leukotriene receptor antagonist The results show that a toni

The results show that a tonic action of ACh on respiration is lacking. However, it is clear that muscarinic cholinergic mechanisms can modulate both eupneic breathing and the cough reflex. When these mechanisms are brought into action is obscure and only tentative proposals can be advanced. ACh in the caudal NTS may facilitate respiratory responses to peripheral chemoreflex activation, in agreement with previous findings in the rat (Furuya et al., 2014; Zoccal et al., 2014). In addition, not only afferent inputs from chemoreceptors, but also from pulmonary rapidly adapting receptors and C-fibers, that are well known to be involved in tachypneic reflex responses (Sant'Ambrogio and Widdicombe, 2001), converge onto caudal NTS leukotriene receptor antagonist (e.g. Machado, 2001; Kubin et al., 2006). Finally, somatosensory afferent signals, including those conveyed by nociceptive afferents, reach the caudal NTS relayed via the dorsal horn neurons (e.g. Kalia et al., 1981; Craig, 1995; Boscan et al., 2002; see Potts and Waldrop, 2005 for further Refs.). Cardiorespiratory changes and in particular tachypnea induced by somatic afferent stimulation (Duranti et al., 1991 also for further Refs.) may be mediated by the caudal NTS and its functional cholinergic system. In this context, it seems also relevant to mention that cough sensitivity is downregulated by exercise-induced hyperventilation as well as by voluntary isocapnic hyperpnea at similar level (Lavorini et al., 2010). Present results confirm that the caudal NTS, the main central terminus of bronchopulmonary afferents, has an important role in cough regulation and is a site of action of several neurotransmitters and neuromodulators. However, recent findings in the cat support a similar role for more rostral portions of the NTS (Poliacek et al., 2017a,b; see also Canning and Mori, 2010; Mutolo, 2017), thus suggesting marked species differences in the anatomical and functional organization of NTS subnuclei. On the other hand, we have to admit that ACh may also act at the level of the different brainstem neural structures involved in the control of this defensive reflex (Mutolo, 2017), as recently observed by Poliacek et al. (2015) by using nicotine microinjections into the cVRG. The observed absence of an apparent functional involvement of nAChRs following ACh microinjections could be due to barbiturate-inhibition of the nicotinic receptor channels (Morin-Surun et al., 1984; Yost and Dodson, 1993; for review see Arias et al., 2006). However, it seems that this inhibitory mechanism does not contribute very much to conceal nicotinic effects, at least in some animal species (Poliacek et al., 2015). In conclusion, the results provide substantial evidence that mAChRs modulate both respiration and cough reflex responses. They may also provide hints for further studies not only on details on caudal NTS cholinergic mechanisms, but also on the development of novel antitussive therapeutic strategies. In this context, it should be recalled that available antitussive therapies have limited efficacy and severe side effects that limit their employment in chronic cough, a clinical condition that considerably impairs the quality of life. On the other hand, an impairment of airway defensive reflexes, including cough and swallowing, is a common feature of some neurodegenerative diseases and could lead to aspiration pneumonia and life-threatening conditions (for review see Mutolo, 2017). We believe that not only studies on animal models of chronic cough or neurodegenerative diseases, but also investigations on the basic neural mechanisms underlying the cough reflex in healthy preparations can reveal novel therapeutic approaches for both downregulation and upregulation of the cough reflex.
Funding This study was supported by grants from the University of Florence. E.C was supported by a postdoctoral fellowship from the Fondazione Internazionale Menarini.
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