Central regulation of the cough reflex: therapeutic implications

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.

Fig. 1

This schematic illustrates some of the central and peripheral mechanisms regulating the cough reflex. Cough is initiated by activation of capsaicin-sensitive C-fibers and capsaicin-insensitive, acid sensitive mechanoreceptors innervating the larynx, trachea and large bronchi. Stimuli evoking cough include TRPV1 (capsaicin, anandamide, resiniferatoxin, protons) and TRPA1 (ozone, toluene diisocyanate, acrolein, cinnamaldehyde) receptor agonists, acid (through TRPV1-dependent and –independent (perhaps ASIC3-dependent) mechanisms), altered airway surface liquid osmolarity, mechanical stimuli (e.g. aspirate, accumulated mucus), bradykinin, and prostanoids. TRPV1-dependent coughing can be enhanced (dashed lines) by the actions of inflammatory mediators. Coughing can also be modulated by activation of other afferent nerve subtypes and by conscious perception of cough stimulation and by psychosocial influences. Central encoding of cough is regulated by both glutamate (via NMDA and nonNMDA receptor activation) and neurokinins (through actions on NK₁, NK₂ and/or NK₃ receptors). Abbreviations: nAChR: nicotinic acetylcholine receptors; SP/NKA: substance P/neurokinin A; TDI: toluene diisocyanate; nTS: nucleus tractus solitarius; TxA₂: thromboxane A₂; LTC₄ and LTD₄: leukotriene C₄ and D₄; EP: E series prostanoid receptors; B2: bradykinin2 receptors; ASIC: acid-sensing ion channel; See text for further details.

Fig. 2

NMDA-type glutamate or neurokinin receptor antagonists prevent experimentally induced coughing in humans and in animals. Coughing was evoked by inhalation of citric acid (humans, pigs, guinea pigs (upper panel)) or capsaicin (rat, guinea pig (lower panel)), or by mechanical probing of the airway mucosa in anesthetized dogs, rabbits and cats. NMDA (dextromethorphan, MK801, APV), NK₁ (αNK₁; CP99994 or SR140333 (pigs), NK₂ (αNK₂; SR48968 or NK₃ (αNK₃; SR142801) receptor antagonists were given systemically (to humans, pigs, dogs, guinea pigs (upper panel)), by icv or central arterial administration (rats, cats, guinea pigs (lower panel)) or by nTS microinjection (rabbits). Comparable effects have been reported with systemic administration of NK3 receptor antagonists in guinea pigs [6,7]. Data are modified from published results [3-5, 10, 39, 69-71].

Fig. 3

The NMDA receptor antagonist dextromethorphan acts centrally to prevent coughing in humans and in guinea pigs. Dextromethorphan given orally but not by inhalation prevented citric acid evoked coughing in human subjects (left panel). Similarly, dextromethorphan administered by microinjection in nTS but not delivered by perfusion directly to the trachea prevented coughing evoked by citric acid applied topically to the tracheal mucosa (right panel). Comparable results have been obtained in studies with other putative antitussive agents. Data are the author's unpublished results or derived from Grattan et al. [69].

Figure 4

The cough reflex requires sustained, high frequency vagal afferent nerve activation. Coughing was evoked in anesthetized guinea pigs by electrically stimulating the tracheal mucosa at optimal stimulation intensity (8 V, 1 msec pulse duration) and various frequencies with 10 second trains every minute for 10 minutes. The percentage of stimulations failing to evoke cough are presented. Data are mean ± sem of 6-10 experiments.