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Department of Pediatrics, Case Western Reserve University, Cleveland, Ohio 44106
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Stimulation of the superior laryngeal nerve (SLN) results in apnea in animals of different species, the mechanism of which is not known. We studied the effect of the GABAA receptor blocker bicuculline, given intravenously and intracisternally, on apnea induced by SLN stimulation. Eighteen 5- to 10-day-old piglets were studied: bicuculline was administered intravenously to nine animals and intracisternally to nine animals. The animals were anesthetized and then decerebrated, vagotomized, ventilated, and paralyzed. The phrenic nerve responses to four levels of electrical SLN stimulation were measured before and after bicuculline. SLN stimulation caused a significant decrease in phrenic nerve amplitude, phrenic nerve frequency, minute phrenic activity, and inspiratory time (P < 0.01) that was proportional to the level of electrical stimulation. Increased levels of stimulation were more likely to induce apnea during stimulation that often persisted beyond cessation of the stimulus. Bicuculline, administered intravenously or intracisternally, decreased the SLN stimulation-induced decrease in phrenic nerve amplitude, minute phrenic activity, and phrenic nerve frequency (P < 0.05). Bicuculline also reduced SLN-induced apnea and duration of poststimulation apnea (P < 0.05). We conclude that centrally mediated GABAergic pathways are involved in laryngeal stimulation-induced apnea.
superior laryngeal nerve; GABAA receptors; reflex-induced apnea; control of breathing; apnea of prematurity
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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STIMULATION OF THE LARYNGEAL mucosa results in apnea in humans as well as in animals of different species (10, 19, 27, 37). This reflex apnea is mediated via stimulation of the superior laryngeal nerve (SLN) (10, 21). It has been suggested that an exaggerated reflex response in newborns may be implicated in multiple pathological processes, including gastroesophageal reflux-induced apnea (19), sudden infant death syndrome (5, 38), and apnea of prematurity (27).
The laryngeal inhibitory reflex has been shown to be influenced by maturation (9, 21, 24, 34). Lee et al. (21) demonstrated respiratory arrest in newborn piglets by maintaining chemical stimulation of the larynx; older piglets did not express a similar response. This maturational change in the laryngeal inhibitory reflex was also found in dogs, monkeys, sheep, and cats (24, 31, 34, 37), as well as in preterm infants (27). However, the mechanisms underlying the maturational changes in the laryngeal reflex are not known. The fact that respiratory arrest may persist beyond the period of laryngeal stimulation suggests stimulation of a central neural mechanism that inhibits respiratory rhythm after cessation of the stimulus (18).
GABA is the major inhibitory neurotransmitter in the central nervous system. GABA expresses its effect through stimulation of ionotropic fast chloride receptors (GABAA) or metabotropic receptors (GABAB) to produce slow prolonged inhibitory signals (28). GABA has been implicated in control of breathing (12) and was found to inhibit breathing mainly via activation of GABAA receptors (12, 13). GABAA receptors have been shown to undergo maturational changes in rats (39). Xia and Haddad (39) demonstrated a much higher GABAA receptor density in the newborn than in the adult rat brain stem. It seems, therefore, that GABA is a good candidate to represent the centrally mediated inhibitory mechanism that controls reflex-induced apnea.
We hypothesized that upregulation of inhibitory neurotransmitter-mediated mechanisms in the brain stem during the neonatal period enhances the susceptibility of newborns to reflex-induced apnea. The aim of this study was to characterize the role of GABA in this phenomenon by blocking the effects of the inhibitory neurotransmitter GABA on SLN stimulation-induced apnea.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Newborn piglets, 5-10 days old, were purchased from a local vendor (n = 18). The animals were divided into two groups according to the route of administration of the GABAA receptor blocker bicuculline: intravenously (n = 9) and intracisternally (n = 9). A warming pad was used to maintain body temperature at 37-38°C. In our initial studies (intravenous bicuculline), animals (n = 9) were anesthetized using inhaled methoxyflurane (Metofane, Pitman Moore). However, when methoxyflurane became unavailable, later animals (intracisternal bicuculline, n = 9) were initially sedated with a mixture of intramuscular xylazine (1.4 mg/kg) and ketamine (7.2 mg/kg) followed by intravenous thiopental sodium (25-30 mg/kg). The trachea was intubated, and the animals were placed on a volume ventilator (Harvard Apparatus). The volume and frequency of tidal breaths were adjusted to maintain a stable eucapneic arterial PCO2 of 35-40 Torr using an end-tidal CO2 analyzer while using an inspired O2 concentration of 100%. A peripheral intravenous line was placed, and the femoral artery was catheterized for blood pressure monitoring and blood gas drawing.
To avoid the confounding effects of anesthesia on breathing and the
laryngeal reflex (10, 21, 24), midcollicular decerebration was performed using the following procedure, as we previously described
in the piglet (6). A 3- to 4-cm-long incision was cut over
the parietal ridge, and the skin was lifted, the skull bone just
rostral to the parietooccipital bony ridge was removed parallel to the
ridge, and the dura mater was exposed. The dura was incised right and
left of the superior sagittal sinus. A thin spatula was introduced
through the incisions at an angle of 70° and advanced until it
touched the floor of the skull; then the spatula was swung gently right
and left, completing the decerebration. The anesthesia was discontinued
after the entire surgery was completed, and the animals were allowed to
recover for 
1 h before any experimental recordings were obtained.
Gallamine triethiodide (10 mg/kg) was used for paralysis.
The phrenic nerve was dissected, desheethed, and placed on a bipolar recording electrode. The phrenic nerve electroneurogram (ENG) was amplified (model PS11, Grass Instruments) and rectified, and the moving average signal was connected to a strip paper recorder and a computer analog. The SLN on one side was identified as it exits from the nodose ganglion, dissected, desheethed, and placed on a bipolar electrode connected to a stimulator (model S11, Grass Instruments). The SLN threshold was identified as the amount of electrical current needed to decrease the phrenic amplitude by 20%. Stimulation was performed using constant-voltage and constant-frequency (25-Hz) impulses, and variable current was applied through a photoelectric isolation unit (model PSIU6, Grass Instruments). Two experimental protocols were employed. In the first protocol (n = 9), the GABAA receptor inhibitor bicuculline was administered intravenously in a continuous infusion over 10 min at a dose of 0.1-0.2 mg/kg body wt. In the second protocol (n = 9), a catheter was placed into the cisterna magna through the atlantooccipital membrane, and patency was verified by withdrawing cerebrospinal fluid. Bicuculline was injected intracisternally at a total dose of 0.1-0.2 mg. The doses of bicuculline were determined from preliminary studies that showed that these doses were not associated with a significant effect on hemodynamic status of the animals.
The phrenic nerve ENG was measured in response to multiple stimulations of the SLN (threshold, 1.5 times threshold, 2 times threshold, and 4 times threshold), each of 15-s duration, before and after intracisternal or intravenous administration of bicuculline.
Data collection and statistical analysis. The data were collected and analyzed using a custom-made computer program. The phrenic nerve discharge at baseline was analyzed for 1 min before SLN stimulation and then for 15 s at each level of stimulation before and after bicuculline administration. The phrenic ENG was analyzed to reflect changes in phrenic nerve amplitude, inspiratory time (TI), expiratory time (TE), and frequency during different levels of stimulation, as well as the duration of apnea after cessation of stimulation. The phrenic nerve amplitude and minute activity (amplitude × frequency) responses were expressed as a percentage of the control values, control being 100%.
One-way ANOVA was used to test the effect of increasing levels of SLN stimulation on phrenic nerve activity before and after bicuculline administration. Two-way ANOVA was used to test the effect of bicuculline administration on the phrenic nerve responses to SLN stimulation, with Newman-Keuls test for post hoc comparisons. Paired t-test was used to compare the duration of poststimulation apnea before and after bicuculline.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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SLN stimulation.
Stimulation of the SLN before bicuculline administration caused a
significant decrease in phrenic nerve amplitude, frequency, TI, and minute phrenic activity (all P < 0.01) that was proportional to the level of stimulation (Fig.
1). Maximal electrical stimulation (at 4 times threshold) caused a decrease in phrenic amplitude to 20 ± 8% of baseline (P < 0.01) and a decrease in minute
phrenic activity to 9 ± 6% of baseline (P < 0.01). Maximal SLN stimulation also caused a significant decrease in
phrenic nerve frequency from 42 ± 4 to 4 ± 2 breaths/min
(P < 0.01). The decrease in frequency was secondary to
significant prolongation of TE (from 0.9 ± 0.1 to
21.1 ± 5.6 s, P < 0.01). SLN stimulation
caused apnea (total cessation of phrenic activity throughout
stimulation) in a greater number of piglets with increased level of
stimulation: 8 of 18 piglets at 1.5 times threshold, 10 of 18 piglets
at 2 times threshold, and 14 of 18 piglets at 4 times threshold. The
duration of poststimulation apnea was also directly related to level of
electrical stimulation (Fig. 1): from 3.3 ± 1.7 s at 1.5 times threshold stimulation to 15.8 ± 7.1 s at 4 times
threshold.
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Effect of bicuculline on baseline phrenic activity. There was no significant effect of bicuculline administration, intravenous and intracisternal, on the baseline phrenic activity. In nine animals, phrenic nerve amplitude was increased after bicuculline administration; in the other nine animals, phrenic nerve amplitude was decreased. Furthermore, there was no correlation between the effect of bicuculline on the baseline phrenic activity and its ability to block the SLN stimulation-induced decrease in phrenic nerve activity.
Intravenous bicuculline.
There was a significant effect of bicuculline on the phrenic nerve
amplitude, frequency, and minute activity responses to SLN stimulation
(P < 0.05, 2-way ANOVA). Intravenous bicuculline blocked the SLN stimulation-induced decrease in phrenic nerve amplitude, minute phrenic activity, and phrenic nerve frequency. At
maximal SLN stimulation, the phrenic nerve amplitude was 70 ± 24% of baseline and the frequency changed from 36 ± 6 to 27 ± 6 breaths/min (not significant). The resultant minute phrenic activity was 71 ± 27% of baseline with maximal SLN stimulation (not significant; Figs. 2 and
3). Bicuculline blocked the decrease in
phrenic nerve frequency with SLN stimulation through inhibition of the
prolongation in TE (Fig. 4).
There was no difference in the TI response to SLN
stimulation before and after bicuculline administration (Fig. 4).
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Intracisternal bicuculline.
There was a significant effect of intracisternal bicuculline on the
phrenic nerve amplitude, frequency, and minute activity responses to
SLN stimulation (P < 0.01, 2-way ANOVA).
Intracisternal bicuculline attenuated, but did not completely block,
the decrease in phrenic amplitude, frequency, and minute phrenic
activity in response to SLN stimulation (Fig.
5). The phrenic nerve amplitude at
maximal SLN stimulation decreased to 24 ± 12% of baseline after bicuculline (P < 0.01) vs. 7 ± 7% before
bicuculline. The phrenic nerve frequency decreased with maximal
stimulation from 37 ± 4 to 16 ± 6 breaths/min after
bicuculline (P < 0.05) vs. 41 ± 3 to 2 ± 2 breaths/min before bicuculline. The resultant decrease in minute
phrenic activity with SLN stimulation was 34 ± 20% of baseline
(P < 0.01) vs. 4 ± 4% before bicuculline. The
attenuation in phrenic nerve frequency response to SLN stimulation with
bicuculline was achieved by a significant decrease in the prolongation
of TE (P < 0.01).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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In this study, we demonstrated the role of centrally mediated GABAergic mechanisms in mediating SLN stimulation-induced apnea. Inhibition of the effect of endogenously released GABA through blocking GABAA receptors almost abolished reflex-induced apnea. Bicuculline given intravenously or intracisternally was able to block SLN stimulation-induced apnea, indicating that the effect of bicuculline is related to blockade of central GABAA receptors and not peripheral actions of bicuculline. This is further supported by the ability of bicuculline to reduce the duration of poststimulation apnea. To our knowledge, this is the first report linking GABAergic mechanisms with reflex laryngeal-induced apnea.
Reflex-induced apnea elicited through stimulation of the laryngeal mucosa has been well characterized in humans and animals of different species. This reflex apnea is mediated through the SLN, inasmuch as bilateral sectioning of the SLN abolishes laryngeal stimulation-induced apnea (8, 10, 21). This reflex apnea is associated with contraction of the thyroarytenoid muscle, causing closure of the glottis and swallowing movements, signifying active stimulation of brain stem centers. The purpose of such inhibition of breathing combined with closure of upper airways through stimulation of the larynx is not clear. However, Kianicka et al. (15) and Renolleau et al. (29) described spontaneous apneas associated with contraction of the thyroarytenoid muscle and swallowing movements in fetal and preterm lambs. These investigators suggested that glottic closure during apnea might enhance prenatal lung development in fetal lambs by preventing pulmonary fluid efflux from the trachea (15) and might support higher lung volumes and alveolar gas exchange in preterm animals (29). On the other hand, persistence of an exaggerated reflex-induced apnea in preterm and full-term infants might predispose to multiple pathological processes such as gastroesophageal reflux-induced apnea (19), apnea of prematurity (27), and sudden infant death syndrome (5, 31, 38).
Newborn animals of different species have been shown to exhibit an exaggerated response to laryngeal stimulation compared with adult animals (9, 21, 24, 34). Chemical stimulation of the larynx in newborn piglets caused respiratory arrest, whereas older piglets did not express a similar response (8, 21). Maturation of the laryngeal inhibitory reflex is also common to a wide variety of other animals, including dogs, monkeys, sheep, and cats (24, 31, 34, 37). Preterm infants also appear to express such an exaggerated inhibitory reflex, inasmuch as they elicit prolonged apnea in response to instillation of saline in the oropharynx (27). The mechanisms underlying such maturational change in reflex-induced apnea are not known; however, they do not seem to be related to changes in laryngeal receptors (11), changes in central synaptic connections, or maturation of the carotid body (7).
GABA is the main inhibitory neurotransmitter in the central nervous system and has been implicated in control of breathing, although the mechanism whereby it induces respiratory inhibition is still under study. Systemic administration of GABA was found to induce apnea in rats (14), thought to occur via activation of GABAA ionic receptors (12, 13). Czyzyk-Krzeska and Lawson (3) reported that hyperpolarization of medullary neurons during SLN stimulation was reversed by chloride current, indicating a chloride-mediated postsynaptic inhibition. This is similar to the hyperpolarization induced by stimulation of GABAA receptors, which causes direct increases in membrane permeability to chloride ions with subsequent hyperpolarization of the membrane potential (28). These data suggest a potential role for endogenously released GABA in mediating reflex-induced apnea. Structural and functional differences in GABAA receptors have been observed during development (1, 16, 23). GABAA receptors are heterooligomers assembled from four different subunits (33). During embryonic and early postnatal development, the "mix" of GABAA receptor subunits differs from that in adults (16, 23). Furthermore, Xia and Haddad (39) demonstrated a much higher GABAA receptor density in the newborn than in the adult rat brain stem. Therefore, maturation of reflex-induced apnea might be related to maturational changes in the GABAergic system.
Multiple investigators have suggested a role for centrally acting
inhibitory neurotransmitters that might mediate reflex-induced apnea
(3, 17, 18, 20). The strongest evidence for the presence
of such an inhibitory neurotransmitter may be the persistence of
poststimulation apnea (18). Inhibitory mechanisms and
neural factors that have been found to modulate laryngeal
stimulation-induced apnea include cholinergic pathways and endorphins
(30, 35, 36). Richardson et al. (30)
found that blockade of M3 muscarinic receptors resulted in
an age-related decrease in apnea duration induced by laryngeal
stimulation. Storm et al. (36) described an increase in
levels of 
-endorphins in cerebrospinal fluid of newborn piglets that
was related to duration of laryngeal stimulation, and pretreatment of
these animals with naloxone decreased the duration of apnea in response
to laryngeal stimulation. Intracisternal injection of -endorphins
has also been shown to potentiate laryngeal stimulation-induced apnea
(35). These data suggest an interactive role for several
neurotransmitters and neuromodulators in eliciting laryngeal
stimulation-induced apnea. Oertel et al. (25, 26) demonstrated a coexistence of opioid peptides and GABA in the same
neurons. Furthermore, several investigators demonstrated reciprocal
mediation between GABA and endogenous opioids (2, 4, 32,
40). Systemic administration of morphine caused a significant
increase in GABA levels in the substantia nigra (40).
Endogenous opioids have also been found to mediate the effect of GABA
on the vasopressin system in humans (2), whereas GABA has
been found to mediate opioid release in rats (32) and its
analgesic effect (4). These data suggest a complex
interaction between several central inhibitory neurotransmitters in the
regulation of neural output, including respiratory control, as
suggested by the present data.
An explanation for our results, other than direct involvement of GABA in the laryngeal stimulation-induced apnea reflex, might be that bicuculline changed the balance between excitatory and inhibitory pathways toward higher chemosensitivity, increasing the threshold for SLN stimulation-induced apnea (22). We and others previously showed that hypercapnia increases, whereas hypocapnia decreases, the threshold for SLN stimulation-induced apnea (17, 22). Cooling of the ventromedullary surface, a technique used to decrease central chemosensitivity by inhibiting synaptic transmission at this site, decreased the threshold for laryngeal stimulation-induced apnea (22). Theophylline, which stimulates respiratory neural output, has been shown to block SLN stimulation-induced apnea (21). Therefore, the overriding level of respiratory neural output or central chemosensitivity might change the threshold for laryngeal stimulation-induced apnea. However, this does not readily explain the ability of GABAA receptor blockade to eliminate poststimulation apnea.
Intravenous bicuculline appeared more effective than intracisternal
bicuculline in blocking the respiratory inhibition induced by SLN
stimulation. The quantitative difference in the responses to
intravenous vs. intracisternal bicuculline might be related to several
factors. In the intracisternal group, the anesthesia used before
decerebration included thiopental, which is known to augment SLN
stimulation-induced apnea (24). Although the study was not
started until 1 h after the last thiopental dose, a residual effect
of thiopental might have contributed to the difference between the two
responses. In addition, the intravenous bicuculline might have reached
deeper groups of brain stem neurons that are involved in the reflex apnea.
This study does not identify the site of release of GABA or the respiratory groups involved in such a response. However, we propose that stimulation of the SLN results in excitation of second-order neurons that contain GABA and project to medullary inspiratory neurons. Release of GABA may result in hyperpolarization and inhibition of these inspiratory-related neurons and subsequent apnea. On the other hand, the depressing effect of SLN stimulation on the phrenic neurogram might represent lack of inspiratory premotor neuron activity in response to a subthreshold level activity of chemosensory neurons. Further studies are clearly needed to clarify these GABA-mediated pathways.
We conclude that centrally mediated GABAergic pathways are involved in laryngeal stimulation-induced apnea. We further speculate that upregulation of GABAergic mechanisms in newborns and preterm infants may enhance their vulnerability to reflex-induced apnea and contribute to important neonatal pathologies, such as gastroesophageal reflux-induced apnea, sudden infant death syndrome, or apnea of prematurity.
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ACKNOWLEDGEMENTS |
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This work was supported by National Heart, Lung, and Blood Institute Grant HL-62527 and a research award from Rainbow Babies and Childrens Hospital.
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FOOTNOTES |
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Address for reprint requests and other correspondence: J. M. Abu-Shaweesh, Div. of Neonatology, Dept. of Pediatrics, 11100 Euclid Ave., Cleveland, OH 44106 (E-mail: jxa16{at}po.cwru.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 25 August 2000; accepted in final form 24 October 2000.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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