Central regulation of the cough reflex: Therapeutic implications

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Abstract

In many species including humans, antagonists of NMDA-type glutamate receptors such as dextromethorphan, when used at sufficient doses, have been found to be relatively safe and effective antitussives. Similarly, now in five different species (guinea pigs, rabbits, cats, dogs and pigs), neurokinin receptor antagonists have also proven to be safe and effective antitussive agents. Both of these classes of drugs act centrally to prevent cough. A brief review of what is known about the central encoding of cough is presented, as are the advantages of centrally acting antitussives. Also discussed are new insights into cough and NMDA receptor signaling that may lead to the development of more effective antitussive agents with limited side effects and broad application in treating cough associated with a variety of aetiologies.

Introduction

Codeine and dextromethorphan are used extensively and specifically for the treatment of cough and likely exert their effects through central sites of action [1], [2]. The neurokinin receptor antagonists, amongst the more promising class of therapeutics evaluated for cough over the past 20 years, also likely act primarily via actions in the central nervous system (CNS) to prevent or reduce coughing in guinea pigs, rabbits, cats, dogs and pigs [3], [4], [5], [6], [7], [8], [9], [10]. Despite these past successes at treating cough with centrally-acting drugs, most current drug discovery efforts for cough and the majority of the physiological studies of the cough reflex have focused on the peripheral terminals of vagal afferent nerves [11], [12]. We propose that the medullary synapses of the vagal afferents regulating cough are not only the primary site of action of existing antitussive therapies, but that these central terminals are also the most appropriate and desirable site of action of new antitussive therapies. The central synaptic properties of the vagal afferent nerves regulating cough are briefly reviewed and features of these synapses that render them amenable to therapeutic intervention are described.

Section snippets

Central terminations of the vagal afferent nerves regulating cough

Coughing is initiated by activation of either C-fibres or subtypes of mechanically-sensitive, acid-sensitive, capsaicin-insensitive vagal afferents innervating the larynx, trachea and large bronchi [13], [14], [15], [16]. No direct physiological studies of the central terminations of these afferents have been described. There have been several barriers to completing these experiments. For example, C-fibre dependent cough is prevented by general anaesthesia [13], [14], [17], [18], [19], [20].

Why study central processing of afferent signaling regulating cough?

Stimuli that initiate cough have been reasonably well defined [13], [14], [15], [16]. These include mechanical stimuli (e.g. aspirate, accumulated secretions; [3], [4], [5], [10], [14], [39]), changes in airway surface liquid osmolarity [20], [40], [41], [42], [43], [44], [45], bradykinin [14], [16], [46], prostanoids [46], [47], [48], inhaled pollutants/irritants (e.g. cigarette smoke, acetone, SO2; [14], [49], [50]), and activators of the TRPV1 [51], [52] and TRPA1 [51], [53], [54] ion

Pharmacology and central integration of the afferent drive for cough

Studies of synaptic transmission in nTS evoked by the activation of vagal afferent nerves reveal a primary role for nonNMDA glutamate receptors with minimal if any role for NMDA receptors [92], [93]. A primary role for nonNMDA receptors in regulating synaptic transmission initiated by airway and lung afferent nerves has also been published [24], [28], [94]. It is thus a striking and important observation that NMDA receptor antagonists have proven to be highly effective antitussive agents in

Conclusions

New drugs for cough are needed. The most commonly used antitussives are known to act centrally to limit synaptic transmission in the brainstem, which in turn limits coughing. We propose that future research should build upon the successes of drugs such as dextromethorphan and improve upon them by exploiting our increased understanding of the physiology and pathophysiology of cough. Evaluating new therapies that take advantage of the prominent and unique role of NMDA receptor signaling in cough

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    Work summarized in this article was supported by grant from the NIH (HL083192).

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