2-3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline and Cough

We have previously described the physiological and morphological properties of the cough receptors and their sites of termination in the airways and centrally in the nucleus tractus solitarius (nTS). In the present study, we have addressed the hypothesis that the primary central synapses of the cough receptors subserve an essential role in the encoding of cough. We found that cough requires sustained, high-frequency (≥8-Hz) afferent nerve activation. We also found evidence for processes that both facilitate (summation, sensitization) and inhibit the initiation of cough. Sensitization of cough occurs with repetitive subthreshold activation of the cough receptors or by coincident activation of C-fibers and/or nTS neurokinin receptor activation. Desensitization of cough evoked by repetitive and/or continuous afferent nerve activation has a rapid onset (<60 s) and does not differentiate between tussive stimuli, suggesting a central nervous system-dependent process. The cough reflex can also be actively inhibited upon activation of other airway afferent nerve subtypes, including slowly adapting receptors and pulmonary C-fibers. The sensitization and desensitization of cough are likely attributable to the prominent, primary, and unique role of N-methyl-d-aspartate receptor-dependent signaling at the central synapses of the cough receptors. These attributes may have direct relevance to the presentation of cough in disease and for the effectiveness of antitussive therapies.

Topics: 4-Aminopyridine; 6-Cyano-7-nitroquinoxaline-2,3-dione; Anesthesia; Animals; Biphenyl Compounds; Citric Acid; Cough; Dose-Response Relationship, Drug; Electric Stimulation; GABA-A Receptor Antagonists; GABA-B Receptor Agonists; gamma-Aminobutyric Acid; Guinea Pigs; Male; Mechanoreceptors; Propionates; Quinoxalines; Receptors, GABA; Receptors, N-Methyl-D-Aspartate; Recurrent Laryngeal Nerve; Reflex; Respiratory Mucosa; Sensory Receptor Cells; Solitary Nucleus; Substance P; Trachea; Vagus Nerve; Valine