GABA-ergic neurotransmission in the nucleus of the solitary tract modulates cough in the cat (original) (raw)
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Modulation of Cough Reflex by Gaba-Ergic Inhibition in Medullary Raphé of the Cat
Physiological Research, 2020
We studied the effects of GABA receptor agonists microinjections in medullary raphé on the mechanically induced tracheobronchial cough response in anesthetized, unparalyzed, spontaneously breathing cats. The results suggest that GABA-ergic inhibition significantly contributes to the regulation of cough reflex by action of both GABAA and GABAB receptors. The data are consistent with inhomogeneous occurrence of GABA-ergic neurons in medullary raphé and their different involvement in the cough reflex control. Cells within rostral nucleus raphé obscurus with dominant role of GABAA receptors and neurons of rostral nucleus raphé pallidus and caudal nucleus raphé magnus with dominant role of GABAB receptors participate in regulation of cough expiratory efforts. These cough control elements are distinct from cough gating mechanism. GABA-ergic inhibition in the raphé caudal to obex had insignificant effect on cough. Contradictory findings for GABA, muscimol and baclofen administration in med...
British Journal of Pharmacology, 1994
The GABA-B receptor agonists baclofen and 3-aminopropylphosphinic acid (3-APPi) have antitussive activity in the cat and guinea pig. The purpose of this study was to investigate the sites of action of these GABA-B receptor agonists to inhibit the cough reflex. 2 Single intracerebroventricular (i.c.v.) cannulas were placed in the lateral ventricles of anaesthetized guinea pigs. Approximately 1 week later, the animals were exposed to aerosols of capsaicin (0.3 mM) to elicit coughing. Coughs were detected with a microphone and counted. 3 Cough was produced in anaesthetized cats by mechanical stimulation of the intrathoracic trachea and was recorded from electromyograms of respiratory muscle activity. Cannulas were placed for intravenous (i.v.) or, in separate groups of animals, intravertebral arterial (i.a.) administration of baclofen, 3-APPi, the centrally active antitussive drug codeine or the peripherally active antitussive drug BW443c. Dose-response relationships for i.v. and i.a. administration of each drug were generated to determine a ratio of i.v. ED" to i.a. ED50, known as the effective dose ratio (EDR). The EDR will be 20 or greater for a centrally acting drug. 4 In the guinea pig, baclofen (3 mg kg-', s.c.) and 3-APPi (10 mg kg-', s.c.) inhibited capsaicininduced cough by 50% and 35% respectively. The antitussive activity of baclofen was completely blocked by i.c.v. administration of the GABA-B receptor antagonist CGP 35348 (10 jig). Conversely, the antitussive effect of 3-APPi was unaffected by i.c.v. CGP 35348. However, systemic administration of CGP 35348 (30 mg kg-', s.c.) completely blocked the antitussive activity of 3-APPi (10 mg kg-', s.c.). In separate experiments baclofen alone (1 gpg, i.c.v.) inhibited capsaicin-induced cough by 78%. 3-APPi (10 and 100 gg, i.c.v.) had no effect on capsaicin-induced cough in the guinea pig. 5 In the cat, potencies (ED50) of the standards and GABA-B agonists by the i.v. route were: codeine (0.34 mg kg-'), BW443C (0.17 mg kg-'), baclofen (0.63 mg kg-') and 3-APPi (2.3 mg kg-'). Potencies of these drugs by the i.a. route were: codeine, 0.013 mg kg-'; BW443C, 0.06mg kg-'; baclofen, 0.016mg kg-'; and 3-APPi, 0.87 mg kg'. The EDRs for each drug were: codeine, 26; BW443C, 3; baclofen, 39; and 3-APPi, 3. 6 We conclude that in both the cat and guinea pig baclofen inhibits cough by a central site of action, while 3-APPi inhibits cough by a peripheral site of action.
Journal of Neurophysiology, 2017
The importance of neurons in the nucleus of the solitary tract (NTS) in the production of coughing was tested by microinjections of the nonspecific glutamate receptor antagonist kynurenic acid (kyn; 100 mM in artificial cerebrospinal fluid) in 15 adult spontaneously breathing anesthetized cats. Repetitive coughing was elicited by mechanical stimulation of the intrathoracic airway. Electromyograms (EMG) were recorded from inspiratory parasternal and expiratory transversus abdominis (ABD) muscles. Bilateral microinjections of kyn into the NTS rostral to obex [55 ± 4 nl total in 2 locations ( n = 6) or 110 ± 4 nl total in 4 locations ( n = 5)], primarily the ventrolateral subnucleus, reduced cough number and expiratory cough efforts (amplitudes of ABD EMG and maxima of esophageal pressure) compared with control. These microinjections also markedly prolonged the inspiratory phase, all cough-related EMG activation, and the total cough cycle duration as well as some other cough-related ti...
Journal of Neurophysiology, 2021
This study is the first to explore the role of the inspiratory rhythm and pattern generator, the pre-Bötzinger complex (PreBötC), in cough motor pattern formation. In the PreBötC, excitatory glutamatergic neurotransmission affects cough intensity and patterning but not rhythm, and GABAA receptor-related inhibition affects coughing and breathing phase durations similarly to each other. Our data show that the PreBötC is important for cough motor pattern generation, but cough rhythmogenesis appears to be controlled elsewhere.
Role of the dorsomedial medulla in suppression of cough by codeine in cats
Respiratory Physiology & Neurobiology, 2017
The modulation of cough by microinjections of codeine in 3 medullary regions, the solitary tract nucleus rostral to the obex (rNTS), caudal to the obex (cNTS) and the lateral tegmental field (FTL) was studied. Experiments were performed on 27 anesthetized spontaneously breathing cats. Electromyograms (EMG) were recorded from the sternal diaphragm and expiratory muscles (transversus abdominis and/or obliquus externus; ABD). Repetitive coughing was elicited by mechanical stimulation of the intrathoracic airways. Bilateral microinjections of codeine (3.3 or 33 mM, 54 ± 16 nl per injection) in the cNTS had no effect on cough, while those in the rNTS and in the FTL reduced coughing. Bilateral microinjections into the rNTS (3.3 mM codeine, 34 ± 1 nl per injection) reduced the number of cough responses by 24% (P < 0.05), amplitudes of diaphragm EMG by 19% (P < 0.01), of ABD EMG by 49% (P < 0.001) and of expiratory esophageal pressure by 56% (P < 0.001). Bilateral microinjections into the FTL (33 mM codeine, 33 ± 3 nl per injection) induced reductions in cough expiratory as well as inspiratory EMG amplitudes (ABD by 60% and diaphragm by 34%; P < 0.01) and esophageal pressure amplitudes (expiratory by 55% and inspiratory by 26%; P < 0.001 and 0.01, respectively). Microinjections of vehicle did not significantly alter coughing. Breathing was not affected by microinjections of codeine. These results suggest that: 1) codeine acts within the rNTS and the FTL to reduce cough in the cat, 2) the neuronal circuits in these target areas have unequal sensitivity to codeine and/or they have differential effects on spatiotemporal control of cough, 3) the cNTS has a limited role in the cough suppression induced by codeine in cats.
Contribution of medullary raphé to control of coughing—Codeine trials in cat
Respiratory Physiology & Neurobiology, 2012
In order to determine if a codeine-sensitive control system for cough exists in the medullary raphé four microinjections of codeine (3.3 and 16.5 mM; 36.6 ± 0.7 nl 1.5 and 3 mm rostral to the obex at the depths 1.5 and 3 mm; the total dose 1.12 ± 0.3 nmol, 9 animals) were performed on pentobarbitone anesthetized spontaneously breathing cats. Amplitudes of abdominal muscle EMG moving averages during mechanically induced tracheobronchial cough decreased by 18% compared to control coughs (p < 0.05). The duration between maxima of cough diaphragm and abdominal muscle EMG discharge, cough expiratory phase duration and period of relative motor quiescence between coughs were increased (all p < 0.05). Cough number, other cough parameters, and cardiorespiratory characteristics were not altered significantly. Control microinjections of artificial cerebro-spinal fluid had no effect on coughing. Codeine sensitive neurons involved in the generation or modulation of motor pattern of tracheobronchial cough are located in the medullary midline raphé nuclei; however, their contribution to codeine induced cough suppression is limited.
Journal of Applied Physiology, 2006
The caudal ventral respiratory column (cVRC) contains premotor expiratory neurons that play an important role in cough-related expiratory activity of chest wall and abdominal muscles. Microinjection of D,L-homocysteic acid (DLH) was used to test the hypothesis that local activation of cVRC neurons can suppress the cough reflex. DLH (20-50 mM, 10-30 nl) was injected into the region of cVRC in 9 anesthetized spontaneously breathing cats. Repetitive coughing was elicited by mechanical stimulation of the intrathoracic airways. Electromyograms (EMG) were recorded bilaterally from inspiratory parasternal and expiratory transversus abdominis (ABD) and unilaterally from laryngeal posterior cricoarytenoid and thyroarytenoid muscles. Unilateral microinjection of DLH (1-1.5 nmol) elicited bilateral increases in tonic and phasic respiratory ABD EMG activity, altered the respiratory pattern, and laryngeal motor activities. However, DLH also decreased cough frequency by 51±7% compared to control (p<0.001) and the amplitude of the contralateral (−35±3%, p<0.001) and ipsilateral (−34±5%, p<0.001) ABD EMGs during post injection coughs compared to control. The cough alterations were much less pronounced after microinjection of a lower dose of DLH (0.34-0.8 nmol). No cough depression was observed after microinjections of vehicle. These results suggest that an endogenous cough suppressant neuronal network in the region of the cVRC may exist and this network may be involved in the control of cough reflex excitability.
Physiological Research
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 brai...
Physiological research, 2004
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 brai...
Cough and laryngeal muscle discharges in brainstem lesioned anaesthetized cats
Physiological Research
Experiments were carried out to determine whether there are separate drives from the selected neuronal networks of the brainstem affecting the discharge patterns of laryngeal and respiratory pump muscles during cough. Twenty-four non-decerebrate spontaneously breathing cats anesthetized with sodium pentobarbitone were used. Microinjections of kainic acid into the lateral tegmental field of the medulla, medullary midline or pontine respiratory group eliminated the cough evoked by mechanical stimulation of the tracheobronchial and laryngopharyngeal mucosa. These stimuli, in most cases, provoked irregular bursts of discharges in the posterior cricoarytenoid and thyroarytenoid laryngeal muscles (or they had no effect on them). No pattern of laryngeal muscle activities following lesions resembled the laryngeal cough response. Lesions of the target regions did not result in any apparent changes in the eupnoeic pattern of laryngeal activity. Neurons of the medullary lateral tegmental field...