Pulmonary pharmacology最新文献

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The superior laryngeal nerve (SLN) is the main source of laryngeal afferent activity. A clear respiratory modulation can be noted when recording from the peripheral cut end of this nerve in several mammalian species. This modulation is due to three types of sensory endings: cold, pressure and ‘drive’ receptors. Although respiratory-modulated receptors play an important role in the function of the upper airway, they are not generally viewed as a primary factor in the elicitation of cough. Other more likely candidates for this role are thought to be the so-called ‘irritant’ endings. These are receptors that do not discharge in close association with the breathing cycle, but are usually silent or randomly active in control conditions. However, they are promptly recruited when the laryngeal mucosa is exposed to mechanical and/or chemical irritation. In fact, these receptors respond to well recognized tussigenic stimuli and are therefore thought to provide the triggering mechanisms for the cough reflex from the larynx. Endings with similar characteristics are also found in the most proximal areas of the tracheo-bronchial tree. On the basis of their response to irritants, these receptors are identified under the common denomination of ‘irritant receptors’. However, within this category of endings we find a wide range of distinctive characteristics, be this in terms of responsiveness to water solutions of various osmolarity and composition or to particular responses to substances produced within the body (autacoids) or experimentally administered.

This paper provides an overview of our current understanding of the serotonergic and opioidergic mechanisms of cough and antitussives. Systemic administration of 8-OH-DPAT, at doses of 0.1 and 0.3 mg/kg, ip, markedly reduced the number of coughs in rats in a dose-dependent manner. The antitussive effects of 8-OH-DPAT, dihydrocodeine and dextromethorphan were significantly reduced by pretreatment with methysergide, but not with ketanserin. Therefore it is possible to speculate that 5-HT₁receptors, in particular the 5-HT_1Areceptors, may be more important than others with respect to the effect of antitussive drugs. DAMGO, a selective μ-opioid receptor agonist, and U-50,488H, a highly selective κ-opioid receptor agonist, have potent antitussive effects when administered either icv or ip. However, we did not observe a cough-depressant effect of DPDPE, a selective δ-opioid receptor agonist. These results indicate that the antitussive effects of opioids are mediated predominantly by μ- and κ-opioid receptors. On the other hand, naloxonazine, a selective μ₁-opioid receptor antagonist, had no effect on the antitussive effects associated with icv DAMGO. These results indicate that μ₂- rather than μ₁-opioid receptors are involved in μ-opioid receptor-induced antitussive effects. Antitussive effects of dextromethorphan and noscapine were significantly and dose-dependently reduced by pretreatment with rimcazole, a specific antagonist of sites. However, rimcazole did not have a significant effect on the antitussive effect of morphine. These results suggest that sites may be involved in the antitussive mechanism of non-narcotic antitussive drugs.

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While airway rapidly adapting receptors can mediate the cough reflex, much evidence suggests that bronchial C-fibre receptors are also involved in guinea-pigs and man. In man local and systemic C-fibre stimulants have a potent tussive action, which is blocked by low doses of local anaesthetics which leave the reflex bronchoconstriction intact. In guinea-pigs destruction of airway C-fibre receptors by large doses of capsaicin abolishes the cough reflex due to capsaicin and citric acid. Thus there may be subpopulations of airway C-fibres responsible for the different reflexes such as apnoea, cough and bronchoconstriction. The evidence for the role of C-fibre receptors in cough is described and discussed.

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Several potent and selective antagonists for tachykinin receptors are now available and appear as powerful tools to investigate the physiological and pathological roles of tachykinins and to identify the type of receptor involved in their effect. Indeed, a lot of studies have shown that tachykinin NK₂receptor antagonists (SR 48968, MEN 10627) are able to inhibit cough induced by citric acid, capsaicin or allergen challenge in the unanesthetized guinea-pig or mechanical stimulation of the trachea in the cat. The effects of tachykinin NK₁receptor antagonists are still debated, whereas an inhibitory effect of SR 142801, a tachykinin NK₃receptor antagonist, has been reported against citric acid-induced cough in the guinea-pig. Experiments with tachykinin receptor antagonists which do not cross the blood brain barrier suggest that the site of action of tachykinin receptor antagonists is most probably peripheral, but a central action, at least in an area not protected by the blood brain barrier, cannot be excluded. Finally, tachykinin NK₂receptor stimulation seems to be involved in sensitisation of cough reflex.

Coughing is presented by a sudden air expulsion from the airways which is characterized by a typical sound. This sound is so characteristic that it allows identification of the cough and its distinction from other vocal manifestations. The cough sound is a very important symptom of well over 100 diseases and other conditions of medical significance. Changes in its character may have a considerable value in identifying the mechanisms of airway pathology present in respiratory diseases. The cough sound gives information about the pathophysiological mechanisms of coughing by indicating the structural nature of the tissue during therapy that leads to certain patterns of cough. Similarly the character of the cough sound gives information about the behaviour of the glottis and whether the glottis behaves differently in different pathological conditions. Analysis of the cough sound record has significant value in prognosis because its changes may indicate the effectiveness of therapy or the progress of disease. Despite recent progress in cough sound research the attention paid to this interesting physiological and clinical problem is still not sufficient to solve completely various open questions, including our correct knowledge of the mechanism of creation of cough sounds.

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