenting pattern
(I-Aug) in all nine animals (see Figs.
1B and
2). In addition, in seven of the nine animals, there was
early expiratory activity with a decrementing pattern
(E-Dec). The latter activity started at the onset of expiration and
then either slowly declined throughout this phase until the inspiratory
onset (long-lasting E-Dec; 4 animals) or ceased before the end of
expiration (short-lasting E-Dec; 3 animals) (see Figs.
1B and 2). Of the remaining two
animals, one had augmenting activity throughout expiration (E-Aug), and the other had a steady level of expiratory activity above that of the
baseline (Tonic).
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Fig. 1.
A: typical effect of carbachol and
atropine microinjections into pontine tegmentum on respiratory nerve
activities and blood pressure (animal 46). All traces with nerve
activities show, on a compressed time scale, moving averages of
corresponding electroneurograms. After pontine carbachol injection (110 nl, left arrow), strong suppression of
the hypoglossal (XII) and pharyngeal (Phar) nerve activities contrasts
with minimal changes in phrenic (Phr) and recurrent laryngeal (RL)
nerves. Blood pressure (BP) showed a small decrease (~5 mmHg). All
changes produced by carbachol were reversed by pontine injection of
atropine into the same pontine site (220 nl,
right arrow).
B: segments of control activity
(left), maximal carbachol-induced
depression (middle), and
postatropine recovery (right) shown
on an expanded time scale to show distinct inspiratory and expiratory
components of RL and Phar activities. After atropine, activity of Phar
had a large early expiratory peak (*), which was very small before
carbachol.
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Fig. 2.
Cycle-triggered averages of moving average of Phr, RL, XII, and Phar
activities during control (thick solid line), carbachol-induced
depression (thin solid line), and after recovery produced by pontine
atropine (dotted line) (animal 53). Prominent early expiratory
component of activity appeared in all upper airway nerves after
atropine. This activity does not represent coughlike bursts because
respiratory cycles containing such bursts were excluded from averaging.
Vertical dashed line shows time at which traces were aligned
(triggered) during averaging. Sixteen to thirty-three sweeps were
averaged in each condition.
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The activity of XII was principally I-Aug (all 10 animals) (see Figs.
1B and 2). In addition, an expiratory
component occurred with a short-lasting E-Dec pattern (3 animals)
and/or a Tonic pattern (3 animals).
The activity of Phar was predominantly expiratory. In 11 of the 12 animals, it had a late E-Aug pattern (see Fig.
1B); in the remaining animal,
animal
37 (Table 1), it had a long-lasting E-Dec pattern. In addition to this main expiratory component, seven
animals had a small component of I-Aug activity (see Fig. 1B), three had a distinct initial
peak of short-lasting E-Dec activity (see Fig.
1B), and one had a long-lasting
E-Dec pattern.
In addition to the phasic activity occurring with the respiratory
rhythm, in four animals there were intermittent, large-amplitude bursts
of activity having a stereotyped pattern and position within the
respiratory cycle. The bursts started at the onset of expiration and
subsequently declined with a fixed temporal sequence in RL, XII, and
Phar (see Fig. 6 and Table 1). Because they resembled the activity
observed during spontaneous or reflexly evoked coughs recorded from
upper airway nerves by others (7, 33; see Ref. 46 for review), we refer
to them as coughlike bursts.
Carbachol-induced suppression of respiratory activity.
After a variable latency (range 0.5-14 min; mean 3.8 ± 1.2),
pontine microinjections of carbachol always caused a suppression of
spontaneous activity in all upper airway nerves, which developed with a
similar time course in all nerves. This suppression was accompanied by
small decreases in Phr activity in 15 out of 18 injections and in
arterial blood pressure in 17 out of 18 injections. A typical response
(animal
46; see Table 1) is shown in Fig. 1A. Figure
1B illustrates the patterns of nerve
activity in selected segments of the same record on an expanded time
scale during the control period, after carbachol microinjection, and
after the recovery produced by pontine microinjections of atropine.
After carbachol, the activity of all nerves remained depressed for at
least 10 min; then a slow, spontaneous recovery began, which could be
accelerated by injecting atropine into the site where carbachol was
injected earlier (Fig. 1A). The
time course of the recovery produced by pontine atropine, although
typically less rapid than the depressant response to carbachol, was
always similar in all nerves. All intravenous injections of atropine resulted in the reappearance of all those components of nerve activity
that were depressed by carbachol, thus demonstrating the cholinergic
nature of the depression. However, Phr activity was often reduced after
intravenous atropine, and the increases in respiratory rate were more
prominent than those after pontine atropine, suggesting that atropine
exerted additional central effects beyond the pontine region affected
by carbachol. Therefore, quantitative data about changes in nerve
activities after intravenous atropine are not included in this report.
The relative magnitude of the carbachol-induced depression of the main
component of each nerve's activity was always larger in XII and Phar
than in RL and Phr (Fig. 1A). In
addition, distinct components of each nerve's activity were suppressed
to different degrees. In Fig. 1B, both
the I-Aug and the short-lasting E-Dec component of RL activity were
moderately suppressed after carbachol. The I-Aug activity in XII was
more strongly suppressed than that of the RL. Of the three components
that could be distinguished in the control Phar activity, the E-Aug and
the small, short-lasting E-Dec were abolished, whereas the small I-Aug
component remained intact or slightly increased. After the pontine
injection of atropine, the main components of RL, XII, and Phar
activity recovered to a level greater than that before carbachol.
To assess the magnitude of the pontine carbachol- and atropine-induced
changes in the activity of the different nerves, the main component(s)
of each nerve's activity was measured from the cycle-triggered
averages under each condition (Fig. 2). For RL, the amplitudes of the
I-Aug activity and E-Dec activity were measured. For Phar, the
amplitude of the E-Aug activity was measured after the 16 carbachol
injections in 11 animals in which such a pattern was present. For Phr
and XII, only the amplitudes of their I-Aug activities were measured.
Figure 3 shows the mean magnitudes of the
analyzed components of respiratory activity of each nerve after pontine
carbachol, expressed relative to the magnitude of the corresponding
component in the control condition (100%). After carbachol, the
magnitude of the activity of all nerves was significantly less than
control. Mean Phr activity decreased to 87 ± 3.0% of control
(n = 18 injections, P < 0.001),
RLI-Aug activity decreased to 79 ± 3.1% (n = 13, P < 0.001 ),
RLE-Dec activity decreased to 72 ± 4.7% (n = 10, P < 0.01),
XIII-Aug activity decreased to 15 ± 3.2% (n = 15, P < 0.001), and
PharE-Aug activity decreased to
8.3 ± 2.9% (n = 16, P < 0.001). The mean arterial blood
pressure decreased by 12 ± 1.8 mmHg
(n = 18), corresponding to a
relative mean decrease to 89 ± 1.3% of control
(n = 18, P < 0.001). The mean
TI was 3.1 ± 0.5 s (median = 5.3 s) during the control period and 3.2 ± 0.6 s (median = 6.6 s)
after carbachol, and the mean TE
was 5.1 ± 0.4 s (median = 5.8 s) during control and 5.9 ± 0.6 s
(median = 8.3 s) after carbachol. The
TI and
TE values and their differences before and after carbachol were not distributed normally and, therefore, were analyzed after a logarithmic conversion. After the
carbachol injections, log TI did
not change significantly (n = 18, P > 0.9), whereas log
TE was significantly larger
(n = 18, P < 0.05). The average respiratory
rate increased >10% of control in one trial (from 6.2 to 7.0 breaths/min), decreased more than 10% of control in seven trials (from
a mean of 7.4 ± 1.1 to a mean of 6.2 ± 1.1), and remained
unchanged in ten trials (mean 8.8 ± 0.8). The magnitude of the
carbachol-induced suppression was not significantly different between
RLI-Aug and
RLE-Dec activity or between
XIII-Aug and
PharE-Aug activity. In contrast,
RLI-Aug and
RLE-Dec activities were
significantly (P < 0.05) less
suppressed than either XIII-Aug or
PharE-Aug (paired
t-tests with Bonferroni correction).
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Fig. 3.
Magnitude of carbachol-induced depression of nerve activities, blood
pressure, and respiratory timing changes. Mean amplitudes of the
following components of respiratory activities: inspiratory (I) in Phr,
inspiratory and expiratory (E) in RL augmenting (Aug)
(RLI-Aug) and RL decrementing
(Dec) (RLE-Dec), inspiratory in
the XII (XIII-Aug), and
expiratory in Phar (PharE-Aug),
and of arterial BP and durations of inspiration
(TI) and expiration
(TE) are normalized to their
control values. * P < 0.05;
** P < 0.01 (paired
t-tests);
n = number of responses to carbachol
(i.e., number of injections) for which corresponding measurements were
obtained.
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The consistency of the overall pattern of the carbachol-induced
suppression is illustrated in Fig. 4. The
data are presented in their rank order according to the change of Phr
activity after the carbachol injection relative to control (100%). In
all but one case, the activities of RL and Phr after carbachol were
>60% of control, whereas those of XII and Phar were always <40%
of control.
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Fig. 4.
Stereotyped pattern of carbachol-induced suppression of nerve
activities. Peak activities of Phr,
RLI-Aug,
XIII-Aug, and
PharE-Aug after each
microinjection of carbachol are presented relative to their control
value and arranged in rank order according to relative depression of
Phr activity. Labels on abscissa refer
to animal numbers given in Table 1; number to
right of slash indicates whether it
was the first or second injection of carbachol in that animal. For
simplicity, changes in expiratory component of RL were omitted; they
closely followed those of RL inspiratory component (see Fig. 3). Note
that, in all trials, Phar and XII activities became silent or were
depressed to <40% of control
(bottom dotted line), whereas in all
but one case, Phr and RL activities were suppressed by <40%
(top dotted line). Dashed line is
control, precarbachol level, 100%.
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In seven animals, the recovery from the effect of the first, and then
second (n = 3), injection of carbachol
was produced by pontine injections of atropine. After a new steady
state was reached, the nerve activities were in most cases greater than those measured in the precarbachol control state (see Figs. 1 and 2):
Phr, eight of ten trials;
XIII-Aug, eight of nine trials; RLI-Aug and
RLE-Dec, seven of seven trials;
and PharE-Aug, six of nine trials.
Figure 5 shows the mean amplitudes of the
postcarbachol and postatropine activities in each nerve relative to the
precarbachol control amplitude (100%). For these 10 trials, the
amplitude of Phr activity after carbachol was at 84 ± 4.9% of the
precarbachol control (n = 10, P < 0.01), and after
atropine it increased to 136 ± 17% of the precarbachol control
(n = 10, P < 0.05); for RLI-Aug, the amplitude was 75 ± 4.8% (n = 7, P < 0.01) and 113 ± 3%
(n = 7, P < 0.01), respectively; for
RLE-Dec, the amplitude was 70 ± 7.3% (n = 6, P < 0.01) and 169 ± 18% (n = 6, P < 0.01), respectively; for
XIII-Aug, the amplitude was 15 ± 4.4% (n = 9, P < 0.001) and 204 ± 52% (n = 9, P < 0.01), respectively; and for
PharE-Aug, the amplitude was 9 ± 4.1% (n = 10, P < 0.001) and 144 ± 39%
(n = 10, P > 0.1), respectively. Thus only
the postatropine overshoot of
PharE-Aug activity did not reach
statistical significance.
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Fig. 5.
Magnitudes of suppression of nerve activities (open bars) and
subsequent recoveries from effect of carbachol produced by pontine
atropine into same pontine site (hatched bars). Mean magnitudes of Phr,
RLI-Aug,
RLE-Dec,
XIII-Aug, and
PharE-Aug activities are
normalized to their control, precarbachol values. After atropine,
activities of all nerves were larger than in precarbachol control, with
overshoot being significant in all nerves but Phar.
* P < 0.05, ** P < 0.01, *** P < 0.001 for comparisons
to precarbachol control (paired
t-tests);
n = number of tests with carbachol and
subsequent reversals of effect with atropine.
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Carbachol-induced depression of spontaneous cough-like activity.
In four animals, short, stereotyped bursts of activity were generated
spontaneously in the upper airway nerves at the time of inspiratory
offset (Fig. 6; see also Table 1). In an
individual animal, the bursts occurred fairly regularly, albeit, among
animals, the interburst intervals ranged from 2 to 27 respiratory
cycles. The amplitude of the bursts relative to the main respiratory
components of activity was always the largest in Phar. Their duration,
as measured from Phar activity, ranged from 390 to 520 ms (mean 435 ± 29 ms; n = 4).
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Fig. 6.
A: effect of carbachol (110 nl) and
subsequent atropine (140 nl) microinjections into same site of pontine
tegmentum on moving averages of nerve activities in an animal
generating coughlike bursts (animal 53). Bursts were abolished after
carbachol injection (left arrow) and
reappeared after ~8 min when first signs of a spontaneous recovery
(small respiratory-modulated activity in Phar,
middle arrow) occurred. After a
pontine injection of atropine that fully reversed the effect of
carbachol (right arrow), bursts
occurred even more frequently than in the precarbachol control period.
Note that amplitude of coughlike bursts remained constant regardless of
carbachol-induced changes in magnitude of respiratory activity in upper
airway nerves. B: segments of control
(left), and postatropine recovery
(right) activity shown on expanded
time scale. Additional bursts that, unlike the coughlike bursts,
occasionally occurred only in XII were not analyzed.
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In these four animals, seven pontine microinjections of carbachol and
five injections of atropine were made. Figure 6 illustrates the results
of one experiment (animal
53). In this and one other animal,
the cough-like bursts were abolished after carbachol (Fig. 6A), began to appear at full
magnitude when signs of a spontaneous recovery could be recognized from
the reappearance of a small respiratory modulation in XII and Phar, and
occurred with increased frequency after an injection of atropine. In
the remaining two animals, the bursts persisted during the maximal
suppressant effect of carbachol, but their interburst interval
increased to 165 ± 15% of control (4 carbachol microinjections in
2 animals, P < 0.05). After the
reversal of the effect of carbachol by pontine atropine, the interburst
interval decreased below the precarbachol level to 81 ± 14%, and
the amplitude of the bursts in Phar recovered to 101 ± 1.4% of
precarbachol control (not significant,
P > 0.2, and
P > 0.3, respectively,
n = 5, paired
t-tests). In those two animals (4 microinjections) in which the bursts were not abolished by carbachol,
carbachol decreased the mean amplitude of the coughlike bursts in Phar
only to 87 ± 2.7% of control (P < 0.05).
Comparison of the effect of carbachol and reduced
PICO2 on upper airway
nerve activity.
As described, carbachol might have produced some depression of the
central inspiratory drive, as evidenced by a significantdecrease of Phr
activity. In inspiratory-modulated upper airway motoneurons, which may
have steeper input-output characteristics for the central inspiratory
drive input than Phr (11), such a depression could contribute
importantly to their carbachol-induced decrease in activity. To assess
this possibility, we compared the magnitude of the carbachol-induced
decrease in upper airway nerve activity to the magnitude of activity
that was present when the reduced PICO2 diminished the
respiratory drive to the point at which the Phr amplitude was reduced
by the same amount as it was by carbachol. The tests with reduced
PICO2 were performed either
before the carbachol microinjection or after completion of the protocol
with the carbachol and atropine microinjections. Similar results were
obtained in all five tests in three animals, and the data were
combined.
Figure 7 summarizes the changes in activity
induced by carbachol and hypocapnia when the decreases of Phr activity
were equivalent (to 83 ± 3.8 and 83 ± 3.9% of control,
respectively, n = 5). The activities
of all upper airway nerves were suppressed to a significantly greater
degree by carbachol than by hypocapnia. For
RLI-Aug activity, the mean
relative depression due to carbachol microinjections and hypocapnia was
to 77 ± 4.2 and 90 ± 3.3% of control, respectively (P < 0.05, paired
t-test); for
RLE-Dec, the depression was to 66 ± 5.3 and 94 ± 3.7%, respectively
(P < 0.05); for
XIII-Aug, the depression was to 15 ± 7.4 and 74 ± 8.5%, respectively
(P < 0.01); and for
PharE-Aug, the depression was to
2.8 ± 2.8 and 88 ± 6.1%, respectively
(P < 0.01). The changes in
TI and
TE induced by either carbachol
or hypocapnia were not significant (P > 0.1). Thus the strong, differential suppression of Phar and XII
motoneuronal activity was a characteristic of the effect of carbachol
because the magnitudes of suppression induced by hypocapnia were
similar in RLI-Aug,
RLE-Dec,
XIII-Aug, and
PharE-Aug activities
(P > 0.05, paired
t-tests with Bonferroni correction;
see Fig. 7).
View larger version (31K):
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|
Fig. 7.
Comparison of magnitudes of suppression of respiratory nerve activity
by pontine carbachol microinjection (open bars) and reduced partial
pressure of inspired CO2
(PICO2, hatched bars) in
same group of animals. Upper airway nerve activities were measured
after reducing PICO2 so that
decrease of Phr activity was equal to that after carbachol
microinjection in same animal. Mean values of Phr,
RLI-Aug,
RLE-Dec,
XIII-Aug, and
PharE-Aug activities are
normalized to their control precarbachol and prereduced
CO2 values. In all upper airway
nerves, carbachol-induced suppression was larger than that produced by
lowering PICO2.
* P < 0.05 and
** P < 0.01 for comparisons to
precarbachol control (paired t-tests);
n = number of tests with
carbachol and hypocapnia.
|
|
| |
DISCUSSION |
We used a pharmacological model of REM sleep-like postural atonia and
respiratory depression, a decerebrate cat with carbachol injected into
a specific region of the dorsal pontine reticular formation, to study
the pattern of changes in pharyngeal and laryngeal motoneuronal
activity. As outlined in the introduction, the model has been
extensively validated by comparisons of the cellular and behavioral REM
sleep-like effects of carbachol in both intact and decerebrate animals
to those of natural REM sleep (see Refs. 2 and 25 for reviews). Three
features of the particular preparation used in the present study need
to be highlighted. First, the animals were paralyzed and artificially
ventilated at a constant rate and volume, thereby allowing one to
observe the central effects of carbachol in the absence of confounding
reflex effects. Second, because the animals were decerebrate, the
results were not confounded by anesthesia (decerebration and the
residual effects of diazepam could have had their own effects that were
difficult to quantify and relate to natural conditions). Third,
vagotomy removed the suppressant effect of vagal afferents on the
activity of the XII and RL nerves, resulting in strong, consistent
respiratory modulation in these upper airway nerves. Although we did
not directly measure the effect of vagotomy on Phar activity, lung
inflation reduces the activity of a wide variety of upper airway nerves
and muscles (inspiratory and expiratory; nasal, laryngeal, and
pharyngeal) and therefore probably also the activity of Phar (see Ref.
12 for review). In contrast, in nonvagotomized animals or
normal human subjects, the activities of XII and pharyngeal
motoneurons, or the corresponding muscles, are often variable, making
changes in their activity, especially decreases, difficult to quantify.
Under these conditions, we observed a highly consistent and
differential suppressant effect of carbachol on upper airway nerve activity. The suppression was always greater in the motor nerves that
innervate pharyngeal muscles (Phar and XII) than in either the
inspiratory or expiratory components of RL nerve activity. The time
courses of the changes in activity induced by carbachol or atropine
were similar in all the upper airway nerves, indicating that there is a
common system in the pontine tegmentum whose activation by carbachol
leads to stereotyped changes in these different upper airway
motoneuronal pools.
In the cat, RL innervates the posterior cricoarytenoid (PCA),
thyroarytenoid, lateral cricoarytenoid, and arytenoideus muscles. Of
those, PCA is a dilator having mostly inspiratory-related, and some
expiratory and tonic, activity, whereas the remaining muscles are
constrictors with predominantly expiratory activity. Phar innervates
the pharyngeal constrictor muscles (cricopharyngeus, thyropharyngeus,
and hyopharyngeus), which have mostly expiratory, and some tonic,
activity. The respiratory function of these pharyngeal muscles seems to
improve airway patency by stiffening the posterior pharyngeal wall (22,
24). Finally, the medial branch of the XII nerve innervates
predominantly the genioglossal muscle of the tongue, a pharyngeal
dilator with mostly inspiratory, and some early expiratory and tonic,
activity (see Refs. 3 and 12 for reviews). The principal distinct
components of activity recorded from RL, Phar, and XII nerves closely
corresponded to the activities recorded by others from the main upper
airway muscles innervated by those nerves. Nevertheless, because we
recorded the activity of entire nerve trunks, the interpretation of our results in terms of the behavior of individual upper airway muscles needs to be cautious. For example, RL innervates several muscles that
have an E-Dec activity pattern, and the activity of the motoneurons to
different muscles may not have been equally suppressed by carbachol. Therefore, the carbachol-induced reduction of
RLE-Dec activity to 72% of
control could have resulted from the activity of motoneurons to some
muscles being almost completely suppressed and others having very
little change. Thus it is possible that the activity of some laryngeal
motoneurons contained in the RL was suppressed to a much greater extent
than the average for the whole
RLE-Dec activity.
Differential carbachol-induced suppression of upper airway nerve
activity.
The magnitude of the carbachol-induced suppression was not uniform
among the studied pharyngeal and laryngeal nerves. There were minimal
differences in the effect of carbachol between
RLI-Aug and
RLE-Dec activity and between
PharE-Aug and
XIII-Aug activity, with both
components of RL activity suppressed much less than the activity in the
pharyngeal nerves. Thus the observed differences in the magnitude of
the suppression cannot be related to differences between inspiratory-
and expiratory-related motoneurons or to the anatomic location of the
motoneuronal pools, such as hypoglossal versus ambiguus motor nuclei.
In addition, the distinction between laryngeal and pharyngeal
motoneurons is also not absolute, because the activity of at least one
laryngeal muscle with expiratory activity (arytenoideus) is strongly
depressed during REM sleep (20). Thus we could discern no
criterion that was helpful in making predictions about the effect of
REM sleep on the activity of motoneurons innervating distinct
respiratory muscles; rather, each individual muscle seems to have its
own characteristic behavior during changes in sleep-wakefulness states.
Not only the magnitude of, but also the mechanisms causing, the
reduction of motoneuronal activity during REM sleep (and also carbachol-induced atonia) may be different in different motoneuronal pools. Lumbar motoneurons are subjected to a postsynaptic inhibition (8, 30, 31) that can be abolished by strychnine, a glycinergic antagonist (4). In contrast, neither strychnine nor bicuculline, a
GABAergic antagonist, abolishes the carbachol-induced suppression of
XII motoneuronal activity (17), and only part of the REM sleep
suppression of reflexly evoked trigeminal motoneuronal activity can be
explained by an active, postsynaptic inhibition mediated by amino acids
(43). Thus it is possible that a combination of mechanisms underlies
the suppression of activity in the studied upper airway motoneurons
(17, 37).
The observed differences in the magnitude of the suppression must be
related to the pattern of innervation of the different motoneuronal
pools, the pattern of the effects of pontine carbachol on the activity
of the relevant premotor neurons, and the properties of the motoneurons
themselves. In particular, carbachol-induced changes in the phasic
inspiratory and expiratory drives and in tonic inputs (both excitatory
and inhibitory) need to be considered as contributors to the
characteristic pattern of the changes in motoneuronal activity. With
regard to the tonic inputs, it was previously proposed that a
withdrawal of serotonergic excitation plays a major role in the
suppression of XII motoneurons during the carbachol-induced atonia
(19). In a follow-up study, it was determined that the activity of
medullary serotonergic cells with axonal projections to the XII nucleus
is depressed during the carbachol-induced atonia (48) and, more
recently, it was found that laryngeal motoneurons, both inspiratory and
expiratory, are less sensitive than XII motoneurons to the excitatory
effects of serotonin (6). Thus laryngeal activity may be less dependent on an excitatory serotonergic drive. This could explain, at least in
part, the weaker effect of carbachol on laryngeal than XII motoneurons.
In contrast to the tonic serotonergic drive that is withdrawn both in
natural REM sleep and the carbachol-induced atonia, central respiratory
drive is increased during natural REM sleep (34) and only slightly
suppressed in the decerebrate carbachol model (18). Accordingly, we
hypothesize that, at least under our experimental conditions, the
serotonergic drive in XII, and perhaps also in Phar, motoneurons is
more dominant than the respiratory drive, whereas the opposite prevails
in laryngeal motoneurons. This difference may contribute importantly to
the differential effects of carbachol on pharyngeal and laryngeal motoneurons observed in this study.
Although the reduction in the activity of medullary respiratory neurons
elicited by carbachol in the decerebrate cat is slight (18), we had to
consider the possibility that changes in central respiratory drive are
not uniformly distributed among different pools of upper airway
motoneurons, thereby contributing to the observed differences in the
magnitude of suppression between pharyngeal and laryngeal activities
(see Ref. 12 for review). To assess this, we used an alternative means
of decreasing central respiratory drive; we induced a level of
hypocapnia sufficient to cause a reduction in Phr activity equal to the
reduction caused by carbachol. At this level of hypocapnia, the
suppression of upper airway motoneuronal activity was less than that
caused by carbachol for all the analyzed upper airway nerves and,
unlike those with carbachol, the magnitudes of suppression were similar
(see Fig. 7). Thus the effects of reducing the central respiratory
drive to a level similar to that potentially occurring during the
carbachol-induced atonia cannot explain the large differences between
laryngeal and pharyngeal activities after carbachol. Although a small
contribution of the decreased respiratory drive to the
carbachol-induced depression of upper airway nerve activity cannot be
excluded, there is a much stronger effect of carbachol exerted through
pathways independent of those mediating the respiratory drive.
Relationship to upper airway activity during REM sleep.
Pontine carbachol injections in either chronically instrumented,
intact, or decerebrate cats produce many signs that are similar to
those seen during REM sleep. However, the carbachol model has some
important differences: phasic, twitchlike activity rarely occurs, the
respiratory rate and pattern is very regular, and the depression of
activity in different respiratory motoneuronal groups is exaggerated
when compared with that recorded during REM sleep, although the overall
pattern is qualitatively similar in the two states (13, 26, 44). With
respect to the quantitative differences found in our study, we believe
that vagotomy ensured a strong respiratory modulation in all upper
airway nerves, which facilitated the assessment of the suppressant
effect of carbachol. In REM sleep, a suppression of the activity of
pharyngeal muscles is most prominent and consistently seen when the
respiratory-related activity is increased, as during experimental
hypercapnia (36) or in patients with sleep apnea (22, 28, 29). In
contrast, the changes in pharyngeal muscle, including genioglossus,
activity that occur during REM sleep under normal conditions in a
variety of species are less consistent and often small (23,
39-41). Thus increasing the baseline activity of upper airway
motoneurons by various means helps reveal the suppressant effects of
sleep on this activity.
Given the large carbachol-induced suppression of the activity of spinal
respiratory motoneurons in the decerebrate cat carbachol model compared
with natural REM sleep (13), we were surprised to observe a relatively
small suppression of RL nerve activity. It was less than that observed
in chronically instrumented, intact cats during either natural REM
sleep or the carbachol-induced REM sleep-like state (26, 35). In REM
sleep, PCA inspiratory activity falls to ~75% of waking (control)
activity and PCA expiratory activity falls to ~30%. During the
carbachol-induced, REM sleep-like state, the suppression of PCA
inspiratory activity is to ~45% of control, and PCA expiratory
activity is to ~40%. One reason for the difference between those
studies in chronic cats and the present study may be the fact that we
measured whole nerve activity and not individual muscle activity.
Another possible explanation is that in our experiments, due to the
vagotomy, the respiratory drive to laryngeal motoneurons was increased.
Because this drive undergoes small changes after pontine carbachol
(18), the magnitude of the depression of activity expressed relative to
the control activity level would be expected to be smaller than in
nonvagotomized animals. Thus vagotomy, by increasing the respiratory
drive in the studied motoneuronal pools, might have enhanced the
contrast between strong effects of carbachol in pharyngeal motoneurons and weak effects in laryngeal motoneurons.
Effects of carbachol-induced atonia on the fictive coughlike
activity.
In four animals, in addition to the respiratory components of upper
airway nerve activity, stereotyped bursts of activity were generated in
control conditions. They occurred at the offset of inspiration every
few respiratory cycles, suggesting that they were entrained to the
respiratory rhythm but generated by a nonrespiratory pattern generator.
They were unlikely to represent fictive swallows because the latter
occurs at variable points of the respiratory cycle, rather than
strictly at the time of inspiratory offset (e.g., Refs. 7 and 33). On
the basis of their similarity to the patterns of activity observed by
others during fictive cough (e.g., Refs. 7 and 33; see Ref. 46 for
review), we refer to those bursts as coughlike although they lack one
component typical of cough behavior, augmented inspiratory activity
preceding the expiratory burst. Alternatively, these bursts may
correspond to fictive sneezes (32).
Regardless of the exact nature of these bursts, they provide additional
insight into the changes induced by carbachol in distinct premotor
inputs to the studied motoneuronal pools. Carbachol produced two
changes in the characteristics of the bursts: a decrease in frequency
(in 2 animals, the bursts were abolished) and a decrease of their
amplitude in Phar which was still much less than the decrease in the
respiratory activity of this nerve. The former indicates
that pontine carbachol evokes changes in the neuronal circuits
responsible for the initiation of the bursts. These changes were larger
than the rate changes produced in the respiratory rhythm generator,
providing another example of differential effects of pontine carbachol.
Decreases in the burst frequency, up to the point of their abolition,
may correspond to the observation that coughs cannot be evoked during
natural REM sleep (see Ref. 1 and references therein).
The small carbachol-induced change in the amplitude of the cough-like
bursts in Phar contrasts with the profound decrease in the magnitude of
the respiratory modulation of Phar activity. Regardless of whether the
observed respiratory activity and the coughlike bursts were generated
in the same or different Phar motoneurons, this comparison reveals the
presence of large differences in the magnitude of the carbachol-induced
suppression within the pool of vagal motoneurons innervating a
restricted region of the pharynx. This further strengthens the
possibility that carbachol, and by extension REM sleep, exerts its
effects on different motoneuronal pools and premotor neurons in a
highly selective manner that is specific for different outputs and
motor behaviors.
In conclusion, we have used injections of carbachol into the dorsal
pontine tegmentum to study the pattern of the REM sleep-like changes in
the respiratory motor output to the diaphragm and selected upper airway
muscles. We found a stereotyped suppression of activity that was
significantly larger in nerves innervating pharyngeal muscles than in
nerves to either laryngeal muscles or the diaphragm. Given the
similarities between the carbachol-induced atonia and that of REM sleep
(2, 25), it is likely that pontine cholinoceptive neurons affect
distinct upper airway motor outputs similarly during both states.
| |
ACKNOWLEDGEMENTS |
This work was supported by National Heart, Lung, and Blood
Institute Grant HL-42236.
| |
FOOTNOTES |
A preliminary report of this study was published in abstract form (16).
Address for reprint requests: R. O. Davies, Animal Biology, 211E VET,
Univ. of Pennsylvania, 3800 Spruce St., Philadelphia, PA 19104-6046.
Received 21 December 1997; accepted in final form 2 July 1998.
| |
REFERENCES |
1.
Anderson, C. A.,
T. E. Dick,
and
J. Orem.
Respiratory responses to tracheobronchial stimulation during sleep and wakefulness in the adult cat.
Sleep
19:
472-478,
1996[Medline].
2.
Baghdoyan, H. A.
Sleep Science: Integrating Basic Research and Clinical Practice. Basel, Switzerland: Karger, 1997, p. 88-116.
3.
Bartlett, D., Jr.
Upper airway motor systems.
In: Handbook of Physiology. The Respiratory System. Control of Breathing. Bethesda, MD: Am. Physiol. Soc., 1986, sect. 3, vol. II, pt. 1, chapt. 8, p. 223-245.
4.
Chase, M. H.,
P. J. Soja,
and
F. R. Morales.
Evidence that glycine mediates the postsynaptic potentials that inhibit lumbar motoneurons during the atonia of active sleep.
J. Neurosci.
9:
743-751,
1989[Abstract].
5.
Duron, B.,
and
D. Marlot.
Intercostal and diaphragmatic electrical activity during wakefulness and sleep in normal unrestrained adult cats.
Sleep
3:
269-280,
1980[Medline].
6.
Fenik, V.,
L. Kubin,
S. Okabe,
A. I. Pack,
and
R. O. Davies.
Differential sensitivity of laryngeal and pharyngeal motoneurons to iontophoretic application of serotonin.
Neuroscience
81:
873-885,
1997[Medline].
7.
Gestreau, C.,
S. Milano,
A. L. Bianchi,
and
L. Grélot.
Activity of dorsal respiratory group inspiratory neurons during laryngeal-induced fictive coughing and swallowing in decerebrate cats.
Exp. Brain Res.
108:
247-256,
1996[Medline].
8.
Glenn, L. L.,
and
W. C. Dement.
Membrane resistance and rheobase of hindlimb motoneurons during wakefulness and sleep.
J. Neurophysiol.
46:
1076-1088,
1981[Free Full Text].
9.
Guilleminault, C.,
M. W. Hill,
F. B. Simmons,
and
W. C. Dement.
Obstructive sleep apnea: electromyographic and fiberoptic studies.
Exp. Neurol.
62:
48-67,
1978[Medline].
10.
Harding, R.,
S. J. England,
J. R. Stradling,
L. F. Kozar,
and
E. A. Phillipson.
Respiratory activity of laryngeal muscles in awake and sleeping dogs.
Respir. Physiol.
66:
315-326,
1986[Medline].
11.
Haxhiu, M. A.,
E. van Lunteren,
J. Mitra,
and
N. S. Cherniack.
Responses to chemical stimulation of upper airway muscles and diaphragm in awake cats.
J. Appl. Physiol.
56:
397-403,
1984[Abstract/Free Full Text].
12.
Iscoe, S. D.
Respiratory Function of the Upper Airway. New York: Dekker, 1988, p. 125-192.
13.
Kimura, H.,
L. Kubin,
R. O. Davies,
and
A. I. Pack.
Cholinergic stimulation of the pons depresses respiration in decerebrate cats.
J. Appl. Physiol.
69:
2280-2289,
1990[Abstract/Free Full Text].
14.
Kirsten, E. B.,
and
W. M. St. John.
A feline decerebration technique with low mortality and long-term homeostasis.
J. Pharmacol. Methods
1:
263-268,
1978.
15.
Kubin, L.,
R. O. Davies,
and
A. I. Pack.
Control of upper airway motoneurons during REM sleep.
News Physiol. Sci.
13:
91-97,
1998.[Abstract/Free Full Text]
16.
Kubin, L.,
V. Fenik,
A. I. Pack,
and
R. O. Davies.
Stereotyped pattern of suppression of upper airway motor tone during the carbachol-induced, REM sleep-like atonia.
Soc. Neurosci. Abstr.
22:
690,
1996.
17.
Kubin, L.,
H. Kimura,
H. Tojima,
R. O. Davies,
and
A. I. Pack.
Suppression of hypoglossal motoneurons during the carbachol-induced atonia of REM sleep is not caused by fast synaptic inhibition.
Brain Res.
611:
300-312,
1993[Medline].
18.
Kubin, L.,
H. Kimura,
H. Tojima,
A. I. Pack,
and
R. O. Davies.
Behavior of VRG neurons during the atonia of REM sleep induced by pontine carbachol in decerebrate cats.
Brain Res.
592:
91-100,
1992[Medline].
19.
Kubin, L.,
H. Tojima,
R. O. Davies,
and
A. I. Pack.
Serotonergic excitatory drive to hypoglossal motoneurons in the decerebrate cat.
Neurosci. Lett.
139:
243-248,
1992[Medline].
20.
Kuna, S. T.,
G. Insalaco,
and
R. D. Villeponteaux.
Arytenoideus muscle activity in normal adult humans during wakefulness and sleep.
J. Appl. Physiol.
70:
1655-1664,
1991[Abstract/Free Full Text].
21.
Kuna, S. T.,
and
G. Sant'Ambrogio.
Pathophysiology of upper airway closure during sleep.
JAMA
266:
1384-1389,
1991[Abstract].
22.
Kuna, S. T.,
and
J. S. Smickley.
Superior pharyngeal constrictor activation in obstructive sleep apnea.
Am. J. Respir. Crit. Care Med.
156:
874-880,
1997[Abstract/Free Full Text].
23.
Kuna, S. T.,
J. S. Smickley,
and
C. R. Vanoye.
Respiratory-related pharyngeal constrictor muscle activity in normal human adults.
Am. J. Respir. Crit. Care Med.
155:
1991-1999,
1997[Abstract].
24.
Kuna, S. T.,
and
C. R. Vanoye.
Respiratory-related pharyngeal constrictor muscle activity in decerebrate cats.
J. Appl. Physiol.
83:
1588-1594,
1997[Abstract/Free Full Text].
25.
Lydic, R.
Sleep Science: Integrating Basic Research and Clinical Practice. Basel, Switzerland: Karger, 1997, p. 117-142.
26.
Lydic, R.,
H. A. Baghdoyan,
and
C. W. Zwillich.
State-dependent hypotonia in posterior cricoarytenoid muscles of the larynx caused by cholinoceptive reticular mechanisms.
FASEB J.
3:
1625-1631,
1989[Abstract].
27.
Megirian, D.,
C. F. L. Hinrichsen,
and
J. H. Sherrey.
Respiratory roles of genioglossus, sternothyroid, and sternohyoid muscles during sleep.
Exp. Neurol.
90:
118-128,
1985[Medline].
28.
Mezzanotte, W. S.,
D. J. Tangel,
and
D. P. White.
Influence of sleep onset on upper-airway muscle activity in apnea patients versus normal controls.
Am. J. Respir. Crit. Care Med.
153:
1880-1887,
1996[Abstract].
29.
Mezzanotte, W. S.,
D. J. Tangel,
and
D. P. White.
Waking genioglossal electromyogram in sleep apnea patients versus normal controls (a neuromuscular compensatory mechanism).
J. Clin. Invest.
89:
1571-1579,
1992.
30.
Morales, F.,
and
M. H. Chase.
Postsynaptic control of lumbar motoneuron excitability during active sleep in the chronic cat.
Brain Res.
225:
279-295,
1981[Medline].
31.
Morales, F. R.,
J. K. Engelhardt,
P. J. Soja,
A. E. Pereda,
and
M. H. Chase.
Motoneuron properties during motor inhibition produced by microinjection of carbachol into the pontine reticular formation of the decerebrate cat.
J. Neurophysiol.
57:
1118-1129,
1987[Abstract/Free Full Text].
32.
Nonaka, S.,
T. Unno,
Y. Ohta,
and
S. Mori.
Sneeze-evoking region within the brainstem.
Brain Res.
511:
265-270,
1990[Medline].
33.
Oku, Y.,
I. Tanaka,
and
K. Ezure.
Activity of bulbar respiratory neurons during fictive coughing and swallowing in the decerebrate cat.
J. Physiol. (Lond.)
480:
309-324,
1994[Medline].
34.
Orem, J.
Excitatory drive to the respiratory system in REM sleep.
Sleep
19:
S154-S156,
1996[Medline].
35.
Orem, J.,
and
R. Lydic.
Upper airway function during sleep and wakefulness: experimental studies on normal and anesthetized cats.
Sleep
1:
49-68,
1978[Medline].
36.
Parisi, R. A.,
J. A. Neubauer,
M. M. Frank,
N. H. Edelman,
and
T. V. Santiago.
Correlation between genioglossal and diaphragmatic responses to hypercapnia during sleep.
Am. Rev. Respir. Dis.
135:
378-382,
1987[Medline].
37.
Pedroarena, C.,
P. Castillo,
M. H. Chase,
and
F. R. Morales.
The control of jaw-opener motoneurons during active sleep.
Brain Res.
653:
31-38,
1994[Medline].
38.
Remmers, J. E.
Regulation of Breathing. Part II. New York: Dekker, 1981, p. 1197-1249.
39.
Richard, C. A.,
and
R. M. Harper.
Respiratory-related activity in hypoglossal neurons across sleep-waking states in cats.
Brain Res.
542:
167-170,
1991[Medline].
40.
Sauerland, E. K.,
W. C. Orr,
and
L. E. Hairston.
EMG patterns of oropharyngeal muscles during respiration in wakefulness and sleep.
Electromyogr. Clin. Neurophysiol.
21:
307-316,
1981[Medline].
41.
Sherrey, J. H.,
M. J. Pollard,
and
D. Megirian.
Respiratory functions of the inferior pharyngeal constrictor and sternohyoid muscles during sleep.
Exp. Neurol.
92:
267-277,
1986[Medline].
42.
Siegel, J. M.
Principles and Practice of Sleep Medicine (2nd ed.). Philadelphia, PA: Saunders, 1994, p. 125-144.
43.
Soja, P. J.,
D. M. Finch,
and
M. H. Chase.
Effect of inhibitory amino acid antagonists on masseteric reflex suppression during active sleep.
Exp. Neurol.
96:
178-193,
1987[Medline].
44.
Tojima, H.,
L. Kubin,
H. Kimura,
and
R. O. Davies.
Spontaneous ventilation and respiratory motor output during carbachol-induced atonia of REM sleep in the decerebrate cat.
Sleep
15:
404-414,
1992[Medline].
45.
Vanni-Mercier, G.,
K. Sakai,
J. S. Lin,
and
M. Jouvet.
Mapping of cholinoceptive brainstem structures responsible for the generation of paradoxical sleep in the cat.
Arch. Ital. Biol.
127:
133-164,
1989[Medline].
46.
Widdicombe, J. G.
Reflexes from the upper respiratory tract.
In: Handbook of Physiology. The Respiratory System. Control of Breathing. Bethesda, MD: Am. Physiol. Soc., 1986, sect. 3, vol. II, pt. 1, chapt. 11, p. 363-394.
47.
Wiegand, L.,
C. W. Zwillich,
D. Wiegand,
and
D. P. White.
Changes in upper airway muscle activation and ventilation during phasic REM sleep in normal men.
J. Appl. Physiol.
71:
488-497,
1991[Abstract/Free Full Text].
48.
Woch, G.,
R. O. Davies,
A. I. Pack,
and
L. Kubin.
Behavior of raphe cells projecting to the dorsomedial medulla during carbachol-induced atonia in the cat.
J. Physiol. (Lond.)
490:
745-758,
1996[Medline].
Am J Physiol Regul Integr Compar Physiol 275(4):R1013-R1024
0002-9513/98 $5.00
Copyright © 1998 the American Physiological Society
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Abstract
Introduction
