The role of the pontine respiratory group in the antitussive effect of codeine: Insights from a cat model

The Kölliker-Fuse (KF) nuclei and adjacent lateral and medial parabrachial (PB) complex are parts of the pontine respiratory group (PRG) also known as pneumotaxic centre. PRG is composed of a heterogeneous population of respiratory neurons essential for control of respiratory rate, pattern, and rhythm. The lateral PB is responsible for an inspiratory facilitatory influence, and the medial PB and KF control expiratory facilitatory response. The neurons of PRG are functionally connected via excitatory projections to respiratory nuclei in some other parts of the CNS, such as the ventrolateral medulla including the Bötzinger complex, the preBötzinger complex, and the rostral ventral respiratory group. This connection is essential for optimized respiratory output as well as the cough reflex control. This study aimed to analyze spatio-temporal parameters of mechanically induced tracheobronchial cough after unilateral codeine microinjections in the pontine respiratory group in anesthetized cats. The experiments were performed on 12 anesthetized non-paralyzed male cats (4.13 ± 0.24 kg). The electromyograms (EMGs) were recorded by bipolar insulated wire hook electrodes bilaterally from the diaphragm (DIA) and expiratory transversus abdominis and/or external oblique abdominal (ABD) muscles. Esophageal pressure (EP), blood pressure (BP), and respiratory parameters were recorded and analyzed as well. Craniectomy and partial cerebellectomy were performed with cats placed in a prone position in a stereotaxic frame. The cough reflex was induced mechanically through the cannula in the trachea. The stimulations were provided by the same person using a soft polyethylene fiber going back and forth 4-5 times in duration of 10 seconds. 24 microinjections of 3 mM codeine (total volume 37 ± 1.2 nl; micro-pipette diameter 26.6 ± 4.5 µm) were injected into the KF and PB complex in 8 anesthetized cats. 18 comparable microinjections of artificial cerebrospinal fluid (aCSF) were performed in 6 cats (59 ± 26.2 nl total volume, tip diameter 36 ± 4.0 µm) as well. The EMGs were filtered, amplified, rectified, and integrated and also recorded along with EP and BP waveforms. The number of cough efforts (CN) induced during tracheal mechanical stimulation (average CN per 10-second duration during trial), the ABD and DIA EMG amplitudes, and the amplitudes of EP during the applicable cough phases were evaluated. Codeine microinjections into the PRG did not decrease the number of coughs (from 4.5 ± 0.6 to 4.4 ± 0.7; p > 0.05), which recovered to 4.8 ± 0.6 after 43 minutes). There were no significant changes in cough temporal parameters. However, we observed a significant reduction of the cough ABD EMG amplitudes and expiratory EP. A slight but statistically significant reduction was found in DIA EMG amplitudes together with a non-significant reduction in inspiratory EP amplitudes during cough. Control microinjections of artificial CSF in 6 cats showed no significant effect on cough data in comparison with those after codeine microinjections. Our results show that the involvement of PRG neurons in the antitussive activity of codeine is limited and just the excitatory drive to the other parts of the brainstem were suppressed by the codeine microinjections. This work was supported by grants NIH: NS110169, HD110951, VEGA 1/0275/19, VEGA 1/0092/20. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.