Excessive accumulation of histamine in the body leads to miscellaneous symptoms mediated by its bond to corresponding receptors (H1-H4). Increased concentration of histamine in blood can occur in healthy individuals after ingestion of foods with high contents of histamine, leading to histamine intoxication. In individuals with histamine intolerance (HIT) ingestion of food with normal contents of histamine causes histamine-mediated symptoms. HIT is a pathological process, in which the enzymatic activity of histamine-degrading enzymes is decreased or inhibited and they are insufficient to inactivate histamine from food and to prevent its passage to blood-stream. Diagnosis of HIT is difficult. Multi-faced, non-specific clinical symptoms provoked by certain kinds of foods, beverages and drugs are often attributed to different diseases, such as allergy and food intolerance, mastocytosis, psychosomatic diseases, anorexia nervosa or adverse drug reactions. Correct diagnosis of HIT followed by therapy based on histamine-free diet and supplementation of diamine oxidase can improve patient's quality of life.

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.

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A b s t r a c t Inhalation of aromatic vapours suppressed coughing induced by citric acid (CA) in naive animals. No data are available about their effects in an animal model with primarily up-regulated cough reflex. New data indicate that aromatic vapours suppress cough via effect on nasal sensory nerves.The aim of our study was to ascertain the efficacy of nasal application of 1,8-cineole, thymol and camphor on nasal symptoms and CA induced cough in validated model of up-regulated cough reflex. Guinea pigs (n=13) were sensitized by intraperitoneal administration of ovalbumin (OVA) and sensitization was confirmed 21 days later by skin tests. Sensitized animals were repeatedly challenged with nasal OVA to induce rhinitis, and further experiments (cough challenges) were performed during the early phase of allergic inflammation.Cough was induced by CA in plethysmograph for 10 minutes after nasal pre-treatment with aromatic substances (10 -3 M) in rhinitis model. Cough was recognized from record of sudden airflow changes interrupting breathing pattern and cough sound. Final count of coughs was established by blind analysis using SonicVisualiser Software. Dose responses curves, total cough count and cough latency were analyzed.Repeated intranasal challenge with OVA induces progressively worsening symptoms, and cough induced by CA during acute phase of allergic rhinitis was enhanced. Nasal pre-treatment with 1,8-cineole, thymol and camphor did not prevent onset of nasal symptoms, and the magnitude of symptoms was comparable to those without pretreatment. Camphor had the most potent antitussive effects (number of coughs 25±3 vs. 7±2, p<0.05) followed by thymol (number of coughs 25±3 vs. 14±2, p<0.05). The data for nasal 1,8-cineole challenge did not reach statistical significance. Cough latency followed this trend.Although the magnitude of nasal symptoms is not influenced, the effect on cough is in case of camphor and thymol significant. Our data showed that nasal application of aromatic substances suppress citric acid induced cough in animals with up-regulated cough reflex.

The guinea pig sensitized by ovalbumin is the most widely used model to study cough experimentally, as the neurophysiology of the vagus nerve in the guinea pig is closest to humans. Nonetheless, the choice of the antigen remains questionable, which influences the translation of results into clinical medicine. The present study seeks to develop an alternative model of cough study using house dust mite sensitization (HDM). Thirty guinea pigs were divided into the HDM group, ovalbumin (OVA) group, and control group based on their cough response to 0.4 M citric acid. In the HDM group animals were sensitized by 0.25 %HDM aerosol, which they inhaled for 5 min over 5 days, followed by inhalation of 0.5 %HDM in the same protocol. Sensitization was confirmed by a skin test. Symptoms of allergic rhinitis were induced by intranasal application of 15 μl 0.5 %HDM and cough challenges with citric acid were performed. Airway resistance was measured in vivo by Pennock's method. We found that both HDM and OVA-sensitized groups showed a significantly enhanced nasal reactivity and cough response compared with controls. The airway resistance data did not show significant differences. We conclude that the HDM cough model replicates functional aspects of the OVA model, which may make it an alternative to the latter. However, the superiority of the HDM model for experimental cough studies remains to be further explored.