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. 2017 Dec:246:59-66.
doi: 10.1016/j.resp.2017.07.011. Epub 2017 Aug 1.

Role of the dorsomedial medulla in suppression of cough by codeine in cats

Ivan Poliacek  1 , Michal Simera  2 , Marcel Veternik  1 , Zuzana Kotmanova  1 , Donald C Bolser  3 , Peter Machac  1 , Jan Jakus  1
Affiliations

Role of the dorsomedial medulla in suppression of cough by codeine in cats

Ivan Poliacek et al. Respir Physiol Neurobiol. 2017 Dec.

Abstract

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 33mM, 54±16nl 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 (3.3mM 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 (33mM 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.

Keywords: Airway defense; Brainstem; Lateral tegmental field; Respiratory motor output; Solitary tract nucleus.

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Figures

Fig. 1
Fig. 1
Reconstruction of microinjection sites. Stars represent highlighted positions of the micropipette tip during bilateral microinjections of codeine (code) and vehicle artificial cerebrospinal fluid (aCSF) as determined by fluorescent marker. Inset photographs demonstrate the process. The arrows ‘injection’ point out light spots of a spread of fluorescent marker (typically 0.1–0.2 mm). A: All 12 microinjection locations were found within or near the commissural sub-nucleus of the comNTS. Reference points: comNTS, 12, central canal, medullary surface. B: In the rostral NTS all 24 aCSF (for this figure the spot shown was estimated to be located one-half way between corresponding microinjections at 0.7 and 1.6 mm rostral to the obex) and 10 out of 12 codeine microinjection locations were identified near the solitary tract (TS). Reference points: TS, NTS, 12, Int, the bottom of the 4th ventricle, medullary surface. C: All 14 aCSF and 12 out of 14 microinjection locations were identified in the FTL between NTS and the nucleus ambiguus (NA). Reference points: TS, NTS, 12, NA, LRN, midline, medullary surface. 12: hypoglossal ncl., comNTS: commissural subnucleus of the NTS, GR: gracile ncl., Int: ncl. intercalatus, LRN: lateral reticular ncl., NA: ncl. ambiguus, NTS: ncl. Tractus solitarius, TS: tractus solitarius.
Fig. 2
Fig. 2
Changes in tracheobronchial cough induced by microinjections of codeine into the caudal NTS (cNTS), the rostral NTS (rNTS) and the lateral tegmental field (FTL). Open bars represent percentages of control (100%) within 5 min post-microinjections, gray bars recovery data (7–90 min following microinjections depending on the time when the cough recovery occured). CN: number of coughs; DIA: amplitudes of the diaphragm EMG, EP I: inspiratory amplitudes of esophageal pressure; ABD: amplitudes of abdominal EMG; EP E: expiratory amplitudes of esophageal pressure during cough. *, **, ***: P < 0.05, 0.01, 0.001 compared to the control data; +, ++, +++: P < 0.05, 0.01, 0.001 compared to the recovery data, respectively.
Fig. 3
Fig. 3
Representative examples of coughing changes induced by microinjections of codeine into the caudal NTS (cNTS), the rostral NTS (rNTS) and the lateral tegmental field (FTL). ∫: moving average; DIA: the diaphragm EMG, ABD: the abdominal muscles EMG; EP: esophageal pressure; BP: arterial blood pressure. No significant cough changes were induced by microinjections of codeine into the cNTS. Microinjections of codeine in the rNTS and the FTL resulted in reduction of expiratory and inspiratory cough efforts. Microinjections of codeine into the rNTS also decreased CN. Post-microinjection cough trials were executed within 2–5 min post-injection time window.
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