Silvia Gavliakova

Modulation of cough response by sensory inputs from the nose - role of trigeminal TRPA1 versus TRPM8 channels.

BackgroundCough, the most important airways defensive mechanism is modulated by many afferent inputs either from respiratory tussigenic areas, but also by afferent drive from other organs. In animal models, modulation of cough by nasal afferent inputs can either facilitate or inhibit the cough response, depending on the type of trigeminal afferents stimulated.MethodsIn this study we addressed the question of possible bidirectional modulation of cough response in human healthy volunteers by nasal challenges with TRPA1 and TRPM8 agonists respectively. After nasal challenges with isocyanate (AITC), cinnamaldehyde, (−) menthol and (+) menthol (all 10-3 M) nasal symptom score, cough threshold (C2), urge to cough (Cu) and cumulative cough response were measured).ResultsNasal challenges with TRPA1 relevant agonists induced considerable nasal symptoms, significantly enhanced urge to cough (p<0.05) but no statistically significant modulation of the C2 and cumulative cough response. In contrast, both TRPM8 agonists administered to the nose significantly modulated all parameters including C2 (p<0.05), Cu (p<0.01) and cumulative cough response (p <0.01) documenting strong anti irritating potential of menthol isomers.ConclusionsIn addition to trigeminal afferents expressing TRP channels, olfactory nerve endings, trigemino – olfactoric relationships, the smell perception process and other supramedullar influences should be considered as potential modulators of the cough response in humans.

Antitussive effects of nasal thymol challenges in healthy volunteers.

Eighteen healthy volunteers with normal lung function were tested for cough. Before and after nasal administration of thymol (0.025 ml, 10(-3) M) into both nostrils, urge-to-cough, cough threshold, cumulative and total count of coughs per provocation were estimated during standardized and validated capsaicin cough challenge. Nasal thymol challenges induced pleasant olfactory sensation and in 6 out of the 18 subjects also mild cooling sensation. Cough threshold was not influenced when compared with intranasal saline and vehicle challenges (12.5 vs. 13.2 vs. 10.2 μM of capsaicin to induce two or more coughs (C2), respectively), but the total count of coughs after nasal thymol challenge was significantly lower than that obtained after saline or vehicle (19 vs. 20 vs. 14 coughs/provocation, respectively; p<0.05). Importantly, subjects did not report the urge to cough, which appeared to correspond to C2. We conclude that the modulation of cough by thymol is mostly of olfactory origin.

The effects of nasal irritant induced responses on breathing and cough in anaesthetized and conscious animal models

There is little evidence to support the down-regulation of coughing from the nose. The cough response to citric acid (CA) was studied in anesthetized and conscious guinea pigs after nasal pretreatment with saline, 1% DMSO, allylisothiocyanate (TRPA1 agonist) and allylisothiocyanate +AP-18 (TRPA1 antagonist). Cough was induced by adding citric acid (CA) to the tracheal perfusion in anaesthetized animals, or by inhaling 0.4M CA in conscious animals. The cough response was counted from the dose response curves, airflow traces and cough sound analysis. In conscious animals, nasal allylisothiocyanate induced reproducible, dose dependent nasal symptoms and a significant drop in respiratory rate. Cough induced by CA was suppressed after nasal allylisothiocyanate (p<0.05), and this effect was prevented by AP-18 (1mM). In anaesthetized animals, nasal allylisothiocyanate induced a significant drop in respiratory rate. Cough induced subsequently by CA was suppressed when compared to baseline and vehicle responses (p<0.05). The reasons for the suppression of CA induced cough by TRPA1 agonist applied to the nose are not clear and remain to be elucidated.

The role of nasal trigeminal nerves expressing TRP channels in modulation of cough threshold and urge to cough – possible clinical application

Cough is a phenomenon frequently associated with upper airway diseases and as a reflex is modulated by many afferent inputs either from respiratory tussigenic areas, but also by afferent drive from other organs. Modulation of cough by nasal afferent inputs could either facilitate cough response or inhibit it in animal models, depending on the type of trigeminal afferents which are stimulated. In recent study we focused on afferents expressing TRPA1, TRPM8 & TRPV3 channels -- channels known as relevant for airway irritants (TRPA1), menthol and other cooling substances (TRPM8) and thymol (TRPV3). Particularly menthol and thymol are substances which are frequently used in over-the-counter medication for cough and common cold based on empirical approach. Objective evidence regarding the modulation of cough in humans has never been reported. 60 human healthy volunteers participated in the study, and they have been challenged by intranasal drops containing agonists of selected ion channels: isocyanate (AITC) & cinnamaldehyde for TRPA1, (-) menthol and (+) menthol for TRPM8 and thymol for TRPV3 ion channels in randomized order (all 10-3 M). Nasal symptom score, cough threshold (C2), urge to cough (Cu) and cumulative cough response had been assessed using capsaicin cough challenge tests. Nasal challenges of TRPA1 relevant agonists induced considerable nasal symptoms, significantly enhanced urge to cough (p < 0.05) but modulation of C2 and cumulative cough response did not reach significance level. Both TRPM8 agonists and TRPV3 agonist thymol administered to the nose significantly modulated all parameters including C2 (p<0.05), Cu (p <0.01) and cumulative cough response (p < 0.01) documenting strong anti irritating and antitussive potential of menthol isomers and thyme. Nasal afferent drive modulates cough reflex in human healthy volunteers and this knowledge could have clinical application involved in relieving lower airway symptoms in subjects with upper airway diseases. The role of trigeminal afferents, olfactory nerve endings, smell perception process and other supramedullar influences have to be taken into consideration as relevant enough to modulate cough response in humans.

Effect of histamine H3 receptor selective agonist imetit on cough and symptoms of allergic rhinitis in animal model of upper airway cough syndrome

Background Upper airway diseases (e.g. allergic rhinitis (AR)) are one of most common causes of chronic cough in subjects with negative X-ray finding. In UACS (upper airway cough syndrome), cough is strongly associated with the ongoing nasal inflammation. Effective treatment of nasal inflammation may lead to down regulation of pathologically enhanced chronic cough. Histamine plays a critical role in upper airway diseases. All known histamine receptors (H1R, H2R, H3R, and H4R) have been demonstrated in the nasal mucosa. Old generation of antihistamines (inverse agonists of H1R) are empirically used in treatment of UACS, although their clinical use is limited by their serious adverse effects. The aim of our study was to ascertain the effect of H3R selective agonist imetit known to suppress release of substance P from afferent nerves in allergic nasal inflammation on cough and symptoms of AR in an animal model.

First experiences with cough sensitivity in model of allergic rhinitis induced in HDM-sensitized guinea pigs

Background Nowadays, the vast majority of research focusing on cough in sensitive and/or hyperreactive airways is done on an animal model of guinea pigs intraperitoneally sensitized by ovalbumin. There are no objections to model animal – the neurophysiology and neuropharmacology of their n. X are closest to humans. However, the choice of ovalbumin as model antigen together with the route of administration remains questionable – allergy to chicken eggs in humans manifests as food allergy, not respiratory allergy. These limitations may represent possible obstacles in translation of results in daily clinical practice. Therefore there is need to develop and validate new model of airway hypersensitivity, which would simulate real-life conditions more closely and new model could improve translation of results. Most important indoor allergen for people are house dust mites (HDM), most common species being D. pteronyssius and D. farinae. Their allergenic potential is complex – it includes immunogenic epitopes, faecal pellets, lipopolysaccharides, betaglucans and chitin.

Three-Dimensional Computer Model of Brainstem Respiratory Neuronal Circuits - Application for Research in Respirology

Abstract Methods that had been applied to study central neuronal circuits regulating cough and respiratory reflexes so far rely on recording performed in vivo, ex vivo, micro injecting and lesion methods. Based on the available data it is clear that this network is complicated, multilevel, holarchical, undergoing reconfiguration under afferent inputs. For many students and researchers it is complicated to get a virtual spatial image of these cooperating neuronal populations. The project was aimed to create graphical three-dimensional computer model of the brainstem using environment MATLAB and the matrix algebra to visualize neuron localization within the brainstem. Relevant data for the model had been taken from recent and also former research papers published in particular areas. This model may help scientists to visualize groups of neurons, help them to find targets for microinjecting or lesion studies together with stereotaxic positioning. The model is upgradeable and highly flexible for future use, research and teaching applications in MATLAB environment. MATLAB is a high-level language and interactive environment that enables you to perform computationally intensive tasks faster than with traditional programming languages