Adaptive Mechanisms Governing Tracheobronchial Cough: In Vivo Experiments and Model Simulations

Abstract

Repetitive coughing can be suppressed in a dose‐dependent manner in response to administration of cough suppressant drugs in anesthetized cats. Cough suppression by these drugs manifests as a reduction in cough number and expiratory motor drive. Cough phase durations and inspiratory motor drive are unaffected by these drugs in the cat. The mechanism by which antitussive drugs exert these effects is unknown. We speculated that depression of synaptic excitability at the first central synapse of cough receptor afferents could contribute to this effect. To test this hypothesis, we conducted simulations using a well‐established computational model of the peripheral afferents and the central circuit that is proposed to account for cough and breathing. Modulation of the conductance of the first central synapse and then the firing probability of cough receptors predicted inverse relationships between these parameters, and cough number and expiratory motor drive. However, these simulations also predicted that reductions in the magnitudes of these parameters would result in longer cough cycle times, with a greater impact of synaptic conductance on this relationship. These predictions are not consistent with the known action of antitussive drugs on the cough motor pattern. Similarities to the results of these simulations were observed between coordinated in vivo experiments in anesthetized spontaneously breathing cats. A repetitive cough protocol was conducted in which naïve animals were challenged with a sequence of trials in which the intrathoracic trachea was mechanically stimulated to elicit coughing. Cough number and expiratory motor drive decreased by approximately 50% over the course of 15–20 consecutive trials. Total cough cycle duration increased by 46% (p<0.02) accounting for the decreased number of coughs during the protocol. Significant prolongations of cough TI, E1, and E2 were also observed. The data support: (i) significant adaptive processes of naïve animals to a sequential cough stimulation protocol, (ii) a different phenotype of this adaptive process than that associated with cough suppressants, (iii) potential mechanisms for this adaptive process that could include reduced excitation of both peripheral afferents and their first synapse with a larger contribution of the central component to the adaptation.Support or Funding InformationSupported by HL 103415, HL 111215, HL 109025