resiniferatoxin and Cough

Capsaicin has long been known to act selectively on a subpopulation of neurons to produce initial excitation, followed by a prolonged neuroinhibitory action commonly referred to as 'capsaicin desensitization'. This property has been exploited extensively as a tool with which to investigate the role of these nerves in the normal and pathophysiology of the airways. However, the cellular basis for these effects is only now beginning to be understood. The purpose of this review is to summarize recent findings that provide new insights into the mechanisms by which capsaicin acts to exert its effects. These findings suggest that capsaicin acts at a receptor that is either tightly coupled to, or indeed is, a relatively non-selective cation channel. Binding of capsaicin to this receptor allows both sodium and calcium (and possibly potassium) ions to flow down their concentration gradients, causing initial depolarization and neurotransmitter release. Prolonged exposure to capsaicin produces a subsequent desensitization or neuroinhibition. The neuroinhibition has now been shown to be of two types: capsaicin-specific and non-specific. The former is characterized by a loss of the acute excitatory response evoked by application of capsaicin, but maintained responses to other stimuli. The latter is characterized by a loss of responsiveness to all stimuli and is probably associated with the neurotoxic effect of this agent. Despite these recent findings, many questions remain regarding the nature and physiological role of the capsaicin receptor. The availability of two new probes for this receptor, ruthenium red and resiniferatoxin, promises to provide at least some of the answers to these intriguing questions.

Topics: Action Potentials; Animals; Capsaicin; Cells, Cultured; Cough; Diterpenes; Humans; Ion Channels; Nerve Fibers; Neurons, Afferent; Ruthenium Red

Ethanol is a chemical irritant able to induce a large variety of effects in the airways. It has been reported that ethanol sensitizes the transient receptor potential vanilloid-1 (TRPV1) to various stimuli and inhalation of ethanol enhances the cough mediated by TRPV1 activation (capsaicin) in patients suffering of airway sensory hyperreactivity. Here, we set out to investigate whether ethanol sensitizes the cough induced by TRPV1 activation in a guinea pig model and the possible mechanism of such exacerbating effect. Aerosolized resiniferatoxin (RTX, 0.5 microM) and hypertonic saline (7%) produced a cough response dependent and independent of TRPV1 activation, respectively. Ethanol (3%, 10 min) inhalation, that per se did not cause any tussive response, significantly increased the number of coughs evoked by RTX inhalation without affecting hypertonic saline (7%) induced cough. Potentiation by ethanol of the tussive response to RTX was prevented by the PKC inhibitor, GF109203X (GFX). In conclusion, ethanol selectively exaggerates, via a PKC-dependent pathway, the cough response evoked by TRPV1 stimulation. The present results may contribute to explain respiratory distresses sometimes associated to alcohol consumption, including cough and asthma.

Topics: Administration, Inhalation; Animals; Cough; Disease Models, Animal; Diterpenes; Ethanol; Guinea Pigs; Male; Protein Kinase C; Saline Solution, Hypertonic; TRPV Cation Channels

A lowered threshold to the cough response frequently accompanies chronic airway inflammatory conditions. However, the mechanism(s) that from chronic inflammation results in a lowered cough threshold is poorly understood. Irritant agents, including capsaicin, resiniferatoxin, and citric acid, elicit cough in humans and in experimental animals through the activation of the transient receptor potential vanilloid 1 (TRPV1). Protease-activated receptor-2 (PAR2) activation plays a role in inflammation and sensitizes TRPV1 in cultured sensory neurons by a PKC-dependent pathway. Here, we have investigated whether PAR2 activation exaggerates TRPV1-dependent cough in guinea pigs and whether protein kinases are involved in the PAR2-induced cough modulation. Aerosolized PAR2 agonists (PAR2-activating peptide and trypsin) did not produce any cough per se. However, they potentiated citric acid- and resiniferatoxin-induced cough, an effect that was completely prevented by the TRPV1 receptor antagonist capsazepine. In contrast, cough induced by hypertonic saline, a stimulus that provokes cough in a TRPV1-independent manner, was not modified by aerosolized PAR2 agonists. The PKC inhibitor GF-109203X, the PKA inhibitor H-89, and the cyclooxygenase inhibitor indomethacin did not affect cough induced by TRPV1 agonists, but abated the exaggeration of this response produced by PAR2 agonists. In conclusion, PAR2 stimulation exaggerates TRPV1-dependent cough by activation of diverse mechanism(s), including PKC, PKA, and prostanoid release. PAR2 activation, by sensitizing TRPV1 in primary sensory neurons, may play a role in the exaggerated cough observed in certain airways inflammatory diseases such as asthma and chronic obstructive pulmonary disease.

Topics: Animals; Capsaicin; Citric Acid; Cough; Cyclic AMP-Dependent Protein Kinases; Cyclooxygenase Inhibitors; Diterpenes; Guinea Pigs; Indomethacin; Inflammation; Isoquinolines; Male; Neurons, Afferent; Protein Kinase C; Protein Kinase Inhibitors; Receptor, PAR-2; Saline Solution, Hypertonic; Sulfonamides; TRPV Cation Channels; Trypsin

The cough response following inhalation challenge with the sensory nerve irritant resiniferatoxin was compared with that of capsaicin and citric acid in guinea-pig and man. Capsaicin and citric acid gave comparable dose-response curves in the two species. The mean (+/- SEM) concentration producing five coughs in man was 141.3 (1.3) mM (n = 10) for citric acid and 2.8 (1.3) microM (n = 10) for capsaicin. Those for the guinea-pig were 74.1 (1.2) mM (n = 10) for citric acid and 6.0 (2.4) microM (n = 10) for capsaicin. Resiniferatoxin was active at a lower concentration than either citric acid or capsaicin and maximal tolerable cough response was achieved at concentrations of 3 microM (n = 5) in guinea-pig and 300 nM (n = 1) in man. The cough response to resiniferatoxin was greatly prolonged in both guinea-pig and man. Resiniferatoxin, like capsaicin, caused respiratory distress in the guinea-pig which is linked to bronchoconstriction. Resiniferatoxin probably causes cough by stimulation of capsaicin sensitive neurones.

Topics: Administration, Inhalation; Adult; Animals; Bronchoconstriction; Capsaicin; Citrates; Citric Acid; Cough; Diterpenes; Dose-Response Relationship, Drug; Dyspnea; Female; Guinea Pigs; Humans; Male; Middle Aged; Reflex; Respiration; Respiratory Function Tests

In the present study we evaluated the effects of ruthenium red, a blocker of transmembrane Ca2+ fluxes, on bronchoconstriction and the release of calcitonin gene-related peptide-like immunoreactivity induced by different stimuli in the isolated perfused guinea-pig lung. Vagal stimulation (1 Hz, 1 min), capsaicin (10(-8) M, 10(-6) M), resiniferatoxin (3 x 10(-10) M), nicotine (10(-4) M), bradykinin (5 x 10(-6) M) and histamine (10(-5) M) evoked bronchoconstriction and calcitonin gene-related peptide-like immunoreactivity overflow. Ruthenium red (5 x 10(-6) M) almost completely inhibited the bronchoconstriction and calcitonin gene-related peptide-like immunoreactivity overflow induced by capsaicin and resiniferatoxin but did not influence the effects induced by vagal nerve stimulation, nicotine, bradykinin or histamine. The 20-deacetylated derivative of resiniferatoxin (ROPA), which lacks the homovanillyl ester group, did not evoke release or bronchoconstriction. Ruthenium red (3 x 10(-4) M) aerosol attenuated the cough induced by nebulized citric acid in conscious guinea-pigs. Citric acid-induced coughing is mediated via capsaicin-sensitive neurons. However, cigarette smoke-induced coughing, which involves capsaicin-resistant mechanisms, was not affected by ruthenium red. In conclusion, ruthenium red selectively inhibits the capsaicin, resiniferatoxin and citric acid-induced excitation of the sensory nerves as revealed by calcitonin gene-related peptide-like immunoreactivity release, bronchoconstriction and coughing, suggesting that these agents share a common mechanism of action.

Topics: Animals; Bradykinin; Bronchoconstriction; Calcitonin Gene-Related Peptide; Capsaicin; Citrates; Citric Acid; Cough; Diterpenes; Female; Guinea Pigs; Histamine; Lung; Male; Neurons, Afferent; Nicotine; Ruthenium Red; Smoking; Vagus Nerve