Altered neural activity in brain cough suppression networks in cigarette smokers

Abstract

Cough is important for airway defence, and studies in healthy animals and humans have revealed multiple brain networks intimately involved in the perception of airway irritation, cough induction and cough suppression. Changes in cough sensitivity and/or the ability to suppress cough accompany pulmonary pathologies, suggesting a level of plasticity is possible in these central neural circuits. However, little is known about how persistent inputs from the lung might modify the brain processes regulating cough.In the present study, we used human functional brain imaging to investigate the central neural responses that accompany an altered cough sensitivity in cigarette smokers.In nonsmokers, inhalation of the airway irritant capsaicin induced a transient urge-to-cough associated with the activation of a distributed brain network that included sensory, prefrontal and motor cortical regions. Cigarette smokers demonstrated significantly higher thresholds for capsaicin-induced urge-to-cough, consistent with a reduced sensitivity to airway irritation. Intriguingly, this was accompanied by increased activation in brain regions known to be involved in both cough sensory processing (primary sensorimotor cortex) and cough suppression (dorsolateral prefrontal cortex and the midbrain nucleus cuneiformis). Activations in the prefrontal cortex were highest among participants with the least severe smoking behaviour, whereas those in the midbrain correlated with more severe smoking behaviour.These outcomes suggest that smoking-induced sensitisation of central cough neural circuits is offset by concurrently enhanced central suppression. Furthermore, central suppression mechanisms may evolve with the severity of smoke exposure, changing from initial prefrontal inhibition to more primitive midbrain processes as exposure increases.

Evidence for Alpha7Nicotinic Receptor Activation During the Cough Suppressing Effects Induced by Nicotine and Identification of ATA-101 as a Potential Novel Therapy for the Treatment of Chronic Cough

“…We found responsiveness to capsaicin challenges was diminished in healthy smokers when compared to age matched nonsmoking controls (Dicpinigaitis et al, 2003). Comparable observations in healthy smokers were made by other research groups (Millqvist and Bende, 2001;Kanezaki et al, 2010) and a study by Ando and colleagues using functional Magnetic Resonance Imaging (fMRI) also observed a diminished sensitivity to tussive challenges in smokers, with evidence for an enhanced descending central inhibitory control (Ando et al, 2019). We followed up our study comparing smokers and nonsmokers with the observation of a rapidly emerging and sustained cough hypersensitivity in smokers over 8 weeks of abstinence from cigarettes (Dicpinigaitis et al, 2006).…”

“…Also tempering our enthusiasm is the somewhat modest (~50%) inhibitory effects of all of the nAChR agonists on evoked cough and the reality that our studies in guinea pigs identifying the α 7 nAChR subtype as a therapeutic target doesn't rule out the possibility that the antitussive actions of nicotine in healthy volunteers may be the result of engaging nAChR subtype(s) other than the α 7 nAChRs. The cough suppressing effects of nicotine that have been documented in healthy human volunteers could even be lost as a result of the pathologies leading to chronic refractory cough (Ando et al, 2019;Cho et al, 2019). It is also worth noting that while ATA-101 is a reasonable clinical candidate, it may not be the ideal candidate.…”

The interrelatedness of chronic cough and chronic pain

“…A double-blind, placebo-controlled trial by ABDULQAWI et al [18] reported that Gefapixant, a P2X3 receptor antagonist, reduced cough frequency by 75% in patients with refractory chronic cough. Furthermore, persistent sensory airway irritation might alter the central processing of cough-related stimuli such that the perception of airway irritation becomes less dependent on sensory input [34]. A functional brain imaging study in patients with chronic cough demonstrated evidence of central sensitisation and dysfunctional control of the inhibitory systems [35,36].…”

Peripheral and central mechanisms of cough hypersensitivity

“…A recent clinical study directly investigating cough suppression capacity in chronic refractory cough patients showed that heightened capsaicin cough sensitivity was accompanied by a reduced capacity to voluntarily suppress evoked coughing (126). In an alternate cohort of cigarette smokers who instead experienced decreased sensitivity to cough evoking stimuli (i.e., higher threshold to elicit the urge-to-cough and cough), an opposite central neural phenotype was observed in that they responded to capsaicin challenge with increased activity in descending inhibitory network activity (127). Together these data suggest that changes in the efficacy of central inhibitory systems may play a significant role in determining cough in response to airway irritant stimuli.…”