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. 2021 Mar 5:12:640682.
doi: 10.3389/fphys.2021.640682. eCollection 2021.

Intra-Arterial, but Not Intrathecal, Baclofen and Codeine Attenuates Cough in the Cat

Wendy L Olsen  1 , Melanie Rose  1 , Frank J Golder  1 , Cheng Wang  1 , Julie C Hammond  1 , Donald C Bolser  1
Affiliations

Intra-Arterial, but Not Intrathecal, Baclofen and Codeine Attenuates Cough in the Cat

Wendy L Olsen et al. Front Physiol. .

Abstract

Centrally-acting antitussive drugs are thought to act solely in the brainstem. However, the role of the spinal cord in the mechanism of action of these drugs is unknown. The purpose of this study was to determine if antitussive drugs act in the spinal cord to reduce the magnitude of tracheobronchial (TB) cough-related expiratory activity. Experiments were conducted in anesthetized, spontaneously breathing cats (n = 22). Electromyograms (EMG) were recorded from the parasternal (PS) and transversus abdominis (TA) or rectus abdominis muscles. Mechanical stimulation of the trachea or larynx was used to elicit TB cough. Baclofen (10 and 100 μg/kg, GABA-B receptor agonist) or codeine (30 μg/kg, opioid receptor agonist) was administered into the intrathecal (i.t.) space and also into brainstem circulation via the vertebral artery. Cumulative doses of i.t. baclofen or codeine had no effect on PS, abdominal muscle EMGs or cough number during the TB cough. Subsequent intra-arterial (i.a.) administration of baclofen or codeine significantly reduced magnitude of abdominal and PS muscles during TB cough. Furthermore, TB cough number was significantly suppressed by i.a. baclofen. The influence of these drugs on other behaviors that activate abdominal motor pathways was also assessed. The abdominal EMG response to noxious pinch of the tail was suppressed by i.t. baclofen, suggesting that the doses of baclofen that were employed were sufficient to affect spinal pathways. However, the abdominal EMG response to expiratory threshold loading was unaffected by i.t. administration of either baclofen or codeine. These results indicate that neither baclofen nor codeine suppress cough via a spinal action and support the concept that the antitussive effect of these drugs is restricted to the brainstem.

Keywords: GABA-B receptor agonist; airway protection; antitussives; baclofen; codeine; cough; intrathecal; opioid.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Examples of EMG responses of parasternal and transversus abdominis muscles during cough in a single animal. (A) CSF and saline adminstration, (B) baclofen administration, and (C) codeine administration. TA, transversus abdominis muscle EMG; PS, parasternal muscle EMG. Horizontal bars are periods of cough trials.
FIGURE 2
FIGURE 2
Influence of baclofen on (A) the number of tracheobronchial cough, (B) the magnitude of transversus abdominis muscle during tracheobronchial cough, and (C) the magnitude of parasternal muscle during tracheobronchial cough. A two-way ANOVA revealed a significant difference between the control and baclofen group (A) p = 0.008, (B) p = 0.013, and (C) p = 0.007. The baclofen group had fewer number of coughs and smaller magnitudes of the transversus abdominis and parasternal muscles during tracheobronchial cough when compared to the control group. Specifically, a one-way ANOVA revealed the baclofen group had a significant reduction in: number of coughs at the 10 μg/kg i.a. (p = 0.049) and the 100 μg/kg i.a. dose (p = 0.004), magnitude of the transversus abdominis muscle at the 100 μg/kg i.a. dose (p < 0.001), and magnitude of the parasternal muscle at the 100 μg/kg i.a. dose (p = 0.001). Each bar represents the mean ± s.e.m of six animals who received baclofen (Baclofen Group) and 4 control animals (Control Group). Cough numbers were normalized by totaling the number of coughs and dividing by the number of trials. Amplitudes were normalized by magnitudes observed in the vehicle period. An asterisk (*p < 0.05, **p < 0.005, ***p < 0.001) indicates a significant reduction in amplitude in cough and amplitude relative to vehicle and the Control Group.
FIGURE 3
FIGURE 3
Influence of baclofen and codeine on responses of the transversus abdominis muscle EMG to expiratory threshold loads. Each graph contains a control condition where the gray bar represents the mean change in amplitude and the black circles are plotted individual data. The white bar is indicative of the mean responses during the drug intervention (i.e., baclofen or codeine as indicated by the title) and each white circle is the plotted individual data. Neither intrathecal or intra-arterial baclofen or codeine altered transversus abdominis (TA) magnitudes during expiratory threshold loading. Values are normalized maximum TA magnitudes during expiratory threshold loads of 15 cm H2O. Each bar represents the mean ± s.e. mean of five animals for baclofen (p = 0.43), five animals for codeine (p = 0.31), and four control-treated animals using a two-way ANOVA.
FIGURE 4
FIGURE 4
Influence of baclofen on the magnitude of transversus abdominis EMGs during noxious pinch of the tail. A two-way ANOVA revealed a significant difference between the baclofen and control group, p < 0.001. Intrathecal baclofen significantly reduced the transversus abdominis (TA) EMG during noxious pinch of the tail at both doses. Subsequent intra-arterial administration of baclofen did not reduce this EMG further. Each bar represents the mean ± s.e. mean of seven animals who received baclofen (10 μg/kg i.t., p < 0.001; 100 μg/kg i.t., p < 0.001; 10 μg/kg i.a., p < 0.001; 100 μg/kg i.a., p < 0.001) and 8 control animals using a one-way repeated measures ANOVA Amplitudes were normalized to those observed in the vehicle trials. Stimulus was applied for approximately 40 s. An asterisk (*p < 0.001) indicates a significant reduction in amplitude relative to vehicle control.
FIGURE 5
FIGURE 5
Influence of codeine on (A) the number of tracheobronchial cough, (B) the magnitude of transversus abdominis muscle during tracheobronchial cough, and (C) the magnitude of parasternal muscle during tracheobronchial cough. A two-way ANOVA revealed a Group x Dose interaction for (A) p < 0.001, (B) p = 0.030, and (C) p < 0.001. The codeine group had fewer number of coughs and smaller magnitudes of the transversus abdominis and parasternal muscles during tracheobronchial cough at the 30 μg/kg i.a. dose, (A) p < 0.001, (B) p < 0.001, and (C) p < 0.001. Each bar represents the mean ± s.e.m. of five animals who received codeine (Codeine Group) and four control animals (Control Group). Cough numbers were normalized by totaling the number of coughs and dividing by the number of trials. Amplitudes were normalized by magnitudes observed in the vehicle period. An asterisk (*p < 0.001) indicates a significant reduction in amplitude in cough and amplitude relative to vehicle and the Control Group.
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