Behavioral and Regional Brain Responses to Inhalation of Capsaicin Modified by Painful Conditioning in Humans

doi:10.1016/j.chest.2020.08.2105

Chest

Volume 159, Issue 3, March 2021, Pages 1136-1146

https://doi.org/10.1016/j.chest.2020.08.2105 Get rights and content

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 (R² = 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.

Section snippets

Participant Recruitment and Experimental Protocol

Sixteen healthy participants were recruited via advertisements posted on the campus of Monash University (Melbourne, Australia) (nine men and seven women; mean ages, 24.94 ± [SD] 4.39 years). Exclusion criteria included claustrophobia, pregnancy, metal implants, and dental braces. Consent was obtained from the participants in compliance with procedures approved by the Monash University Human Research Ethics Committee (approval 2019.18292) and was consistent with the Declaration of Helsinki.

Psychophysical Testing Session

Psychophysical Results

The geometric means of C2 and S_max were 0.69 μM and 0.23 μM, respectively. Levels of stimuli for conditioning pain were 5.3 ± 1.3 kg/cm² during the psychophysical session and 3.8 ± 0.9 kg/cm² during fMRI scanning.

Both cough (F[1,15] = 30.3; P < .001) and UTC (F[1,15] = 22.2; P < .001) showed conditioning-related decreases in the psychophysical session that averaged (μ ± σ) 47.0% ± 30.8% and 18.7% ± 17.3%, respectively, which was a significant difference between the two outcome variables

Discussion

In this study, we investigated interactions between pain and cough. Painful conditioning stimuli significantly reduced both UTC ratings and cough frequency among individuals inhaling capsaicin. This behavioral effect was accompanied by reductions in BOLD signal responses in brain regions activated by capsaicin inhalation. These consonant findings of behavioral and regional brain responses are likely to represent a modulation of sensory inputs at lower levels of the neuroaxis that leads to a

Interpretation

Concurrent pain has a strong influence on coughing and UTC in healthy humans, effects that are associated with widespread changes in regional brain responses to capsaicin inhalation. This confluence of behavior and brain activity points toward a down-regulation of sensory inputs in the lower brainstem that is perhaps consistent with mechanisms of the diffuse noxious inhibitory controls phenomenon. These outcomes have special significance and constitute a promising target for future studies

Acknowledgments

Author contributions: M. J. F. is the guarantor of this study and takes responsibility of the manuscript. A. B. A had full access to the study data and vouches for the integrity of the data analysis. A. B. A. contributed to study design, data collection, analysis, and manuscript preparation. T. G. B. contributed to study design and manuscript preparation. M. R. D. contributed to study design and manuscript preparation. S. B. M. contributed to study conceptualization, design, data

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: FUNDING/SUPPORT: This research was supported by grants to Drs Mazzone and Farrell from the National Health and Medical Research Council (NHMRC) of Australia (APP1042528). Dr Bautista was funded by an Early Career Fellowship from The Garnett Passe and Rodney Williams Memorial Foundation of Australia and a University of Melbourne Early Career Researcher grant.

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Chest

Education and Clinical Practice: Original ResearchBehavioral and Regional Brain Responses to Inhalation of Capsaicin Modified by Painful Conditioning in Humans

Background

Research Question

Study Design and Methods

Results

Interpretation

Section snippets

Participant Recruitment and Experimental Protocol

Psychophysical Testing Session

Psychophysical Results

Discussion

Interpretation

Acknowledgments

Neuroimage

Curr Opin Pharmacol

Neurosci Biobehav Rev

Neurosci Biobehav Rev

Pulm Pharmacol Ther

Brain Res Rev

Pain

Chest

J Pain

Respir Physiol Neurobiol

Pulm Pharmacol Ther

Respir Med

Neuroimage

Neuroimage

J Pain

Vagal afferent innervation of the airways in health and disease

Physiol Rev

Representation of capsaicin-evoked urge-to-cough in the human brain using functional magnetic resonance imaging

Am J Respir Crit Care Med

Education and Clinical Practice: Original Research
Behavioral and Regional Brain Responses to Inhalation of Capsaicin Modified by Painful Conditioning in Humans