6-cyano-7-nitroquinoxaline-2-3-dione and Cough

As stated by Korpáš and Tomori (1979), cough is the most important airway protective reflex which provides airway defensive responses to nociceptive stimuli. They recognized that active expiratory efforts, due to the activation of caudal ventral respiratory group (cVRG) expiratory premotoneurons, are the prominent component of coughs. Here, we discuss data suggesting that neurons located in the cVRG have an essential role in the generation of both the inspiratory and expiratory components of the cough reflex. Some lines of evidence indicate that cVRG expiratory neurons, when strongly activated, may subserve the alternation of inspiratory and expiratory cough bursts, possibly owing to the presence of axon collaterals. Of note, experimental findings such as blockade or impairment of glutamatergic transmission to the cVRG neurons lead to the view that neurons located in the cVRG are crucial for the production of the complete cough motor pattern. The involvement of bulbospinal expiratory neurons seems unlikely since their activation affects differentially expiratory and inspiratory muscles, while their blockade does not affect baseline inspiratory activity. Thus, other types of cVRG neurons with their medullary projections should have a role and possibly contribute to the fine tuning of the intensity of inspiratory and expiratory efforts.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Cough; Excitatory Amino Acid Antagonists; Exhalation; Humans; Inhalation; Medulla Oblongata; Microinjections; Neurons; Phrenic Nerve; Reflex; Respiratory Mechanics

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

We investigated the role of ionotropic glutamate receptors located within the caudal portions of the nucleus tractus solitarii (cNTS) and the caudal ventral respiratory group (cVRG) in the mediation of coughing evoked by citric acid inhalation in spontaneously breathing rabbits under pentobarbitone anaesthesia. Bilateral microinjections (30-50nl) of 10mM CNQX and 10mM D-AP5 were performed to block non-NMDA and NMDA receptors, respectively. An attempt was also made to investigate the effects of ionotropic glutamate receptor blockade within the cVRG on sneezing induced by mechanical stimulation of the nasal mucosa. Blockade of non-NMDA receptors within the cNTS abolished coughing and associated tachypneic responses, while blockade of NMDA receptors only reduced cough responses. Blockade of non-NMDA receptors within the cVRG always abolished spontaneous rhythmic abdominal activity as well as coughing and associated tachypneic responses; blockade of NMDA receptors only reduced spontaneous rhythmic abdominal activity and coughing. As to sneezing, blockade of non-NMDA receptors within the cVRG suppressed the expiratory thrusts without affecting the inspiratory preparatory bursts, while blockade of NMDA receptors only strongly attenuated the expiratory thrusts. This study is the first to provide evidence that ionotropic glutamate receptors, and especially non-NMDA receptors, are involved in the mediation of coughing induced by citric acid inhalation and to suggest that citric acid-activated cough-related afferents terminate within the cNTS. Present data also corroborate the notion that the cVRG is involved in the generation of the whole cough motor pattern, but seems to represent merely an expiratory output system for sneezing.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Administration, Inhalation; Animals; Citric Acid; Cough; Electromyography; Excitatory Amino Acid Antagonists; Excitatory Amino Acids; Humans; Microinjections; Phrenic Nerve; Rabbits; Receptors, N-Methyl-D-Aspartate; Respiratory Center; Respiratory Mechanics; Sneezing; Solitary Nucleus