Cough, expiration and aspiration reflexes following kainic acid lesions to the pontine respiratory group in anesthetized cats

The importance of neurons in the pontine respiratory group for the generation of cough, expiration, and aspiration reflexes was studied on non-decerebrate spontaneously breathing cats under pentobarbitone anesthesia. The dysfunction of neurons in the pontine respiratory group produced by bilateral microinjection of kainic acid (neurotoxin) regularly abolished the cough reflexes evoked by mechanical stimulation of both the tracheobronchial and the laryngopharyngeal mucous membranes and the expiration reflex mechanically induced from the glottis. The aspiration reflex elicited by similar stimulation of the nasopharyngeal region persisted in 73% of tests, however, with a reduced intensity compared to the pre-lesion conditions. The pontine respiratory group seems to be an important source of the facilitatory inputs to the brainstem circuitries that mediate cough, expiration, and aspiration reflexes. Our results indicate the significant role of pons in the multilevel organization of brainstem networks in central integration of the aforementioned reflexes.     

The expiration reflex in the mouse.

The authors determined the elicitability of the expiration reflex and the mechanoreceptive sensitivity of the respiratory tract in 35 anaesthetized albino mice. They found that the expiration reflex could be elicited from both the oral and the tracheal end and that its intensity was statistically significantly higher in elicitation from the oral end. The only other pronounced respiratory reflexes evoked by mechanical stimulation of the airways were the sneeze reflex and the aspiration reflex, which is present in most animals. The mechanoreceptors of the tracheal and bronchial mucosa were less sensitive to stimulation. In most cases they did not react at all, or with just a single forced inspiration, and at other times only by a change in respiration frequency and amplitude.     

Defensive reflexes of the respiratory tract in dogs.

Intrapleural pressure, the tracheal air flow and tidal volume were recorded simultaneously in pentobarbital-anaesthetized dogs and changes occurring in them during defensive reflexes elicited by mechanical stimulation of the mucosa of different parts of the respiratory tract were evaluated quantitatively. The results show that, in addition to coughing and sneezing provoked by inserting a nylon fibre into the tracheobronchial region, the larynx and the nose, further respiratory reflexes described in other mammals also appear in these animals. Mechanical stimulation of the epipharynx with a fine polyvinylchloride catheter, for instance, also produces in dogs an aspiration reflex characterized by sniff-like inspiratory efforts without subsequent active expiration. Touching the vocal folds, however, produces an expiration reflex consisting of expiratory efforts without preceding inspiratory effort. The character of all these reflexes is typical and closely resembles their character in cats. Stimulation of the various parts of the respiratory tract sometimes evokes an apnoeic reaction instead of typical respiratory defensive reflexes.     

Kainic acid lesions to the lateral tegmental field of medulla: effects on cough, expiration and aspiration reflexes in anesthetized cats

We have tested the hypothesis that neurons of both the ventral reticular nucleus and the adjacent parts of the lateral tegmental field (LTF) may be important for the production of motor programs associated with cough, expiration and aspiration reflexes. Our studies were conducted on non-decerebrate, spontaneously breathing cats under pentobarbitone anesthesia. Dysfunction of the medullary LTF region above the obex, produced by uni- or bilateral injections of kainic acid (a neurotoxin), regularly abolished the cough reflex evoked by mechanical stimulation of both the tracheobronchial and laryngeal regions and in most cases also the expiration reflex induced from the glottal area. However, some electrical activity still occurred in the neurogram of the recurrent laryngeal nerve during probing the laryngeal and glottal regions. Interestingly, the aspiration reflex elicited from the nasopharynx regularly persisted, although with lower intensity after the LTF lesion. Nevertheless, successive midcollicular decerebration performed in four cats also abolished the aspiration reflex. These experiments demonstrate the importance of medullary LTF neurons for the normal occurrence of cough and expiration reflexes. One possible explanation for the elimination of these expulsive processes is that the blockade of the LTF neurons may remove an important source of a facilitatory input to the brainstem circuitries that mediate cough and expiration reflexes. In addition, the potential importance of the mesencephalic reticular formation for the occurrence of the aspiration reflex and the role of the LTF in modulating both the eupnoeic breathing and the blood pressure are also discussed.     

Postnatal development of the Hering-Breuer reflex in the rat

The intensity of the Breuer-Hering inflation reflex was studied in newborn (1 day old), in young (8 days old) and in adult rats (90 days old) under urethane general anaesthesia (1.3 g/kg i.p.). The inflation pressure was adjusted with the aid of a water-valve. The reflex was present in all 3 age groups. An inflation pressure of 0.2 kPa applied in the course of expiration produced a long lasting apnoea in newborn rats which lasted 48 normal respiratory cycles. An inflation pressure of 0.5 kPa in young rats induced an apnoea lasting for only 3 normal respiratory cycles, whereas a pressure of 1 kPa in adult rats led to an apnoea which lasted for 20 normal respiratory cycles. The compliance of the respiratory system in relation to lung weight is approximately 5 times higher in adult rats compared with that of newborn rats. It is approximately double in comparison with young rats. The pressures of inflation mentioned in the 3 age categories can be considered as equieffective from the point of stimulation pulmonary stretch receptors. It can be concluded from these findings that the reflex of Breuer-Hering in newborn rats is more potent in comparison with adult rats, but it is lower in young rats at the age of 8 days. It is suggested that the differences observed are due to functional and anatomical maturation.     

The effect of DOPA on segmental reflexes in rat pups]

In acute experiments on spinal 5-30-day rat puppies, studies have been made of the effect of DOPA (100 mg/kg intraperitoneally) on monosynaptic reflex in extensors (evaluated by parameters of H-reflex) as well as on polysynaptic segmentary reflexes. In 5-7-day animals, mainly the inhibitory effect was observed with a short phase of facilitation of monosynaptic reflex. From the 10th day, facilitatory effect of DOPA becomes a predominant one reaching maximum to the 16th day. Within first 16 days of postnatal life, DOPA exhibits facilitatory effect on short-latent polysynaptic reflexes and inhibits long-latent ones. To the 30th day, reactions which are typical of adult animals are observed: inhibition of short-latent and facilitation of long-latent polysynaptic discharges. The data obtained indicate that in early postnatal development the effect of DOPA on mono- and polysynaptic reflexes qualitatively differs from that in adult animals.     

Activity of bulbar respiratory neurones during cough and other respiratory tract reflexes in cats

Changes evoked by mechanical stimulation of the relevant parts of the respiratory tract in the activity of inspiratory and expiratory neurones in the ventral respiratory group of the medulla oblongata, and in pleural pressure and the diaphragmatic electromyogram, were determined during cough, sneeze and the aspiration and expiration reflexes in 17 anaesthetized (but not paralysed) cats. The results of 72 tests of elicitation of the given reflexes showed that: Compared with the control inspiration, both the mean and the maximum discharge frequency of spontaneously active inspiratory neurones rose during the inspiratory phase of cough, sneeze and the aspiration reflex. Regular recruitment of new inspiratory units was also observed in the inspiratory phase of cough and the aspiration reflex. Compared with the control expiration, both the mean and the maximum discharge frequency of spontaneously active expiratory neurones rose during the cough, sneeze and expiration reflex effort. Recruitment of latent expiratory neurones was always observed in the expulsive phase of the given respiratory processes. The recruitment of latent expiratory neurones was accompanied by reciprocal inhibition of the activity of inspiratory units and recruitment of latent inspiratory neurones by inhibition of the activity of expiratory units and recruitment of latent inspiratory neurones by inhibition of the activity of expiratory units. Regular recruitment of the same expiratory neurones in all expulsive respiratory processes, together with the similar incidence of inspiratory neurones in the inspiratory phase of sneeze and the aspiration reflex, indicates that they are "nonspecific" in character.     

Activity of the laryngeal abductor and adductor muscles during cough, expiration and aspiration reflexes in cats

We studied the temporal relationships and the patterns of electromyographic activities of the posterior cricoarytenoid and thyreoarytenoid muscles (laryngeal abductor and adductor), the diaphragm and abdominal muscles in anesthetized cats during mechanically induced tracheobronchial and laryngopharyngeal coughs, expiration and aspiration reflexes. The posterior cricoarytenoid muscle activity reached the maxima just before the peak of diaphragmatic activity in both types of cough and aspiration reflexes and slightly before the top of abdominal muscle activity in coughs and the expiration reflex. Thus, this muscle contributes to the inspiratory phase of coughs and aspiration reflex and also to the expulsive phase of coughs and the expiration reflex. The thyreoarytenoid muscle presented strong discharges in the compressive phase of coughs and expiration reflex (during the rising part of the abdominal muscle activity) and in the subsequent laryngoconstriction (following the diaphragmal and/or abdominal muscle activity) in all four reflexes. This muscle was also slightly activated at the beginning of the aspiration reflex. The existence of four phases of the cough reflex is also discussed.     

Respiration and airway reflexes after transversal brain stem lesions in cats

The effect of brain stem transection at different levels of the pons Varolii and the medulla oblongata on respiration and on cough and the aspiration and expiration reflex elicited by mechanical stimulation of the relevant parts of the respiratory tract was studied in experiments on 13 anaesthetized, unparalyzed cats. The results of 142 respiratory reflex elicitation tests showed that: 1. Compared with the control state, transection of the upper and middle part of the pons Varolii and transection at the level of the pontomedullary junction reduced the respiration rate (p less than 0.001), increased the duration of inspiration and expiration (p less than 0.001, transection 10 mm rostrally to the obex) and gave rise to apneustic breathing (8 mm), or to tonic, respiration-modulated activity of the phrenic nerve and diaphragm (6 mm). 2. Successive transection of the pons and the pontomedullary junction region led chiefly to a drop in maximum expiratory pleural pressure values (p less than 0.01-0.001) during cough and the expiration reflex and to a drop in maximum inspiratory pleural pressure values during the aspiration reflex (p less than 0.02-0.001). 3. Transection of the upper part of the medulla oblongata always led to permanent arrest of rhythmic respiration, during which cough and the expiration reflex could not be elicited while the aspiration reflex persisted (though in a weakened form). This state was followed by gasping, during which only a highly elicitable aspiration reflex persisted. 4. It can be assumed from the above findings that the central mechanisms responsible for the development of powerful expiratory efforts in cough and the expiration reflex could be localized in the pons Varolii, while those integrating the aspiration reflex are probably localized mainly in the medulla oblongata.     

Effect of hypoxia and hypercapina on the airways defence reflexes

In experiments on 10 adult anaesthetized cats (pentobarbital 30 mg.kg-1 i.p.) the effect of stimultaneous hypoxia and hypercapnia was studied on the defence respiratory reflexes of the airways. Expiratory reflex and cough were elicited by mechanical stimulation of the airways mucosa, and the obtained values were evaluated on basis of the intrapleural pressure. Inhalation of the hypoxic-hypercapnic gas mixture (11% + 7% CO2 in N2) for 15 minutes led to a significant decrease of respiratory frequency, tidal volume and PaCO2, while pHa and PaCO2 also decreased significantly together with the intensity of the expiratory reflex and that of cough. Recent studies, showed that in the course of the effect of hypoxia (11% O2) and of hypercapnia (5% CO2), cough intensity decreased, but the change was not significant. The decrease of the intensity of respiratory defence reflexes under hypoxic-hypercapnic conditions might have been due to the changes of centrally controlling structures, or to the effector part of the reflex arc, resulting from fatigue of the respiratory muscles. The possible effect of anaesthesia exerting a significant influence on the intensity and character of airways defence reflexes could not be excluded.     

Effects of hypoxia on respiratory defence reflexes. Effects of thirty hours' oxygen deficiency on cough, the expiration reflex and sneezing in awake cats

The authors studied, in 11 awake adult cats, the parameters of the expiration reflex (ER), tracheobronchial (TB) and laryngopharyngeal (LPh) cough, the respiratory rate (f), tidal volume (VT), the end tidal fractional CO2 concentration (FETCO2), the pH, the blood gases and the heart rate during 30 hours' isobaric hypoxic hypoxia (FO2 = 0.11). During the whole 30 hours the cats developed hypocapnic hypoxemia, f remained unchanged and VT was markedly elevated. In the acute phase (15 min) of hypoxic hypoxia of the same intensity, changes in respiratory parameters were the same and the intensity of respiratory reflexes increased significantly (Tatár et al. 1984). During prolonged hypoxic hypoxia there were no statistically significant changes in the intensity of the ER and of TB and LPh cough. The authors assume that some adaptation of the central mechanisms regulating the defence reflexes of the airways took place; this hypothesis is warranted, because an increase in the susceptibility of the cough centre during constant conditions of the stimulation of cough receptors would not be biologically expedient. The different changes in the intensity of respiratory defense reflexes in the acute and the prolonged phase of hypoxic hypoxia in the presence of identical changes in respiratory parameters are further indirect evidence pointing to the existence of functional differences between the respiratory centre and the cough centre.     

Cough reflex changes in local tracheitis.

The authors describe changes in the cough reflex in unanaesthetized cats with experimental local tracheitis. Inflammation was produced by a silk suture fixed in the trachea and cough was elicited by mechanical stimulation of different parts of the respiratory tract mucosa. The resultant cough values (the number of efforts, the intensity of the maximum effort and the intensity of the attack) were compared with the corresponding values in healthy cats. In animals with a tracheal suture, inflammation was confined to the trachea. The intensity of cough elicited by stimulation of this region increased significantly compared with normal (on the 15th to 17th day of inflammation), whereas cough elicited from the laryngopharyngeal and tracheobronchial region did not. On about the 20th day of inflammation the authors found a decrease in the intensity of the maximum effort of cough elicited from the inflamed part of the trachea and a decrease in the intensity of the maximum effort and the intensity of the coughing attack elicited from the laryngopharyngeal and tracheobronchial region. They assume that the decrease could have been due to the development of protective inhibition in central structures participating in integration of the cough reflex.     

The expiration reflex from the vocal folds.

The authors present their 30 years' experience with expiration reflex. The reflex can be elicited from vocal folds by mechanical, chemical or electrical stimulation of the superior laryngeal nerve of man and laboratory animals, except mice and rats. It manifests itself by a short, forcible expiratory effort without a preceding inspiration which is indispensable for cough effort. The role of expiration reflex is to prevent penetration of foreign bodies into airways, expelling phlegm and detritus from subglottal area. The initial inspiration before expiration is undesired and could lead to inspiration pneumonia. The reflex is well known to laryngologists as '"laryngeal cough." Its receptors are small in number, localised mainly in medial margin of vocal folds deep in mucosa which can explain their stability in pathological conditions of the larygx. Afferentiation of the reflex is via laryngeal nerve similarly to sneezing and cough. Expiration reflex is not co-ordinated by a single "centre" but rather by a network system in the brain stem. Its motor pattern is supposedly produced by "multifunctional" population of medullar neurones in Botzinger complex and the rostral ventral respiratory group involved also in the genesis of breathing and cough. However, in cats also other neurones may play a vital role in production, shaping and mediation of the motor pattern of respiratory reflex, localised in rostral pons, lateral tegmental field or in the raphe medullar midline.     

Ontogenetic development of etomidate action in rats

Action of etomidate was studied in 219 albino rats 7, 12, 18, 25 days old and adult. Etomidate at the dose of 20 mg/kg i.p. led to a loss of the righting reflex in all age groups. Sleeping time increased with decreasing age up to the 12th day. Seven-day-old rat pups exhibited short sleeping time, approximately at the level of adult animals. Etomidate can be used for general anaesthesia even in young animals but the quantitative differences in its efficacy have to be taken into account.     

Cortical alpha-2a adrenoreceptors involved in the inhibitory control of motor activity in neonatal rats

Involvement of alpha 2A-adrenoceptors in control of motor activity in neonatal rats was investigated using intrabrain injections of antisense deoxyoligonucleotide targeting mRNA of these receptors. Antisense-induced decrease in the receptor expression in the brain accompanied by an augmentation of animal's motor activity, which was evaluated as a number of paddling movements with the right forepaw. This antisense effect was stimulatory and was not related to somatic growth and maturation of reflexes in the animals. The antisensetreated pups differed from controls neither in body weight nor the latency of righting reflex. The data suggest that alpha 2A-adrenoceptors are involved in inhibitory control of motor activity of rat pups from the first day of life.     

Influence of CPAP on reflex responses to tracheal irritation in anesthetized humans

We investigated the effects of lung inflation during continuous positive airway pressure breathing (CPAP) on airway defensive reflexes in 10 enflurane-anesthetized spontaneously breathing humans. The airway defensive reflexes were induced by instillation into the trachea of 0.5 ml of distilled water at two different levels of end-expiratory pressure (0 and 10 cmH2O CPAP). The tracheal irritation at an end-expiratory pressure of 0 cmH2O caused a variety of reflex responses including apnea, spasmodic panting, expiration reflex, cough reflex, an increase in heart rate, and an increase in blood pressure. Lung inflation during CPAP of 10 cmH2O did not exert any influence on these reflex responses in terms of the types, latencies, and durations of reflex responses although the intensity of the expiration reflex and cough reflex was augmented by lung inflation. Our results suggest that the pulmonary stretch receptors do not play an important role in the mechanisms of airway defensive reflexes in humans.     

Expression of GABA and glycine receptors by messenger RNAs from the developing rat cerebral cortex

The ontogenesis of mRNAs coding for GABA and glycine receptors in the cerebral cortex of the rat was examined by extracting poly(A)+ mRNA from the brains of embryonic, postnatal or adult rats and injecting it into Xenopus oocytes. The ability of a messenger to express functional receptors was then assayed by measuring the membrane currents elicited by the agonists. The size of the GABA-induced current increased progressively with age, being undetectable in oocytes injected with mRNA from embryonic day 15 and reaching a maximum in oocytes injected with mRNA from postnatal day 30. In contrast, the glycine-induced response was negligible in oocytes injected with mRNA from the cerebral hemispheres of embryos 15 days old; it increased sharply to a maximum with newborn animals and then decreased with age to become very small with mRNA from adult cortex. GABA and glycine receptors induced by mRNA from the cerebral cortex of all ages are associated with chloride channels.     

Involvement of bulbar respiratory and non-respiratory neurons in onset of expiration reflex

It was shown that excitation of high- and low-threshold superior laryngeal afferents triggers reflexes of varying complexity in a considerable proportion of non-respiratory neurons during experiments on cats anesthetized by Nembutal involving stimulation-induced expiration reflex. Systemic alterations in background firing activity were noted during this reflex in "respiratory" neurons; reflex reaction setting in as a result of low-threshold laryngeal afferent activation was also recorded in 22.4% of this group. Oligo- and polysynaptic excitatory connections were found between low-threshold laryngeal afferents and inspiratory beta neurons, P-cells, and laryngeal muscle motoneurons as opposed to inhibitory connections with inspiratory gammaneurons. This article discusses involvement of the neurons investigated in mechanisms of inspiratory inhibition, closure of the vocal chords, and adaptive decline in breathing rate occurring during expiration reflex.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 22, No. 5, pp. 670–680, September–October, 1990.     

Developmental changes in audiogenic epilepsy and myoclonus in KM rats

The reaction to a single sound stimulation (a bell) applied daily and the time of the first appearance of myoclonus were recorded in Krushinsky-Molodkina (KM) rats of different ages (30, 60, and 150-200 days). The audiogenic seizures in adult animals were of short latency and always resulted in tonic convulsions, which were stable in their patten. In contrast, in young animals (in particular, in 30-day-old rats), the seizures were less pronounced and unstable. The daily sound stimulation produced a gradual development of myoclonic seizures in young and adult rats. In old rats, the stable myoclonus appeared on the 17th day of stimulation, and in 30-day-old animals the myoclonus was recorded on the 26th day. In 60-day-old rats the myoclonus appeared for the first time on the 20th day of stimulation. It is suggested that these age differences can be explained by the btain immaturity (in particular, of neurotransmitter system) in young animals.     

Time-dependent responses of expiration reflex in cats

We investigated the effectiveness of the "expiration reflex" in 10 anesthetized spontaneously breathing cats. The expiration reflex was produced by mechanical stimulation of the vocal folds and electrical stimulation of the superior laryngeal nerve at different moments in the respiratory cycle and at various levels of respiratory chemical drive. The effectiveness of the expiration reflex was evaluated from sudden changes in expiratory flow immediately following the stimulation. Both mechanical and electrical stimulations given during early inspiration caused little or no expiratory efforts, whereas stimulations given during early expiration or hypocapnic apnea produced a typical expiration reflex. Changes in arterial CO2 and O2 partial pressures influenced neither the relationships between the stimulation and its effect on the expiration reflex nor the strength of the expiration reflex. These results indicate that the timing of stimulation with relation to the phase of the respiratory cycle is critical to its effect on the expiration reflex and that changes in respiratory chemical drive do not modify the expiration reflex characteristics.