GABA, muscimol, and baclofen were microinjected into the rostral (rNTS) and caudal solitary tract nucleus (cNTS) in 24 anesthetized cats. Electromyograms (EMGs) of diaphragm (DIA) and abdominal muscles (ABD), blood pressure and esophageal pressure (EP) were recorded and analysed. Bilateral microinjections of 1 mM GABA (total 66 ± 4 nl), 1 mM baclofen (64 ± 4 nl) and unilateral microinjections of 0.5 mM muscimol (33 ± 1 nl) in the rNTS significantly reduced cough number (CN), amplitudes of ABD EMGs, expiratory EP, and prolonged the duration of the cough inspiratory phase. GABA microinjections decreased the amplitudes of cough-related DIA EMGs and inspiratory EP; muscimol microinjections decreased the cough DIA EMG on the contralateral side. Only microinjections of GABA into the cNTS suppressed CN. In some cases, microinjections prolonged the inspiratory phase, lowered respiratory rate, changed the depth of breathing, and increased blood pressure and heart rate. Our results confirm that GABA-ergic inhibitory mechanisms in the rNTS can regulate coughing in the anesthetized cat.

Brainstem respiratory neuronal network significantly contributes to cough motor pattern generation. Neuronal populations in the pre-Bötzinger complex (PreBötC) represent a substantial component for respiratory rhythmogenesis. We studied the role of PreBötC neuronal excitation and inhibition on mechanically induced tracheobronchial cough in 15 spontaneously breathing, pentobarbital anesthetized adult cats (35 mg/kg i.v. initially). Neuronal excitation by unilateral microinjection of glutamate analog D,L-homocysteic acid resulted in mild reduction of cough abdominal electromyogram (EMG) amplitudes and very limited temporal changes of cough compared to effects on breathing (very high respiratory rate, high amplitude inspiratory bursts with a short inspiratory phase and tonic inspiratory motor component). Mean arterial blood pressure temporarily decreased. Blocking glutamate related neuronal excitation by bilateral microinjections of non-specific glutamate receptor antagonist kynurenic acid reduced cough inspiratory and expiratory EMG amplitude and shortened most cough temporal characteristics similarly to breathing temporal characteristics. Respiratory rate decreased and blood pressure temporarily increased. Limiting active neuronal inhibition by unilateral and bilateral microinjections of GABAA receptor antagonist gabazine resulted in lower cough number, reduced expiratory cough efforts, and prolongation of cough temporal features and breathing phases (with lower respiratory rate). The PreBötC is important for cough motor pattern generation. Excitatory glutamatergic neurotransmission in the PreBötC is involved in control of cough intensity and patterning. GABAA receptor related inhibition in the PreBötC strongly affects breathing and coughing phase durations in the same manner, as well as cough expiratory efforts. In conclusion, differences in effects on cough and breathing are consistent with separate control of these behaviors.

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 medullary raphé suggest involvement of coordinated activity of GABA on multiple receptors affecting raphé neurons and/or the local neuronal circuits in the raphé modulating cough motor drive.

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The preBotzinger complex (preBotC) is important in breathing rhythmogenesis, but its role in cough patterning is unknown. We previously microinjected an excitatory neurotransmitter, 5 mM DL‐Homocysteic acid (DLH), into the preBotC, which altered breathing phase timing, but not cough phase timing. To further understand the role of the preBotC in cough rhythmogenesis, we hypothesized that inhibiting the preBotC would also have no effect on cough phase timing but would inhibit coughing. To test this hypothesis, we bilaterally microinjected 50 mM kynurenic acid (KYN, n=6), a broad spectrum excitatory amino acid blocker, and separately 0.1 mM gabazine (GBZ, n=5), a GABA‐A receptor antagonist, into the preBotC in anesthetized, spontaneously breathing adult cats. We recorded electromyograms (EMG) from parasternal (PS), diaphragm (DIA) and internal oblique (ABD) muscles. Cough was elicited by mechanical stimulation of the tracheobronchial tree. KYN microinjection significantly increased breathing frequency (21±2 to 43±10 breaths/min, p<0.05) by changing both inspiratory (TI) and expiratory (TE) durations (TI 1.0±0.1 to 0.6±0.1, p<0.05; TE 1.8±0.3 to 0.9±0.2 s, p<0.05). DIA EMG magnitude and cough number did not change (4.5±0.6 to 3.9±1.4). However, inspiratory duration decreased (TI 1.1±0.1 to 0.7±0.06 s, p<0.05), and while active expiratory duration (TE1) did not change significantly (TE1 1.0±0.11 to 0.8±0.04 s, n.s.), passive expiratory duration (TE2) was altered but not until 2 hours after injection (TE2 baseline: 0.9±0.2; 20 min after injection: 0.6±0.3 s; 2 hrs after injection: 0.50±0.2 s, p<0.05). Both DIA (55±5 % of baseline) and ABD EMG (56±11 % of baseline) amplitudes decreased during cough. GBZ microinjection had the opposite effect on breathing compared to KYN, where breathing frequency decreased (21.0±4.0 to 12.0±1.0 breaths/minute, p<0.05) by altering both TI and TE (TI 1.1±0.1 to 2.1 ±0.3 s, p<0.05; TE 1.9±0.4 to 2.7±0.4 s, p<0.05). With respect to cough, GBZ decreased cough number (5.1±0.6 to 1.5±0.4, p<0.05) and ABD EMG magnitude (38±4 % of baseline, p<0.05), although PS EMG magnitude did not change significantly (147±34 % of baseline). Microinjection of GBZ increased the duration of all phases of cough (TI 1.1±0.1 to 2.1±0.4 s, p<0.05, TE1 0.9±0.05 to 1.8±0.2 s, p<0.05, TE2 1.1±0.70 to 2.4±0.9 s, p=0.06). These data indicate that the preBotC participates in the regulation of cough phase timing and magnitudes in the anesthetized cat. Disruption of excitatory amino acid neurotransmission with KYN primarily affected inspiratory duration whereas GBZ‐induced blockade of GABA‐A receptor transmission had a generalized effect on cough. These data support an important but more complex role for the preBotC in the regulation of the cough motor pattern than that for breathing.Support or Funding InformationSupported by OT2OD023854‐01, HL131716.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.