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Background: Cough is a defense mechanism that protects the airways and lungs in response to airway irritation. The sensory neurons involved in detecting airway irritants and the neural pathways mediating cough share similarities with those that encode pain from the body. Painful conditioning stimuli applied to one body site are known to reduce the perception of pain at another. However, whether the neural regulation of cough is influenced by painful stimuli is not known., Research Question: What are the behavioral and neural outcomes of painful conditioning stimuli on urge-to-cough (UTC) and cough evoked by inhaled capsaicin?, Study Design and Methods: Sixteen healthy participants underwent psychophysical testing and functional MRI while completing a series of capsaicin inhalations to induce UTC and cough. The responses associated with capsaicin inhalation without pain were compared with those after the application of painful conditioning stimuli., Results: Significant decreases were seen behaviorally of 18.7% ± 17.3% (P < .001) and 47.0% ± 30.8% (P < .001) in participants' UTC ratings and cough frequencies, respectively, during the application of pain. UTC ratings were reduced by 24.2% ± 36.5% (P < .005) and increased by 67% ± 40% (P < .001) for capsaicin and saline inhalation, respectively, during the scanning session. Painful conditioning stimuli were associated with widespread decreases in regional brain responses to capsaicin inhalation (P < .001). Several brain regions showed levels of reduced activation attributable to painful conditioning that correlated with related changes in behavioral responses during scanning (R 2  = 0.53)., Interpretation: Pain-related decreases of cough and UTC are accompanied by widespread changes in brain activity during capsaicin inhalation, suggesting that pain can modify the central processing of inputs arising from the airways. A mechanistic understanding of how cough and pain processing interact within the brain may help develop more effective therapies to reduce unwanted coughing., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Key points: Unpleasant respiratory sensations contribute to morbidity in pulmonary disease. In rodents, these sensations are processed by nodose and jugular vagal sensory neurons, two distinct cell populations that differentially project to the airways and brainstem.Whether similar differences exist in bronchopulmonary sensory pathways in humans is unknown.We use functional magnetic resonance imaging during inhalation of capsaicin and ATP, showing that airway nodose pathways project centrally to the nucleus of the solitary tract, whereas jugular pathways input into the trigeminal brainstem nuclei.We also show differences between the efficacy of nodose and jugular stimuli to evoke cough and activity in motor control regions of the brain.Our data suggest that humans have two distinct vagal sensory neural systems governing airway sensations and this may have implications for the development of new antitussive therapies. In rodents, nodose vagal sensory neurons preferentially innervate the distal airways and terminate centrally in the nucleus of the solitary tract. By contrast, jugular vagal sensory neurons preferentially innervate the proximal airways and terminate in the paratrigeminal nucleus in the dorsolateral medulla. This differential organization suggests distinct roles for nodose and jugular pathways in respiratory sensory processing. However, it is unknown whether bronchopulmonary afferent pathways are similarly arranged in humans. We set out to investigate this using high resolution brainstem and whole brain functional magnetic resonance imaging in healthy human participants when they were inhaling stimuli known to differentially activate nodose and jugular pathways. Inhalation of capsaicin or ATP evoked respiratory sensations described as an urge‐to‐cough, although ATP was significantly less effective compared to capsaicin at evoking the motor act of coughing. The nodose and jugular neuron stimulant capsaicin increased blood oxygen level‐dependent (BOLD) signals extending across the dorsomedial and dorsolateral medulla, encompassing regions containing both the nucleus of the solitary tract and the paratrigeminal nucleus. By contrast, at perceptually comparable stimulus intensities, the nodose‐selective stimulant ATP resulted in BOLD signal intensity changes that were confined to the area of the nucleus of the solitary tract. During whole brain imaging, capsaicin demonstrated a wider distributed network of activity compared to ATP, with significantly increased activity in regions involved with motor control functions. These data suggest that functional and neuroanatomical differences in bronchopulmonary nodose and jugular sensory pathway organization are conserved in humans and also that this has implications for understanding the neurobiological mechanisms underpinning cough. Key points: Unpleasant respiratory sensations contribute to morbidity in pulmonary disease. In rodents, these sensations are processed by nodose and jugular vagal sensory neurons, two distinct cell populations that differentially project to the airways and brainstem.Whether similar differences exist in bronchopulmonary sensory pathways in humans is unknown.We use functional magnetic resonance imaging during inhalation of capsaicin and ATP, showing that airway nodose pathways project centrally to the nucleus of the solitary tract, whereas jugular pathways input into the trigeminal brainstem nuclei.We also show differences between the efficacy of nodose and jugular stimuli to evoke cough and activity in motor control regions of the brain.Our data suggest that humans have two distinct vagal sensory neural systems governing airway sensations and this may have implications for the development of new antitussive therapies. [ABSTRACT FROM AUTHOR]

Coughing is an airway protective behavior elicited by airway irritation. Animal studies show that airway sensory information is relayed via vagal sensory fibers to termination sites within dorsal caudal brain stem and thereafter relayed to more rostral sites. Using functional magnetic resonance imaging (fMRI) in humans, we previously reported that inhalation of the tussigenic stimulus capsaicin evokes a perception of airway irritation ("urge to cough") accompanied by activations in a widely distributed brain network including the primary sensorimotor, insular, prefrontal, and posterior parietal cortices. Here we refine our imaging approach to provide a directed survey of brain stem areas activated by airway irritation. In 15 healthy participants, inhalation of capsaicin at a maximal dose that elicits a strong urge to cough without behavioral coughing was associated with activation of medullary regions overlapping with the nucleus of the solitary tract, paratrigeminal nucleus, spinal trigeminal nucleus and tract, cardiorespiratory regulatory areas homologous to the ventrolateral medulla in animals, and the midline raphe. Interestingly, the magnitude of activation within two cardiorespiratory regulatory areas was positively correlated (r² = 0.47, 0.48) with participants' subjective ratings of their urge to cough. Capsaicin-related activations were also observed within the pons and midbrain. The current results add to knowledge of the representation and processing of information regarding airway irritation in the human brain, which is pertinent to the pursuit of novel cough therapies. [ABSTRACT FROM AUTHOR]