As stated by Korpáš and Tomori (1979), cough is the most important airway protective reflex which provides airway defensive responses to nociceptive stimuli. They recognized that active expiratory efforts, due to the activation of caudal ventral respiratory group (cVRG) expiratory premotoneurons, are the prominent component of coughs. Here, we discuss data suggesting that neurons located in the cVRG have an essential role in the generation of both the inspiratory and expiratory components of the cough reflex. Some lines of evidence indicate that cVRG expiratory neurons, when strongly activated, may subserve the alternation of inspiratory and expiratory cough bursts, possibly owing to the presence of axon collaterals. Of note, experimental findings such as blockade or impairment of glutamatergic transmission to the cVRG neurons lead to the view that neurons located in the cVRG are crucial for the production of the complete cough motor pattern. The involvement of bulbospinal expiratory neurons seems unlikely since their activation affects differentially expiratory and inspiratory muscles, while their blockade does not affect baseline inspiratory activity. Thus, other types of cVRG neurons with their medullary projections should have a role and possibly contribute to the fine tuning of the intensity of inspiratory and expiratory efforts.

Department of Experimental and Clinical Medicine Physiological Sciences Section University of Florence Florence Italy

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ANDERSON TM, GARCIA AJ, III, BAERTSCH NA, POLLAK J, BLOOM JC, WEI AD, RAI KG, RAMIREZ JM. A novel excitatory network for the control of breathing. Nature. 2016;536:76–80. doi: 10.1038/nature18944. PubMed DOI PMC

ARITA H, KOGO N, KOSHIYA N. Morphological and physiological properties of caudal medullary expiratory neurons of the cat. Brain Res. 1987;401:258–266. doi: 10.1016/0006-8993(87)91410-7. PubMed DOI

BAEKEY DM, MORRIS KF, NUDING SC, SEGERS LS, LINDSEY BG, SHANNON R. Medullary raphe neuron activity is altered during fictive cough in the decerebrate cat. J Appl Physiol. 2003;94:93–100. doi: 10.1152/japplphysiol.00341.2002. PubMed DOI

BIANCHI AL, DENAVIT-SAUBIE M, CHAMPAGNAT J. Central control of breathing in mammals: neuronal circuitry, membrane properties, and neurotransmitters. Physiol Rev. 1995;75:1–45. doi: 10.1152/physrev.1995.75.1.1. PubMed DOI

BOLSER DC, DAVENPORT PW. Functional organization of the central cough generation mechanism. Pulm Pharmacol Ther. 2002;15:221–225. doi: 10.1006/pupt.2002.0361. PubMed DOI

BONGIANNI F, CORDA M, FONTANA GA, PANTALEO T. Chemical activation of caudal medullary expiratory neurones alters the pattern of breathing in the cat. J Physiol. 1994;474:497–507. doi: 10.1113/jphysiol.1994.sp020040. PubMed DOI PMC

BONGIANNI F, MUTOLO D, FONTANA GA, PANTALEO T. Discharge patterns of Bötzinger complex neurons during cough in the cat. Am J Physiol Regul Integr Comp Physiol. 1998;274:R1015–R1024. doi: 10.1152/ajpregu.1998.274.4.R1015. PubMed DOI

BONGIANNI F, MUTOLO D, NARDONE F, PANTALEO T. Ionotropic glutamate receptors mediate excitatory drive to caudal medullary expiratory neurons in the rabbit. Brain Res. 2005;1056:145–157. doi: 10.1016/j.brainres.2005.07.019. PubMed DOI

BONHAM AC, JESKE I. Cardiorespiratory effects of DL-homocysteic acid in caudal ventrolateral medulla. Am J Physiol. 1989;256:H688–H696. doi: 10.1152/ajpheart.1989.256.3.H688. PubMed DOI

CHITRAVANSHI VC, SAPRU HN. Phrenic nerve responses to chemical stimulation of the subregions of ventral medullary respiratory neuronal group in the rat. Brain Res. 1999;821:443–460. doi: 10.1016/S0006-8993(99)01139-7. PubMed DOI

CINELLI E, BONGIANNI F, PANTALEO T, MUTOLO D. Modulation of the cough reflex by GABA(A) receptors in the caudal ventral respiratory group of the rabbit. Front Physiol. 2012;3:403. doi: 10.3389/fphys.2012.00403. PubMed DOI PMC

CINELLI E, BONGIANNI F, PANTALEO T, MUTOLO D. Suppression of the cough reflex by alpha 2-adrenergic receptor agonists in the rabbit. Physiol Rep. 2013;1:e00122. doi: 10.1002/phy2.122. PubMed DOI PMC

del NEGRO CA, FUNK GD, FELDMAN JL. Breathing matters. Nat Rev Neurosci. 2018;19:351–367. doi: 10.1038/s41583-018-0003-6. PubMed DOI PMC

DUTSCHMANN M, HERBERT H. The Kolliker-Fuse nucleus gates the postinspiratory phase of the respiratory cycle to control inspiratory off-switch and upper airway resistance in rat. Eur J Neurosci. 2006;24:1071–1084. doi: 10.1111/j.1460-9568.2006.04981.x. PubMed DOI

DUTSCHMANN M, JONES SE, SUBRAMANIAN HH, STANIC D, BAUTISTA TG. The physiological significance of postinspiration in respiratory control. Prog Brain Res. 2014;212:113–130. doi: 10.1016/B978-0-444-63488-7.00007-0. PubMed DOI

EZURE K. Synaptic connections between medullary respiratory neurons and considerations on the genesis of respiratory rhythm. Prog Neurobiol. 1990;35:429–450. doi: 10.1016/0301-0082(90)90030-K. PubMed DOI

FELDMAN JL, DEL NEGRO CA, GRAY PA. Understanding the rhythm of breathing: so near, yet so far. Annu Rev Physiol. 2013;75:423–452. doi: 10.1146/annurev-physiol-040510-130049. PubMed DOI PMC

FELDMAN JL, LOEWY AD, SPECK DF. Projections from the ventral respiratory group to phrenic and intercostal motoneurons in cat: an autoradiographic study. J Neurosci. 1985;5:1993–2000. doi: 10.1523/JNEUROSCI.05-08-01993.1985. PubMed DOI PMC

GERRITS PO, HOLSTEGE G. Pontine and medullary projections to the nucleus retroambiguus: a wheat germ agglutinin-horseradish peroxidase and autoradiographic tracing study in the cat. J Comp Neurol. 1996;373:173–185. doi: 10.1002/(SICI)1096-9861(19960916)373:2<173::AID-CNE2>3.0.CO;2-0. PubMed DOI

HOLSTEGE G. Anatomical study of the final common pathway for vocalization in the cat. J Comp Neurol. 1989;284:242–252. doi: 10.1002/cne.902840208. PubMed DOI

HOLSTEGE G, KUYPERS HG. The anatomy of brain stem pathways to the spinal cord in cat. A labeled amino acid tracing study. Prog Brain Res. 1982;57:145–175. doi: 10.1016/S0079-6123(08)64128-X. PubMed DOI

IKEDA K, KAWAKAMI K, ONIMARU H, OKADA Y, YOKOTA S, KOSHIYA N, OKU Y, IIZUKA M, KOIZUMI H. The respiratory control mechanisms in the brainstem and spinal cord: integrative views of the neuroanatomy and neurophysiology. J Physiol Sci. 2017;67:45–62. doi: 10.1007/s12576-016-0475-y. PubMed DOI PMC

ISCOE S. Control of abdominal muscles. Prog Neurobiol. 1998;56:433–506. doi: 10.1016/S0301-0082(98)00046-X. PubMed DOI

JIANG C, LIPSKI J. Extensive monosynaptic inhibition of ventral respiratory group neurons by augmenting neurons in the Bötzinger complex in the cat. Exp Brain Res. 1990;81:639–648. doi: 10.1007/BF02423514. PubMed DOI

JONES SE, SAAD M, LEWIS DI, SUBRAMANIAN HH, DUTSCHMANN M. The nucleus retroambiguus as possible site for inspiratory rhythm generation caudal to obex. Respir Physiol Neurobiol. 2012;180:305–310. doi: 10.1016/j.resp.2011.12.007. PubMed DOI PMC

JONES SE, STANIC D, DUTSCHMANN M. Dorsal and ventral aspects of the most caudal medullary reticular formation have differential roles in modulation and formation of the respiratory motor pattern in rat. Brain Struct Funct. 2016;221:4353–4368. doi: 10.1007/s00429-015-1165-x. PubMed DOI

KASÉ Y. Antitussive agents and their sites of action. Trends Pharmacol Sci. 1980;1:237–239. doi: 10.1016/0165-6147(80)90008-5. DOI

KORPÁŠ J, TOMORI Z. Cough and Other Respiratory Reflexes. Karger; Basel: 1979.

LIPSKI J, TRZEBSKI A, CHODOBSKA J, KRUK P. Effects of carotid chemoreceptor excitation on medullary expiratory neurons in cats. Respir Physiol. 1984;57:279–291. doi: 10.1016/0034-5687(84)90077-X. PubMed DOI

MERRILL EG, LIPSKI J, KUBIN L, FEDORKO L. Origin of the expiratory inhibition of nucleus tractus solitarius inspiratory neurones. Brain Res. 1983;263:43–50. doi: 10.1016/0006-8993(83)91198-8. PubMed DOI

MUTOLO D. Brainstem mechanisms underlying the cough reflex and its regulation. Respir Physiol Neurobiol. 2017;243:60–76. doi: 10.1016/j.resp.2017.05.008. PubMed DOI

MUTOLO D, BONGIANNI F, CINELLI E, PANTALEO T. Depression of cough reflex by microinjections of antitussive agents into caudal ventral respiratory group of the rabbit. J Appl Physiol. 2010;109:1002–1010. doi: 10.1152/japplphysiol.00406.2010. PubMed DOI

MUTOLO D, BONGIANNI F, PANTALEO T. Effects of lignocaine blockades and kainic acid lesions in the Bötzinger complex on spontaneous expiratory activity and cough reflex responses in the rabbit. Neurosci Lett. 2002;332:175–179. doi: 10.1016/S0304-3940(02)00954-0. PubMed DOI

NEWSOM DAVIS J, PLUM F. Separation of descending spinal pathways to respiratory motoneurons. Exp Neurol. 1972;34:78–94. doi: 10.1016/0014-4886(72)90189-6. PubMed DOI

OKU Y, OKABE A, HAYAKAWA T, OKADA Y. Respiratory neuron group in the high cervical spinal cord discovered by optical imaging. Neuroreport. 2008;19:1739–1743. doi: 10.1097/WNR.0b013e328318edb5. PubMed DOI

OKU Y, TANAKA I, EZURE K. Activity of bulbar respiratory neurons during fictive coughing and swallowing in the decerebrate cat. J Physiol. 1994;480:309–324. doi: 10.1113/jphysiol.1994.sp020361. PubMed DOI PMC

OTT MM, NUDING SC, SEGERS LS, LINDSEY BG, MORRIS KF. Ventrolateral medullary functional connectivity and the respiratory and central chemoreceptor-evoked modulation of retrotrapezoid-parafacial neurons. J Neurophysiol. 2011;105:2960–2975. doi: 10.1152/jn.00262.2010. PubMed DOI PMC

PANTALEO T, BONGIANNI F, MUTOLO D. Central nervous mechanisms of cough. Pulm Pharmacol Ther. 2002;15:227–233. doi: 10.1006/pupt.2002.0358. PubMed DOI

PISANSKI A, PAGLIARDINI S. The parafacial respiratory group and the control of active expiration. Respir Physiol Neurobiol. 2019;265:153–160. doi: 10.1016/j.resp.2018.06.010. PubMed DOI

POLIACEK I, CORRIE LW, ROSE MJ, WANG C, BOLSER DC. Influence of microinjections of D,L-homocysteic acid into the Bötzinger complex area on the cough reflex in the cat. J Physiol Pharmacol. 2008;59(Suppl 6):585–596. PubMed PMC

POLIACEK I, CORRIE LW, WANG C, ROSE MJ, BOLSER DC. Microinjection of DLH into the region of the caudal ventral respiratory column in the cat: evidence for an endogenous cough-suppressant mechanism. J Appl Physiol. 2007;102:1014–1021. doi: 10.1152/japplphysiol.00616.2006. PubMed DOI PMC

POLIACEK I, ROSE MJ, PITTS TE, MORTENSEN A, CORRIE LW, DAVENPORT PW, BOLSER DC. Central administration of nicotine suppresses tracheobronchial cough in Anaesthetized cats. J Appl Physiol. 2015;118:265–272. doi: 10.1152/japplphysiol.00075.2014. PubMed DOI PMC

POLIACEK I, WANG C, CORRIE LW, ROSE MJ, BOLSER DC. Microinjection of codeine into the region of the caudal ventral respiratory column suppresses cough in anaesthetized cats. J Appl Physiol. 2010;108:858–865. doi: 10.1152/japplphysiol.00783.2009. PubMed DOI PMC

RICHTER DW, SMITH JC. Respiratory rhythm generation in vivo. Physiology (Bethesda) 2014;29:58–71. doi: 10.1152/physiol.00035.2013. PubMed DOI PMC

SHANNON R, BAEKEY DM, MORRIS KF, LI Z, LINDSEY BG. Functional connectivity among ventrolateral medullary respiratory neurones and responses during fictive cough in the cat. J Physiol. 2000;525:207–224. doi: 10.1111/j.1469-7793.2000.00207.x. PubMed DOI PMC

SHANNON R, BAEKEY DM, MORRIS KF, LINDSEY BG. Brainstem respiratory networks and cough. Pulm Pharmacol. 1996;9:343–347. doi: 10.1006/pulp.1996.0045. PubMed DOI

SHANNON R, BAEKEY DM, MORRIS KF, NUDING SC, SEGERS LS, LINDSEY BG. Production of reflex cough by brainstem respiratory networks. Pulm Pharmacol Ther. 2004;17:369–376. doi: 10.1016/j.pupt.2004.09.022. PubMed DOI

SMITH JC, MORRISON DE, ELLENBERGER HH, OTTO MR, FELDMAN JL. Brainstem projections to the major respiratory neuron populations in the medulla of the cat. J Comp Neurol. 1989;281:69–96. doi: 10.1002/cne.902810107. PubMed DOI

SUBRAMANIAN HH, HOLSTEGE G. The nucleus retroambiguus control of respiration. J Neurosci. 2009;29:3824–3832. doi: 10.1523/JNEUROSCI.0607-09.2009. PubMed DOI PMC

SUBRAMANIAN HH, HUANG ZG, SILBURN PA, BALNAVE RJ, HOLSTEGE G. The physiological motor patterns produced by neurons in the nucleus retroambiguus in the rat and their modulation by vagal, peripheral chemosensory, and nociceptive stimulation. J Comp Neurol. 2018;526:229–242. doi: 10.1002/cne.24318. PubMed DOI

SUGIYAMA Y, SHIBA K, MUKUDAI S, UMEZAKI T, SAKAGUCHI H, HISA Y. Role of the retrotrapezoid nucleus/parafacial respiratory group in coughing and swallowing in guinea pigs. J Neurophysiol. 2015;114:1792–1805. doi: 10.1152/jn.00332.2015. PubMed DOI PMC

von EULER C. Brain stem mechanisms for generation and control of breathing pattern. In: CHERNIACK NS, WIDDICOMBE JG, editors. Handbook of Physiology. The Respiratory System. Control of Breathing. American Physiological Society; Bethesda, MA: 1986. pp. 1–67.

WIDDICOMBE JG. Reflexes from the upper respiratory tract. In: CHERNIACK NS, WIDDICOMBE JG, editors. Handbook of Physiology. The Respiratory System. Control of Breathing. American Physiological Society; Bethesda, MD: 1986. pp. 363–394.

ZHENG Y, RICHE D, REKLING JC, FOUTZ AS, DENAVIT-SAUBIE M. Brainstem neurons projecting to the rostral ventral respiratory group (VRG) in the medulla oblongata of the rat revealed by co-application of NMDA and biocytin. Brain Res. 1998;782:113–125. doi: 10.1016/S0006-8993(97)01251-1. PubMed DOI

Legacy of Prof. Juraj Korpáš: International Impact of Slovak School of Experimental Respirology