capsazepine and Cough

The mechanism of cough hypersensitivity induced by particulate matter 2.5 (PM2.5) remains elusive. The current study was designed to explore the effect of transient receptor potential vanilloid-1 (TRPV1) on cough hypersensitivity in airway and central nervous system.. The PM2.5-induced chronic cough model of guinea pig was established by exposure to different doses of PM2.5 for three weeks. After exposure, the animals were microinjected with TRPV1 agonist capsaicine, antagonist capsazepine in the dorsal vagal complex respectively. Cough sensitivity was measured by determining the provocative concentration of citric acid inducing 5 or more coughs (C5). Airway inflammation was detected by hematoxylin eosin (HE) staining and Evans blue fluorescence, and substance P (SP) and TRPV1 expressions in airway were observed by immunohistochemical staining. TRPV1 expressions in the dorsal vagal complex were observed by immunofluorescence. Retrograde tracing by pseudorabies virus-Bartha (PRV-Bartha) was conducted to confirm the regulatory pathway between airway and central nervous system.. PM2.5 induced TRPV1 expressions in both of airway and dorsal vagal complex and airway neurogenic inflammation. Airway vascular permeability increased after being exposed to PM2.5. The expressions of SP in the airway and airway inflammation was increased after microinjecting TRPV1 agonist, and decreased after microinjecting TRPV1 antagonist. PRV infected neurons in medulla oblongata mainly located in the dorsal vagal complex.. These findings show that TRPV1 in the dorsal vagal complex could promote airway neurogenic inflammation and cough reflex sensitivity through neural pathways of vagal complex-airways, which indicate the therapeutic potential of specific inhibition of TRPV1 for chronic cough induced by PM2.5.

Topics: Animals; Capillary Permeability; Capsaicin; Central Nervous System Diseases; Cough; Guinea Pigs; Herpesvirus 1, Suid; Hypersensitivity; Male; Particulate Matter; Respiratory Hypersensitivity; Signal Transduction; Substance P; TRPV Cation Channels; Vagus Nerve

Detection for cough in mice has never yielded clearly audible sounds, so there is still a great deal of debates as to whether mice can cough in response to tussive stimuli. Here we introduce an approach for detection of mouse cough based on sound monitoring and airflow signals. 40 Female BALB/c mice were pretreated with normal saline, codeine, capasazepine or desensitized with capsaicin. Single mouse was put in a plethysmograph, exposed to aerosolized 100 µmol/L capsaicin for 3 min, followed by continuous observation for 3 min. Airflow signals of total 6 min were recorded and analyzed to detect coughs. Simultaneously, mouse cough sounds were sensed by a mini-microphone, monitored manually by an operator. When manual and automatic detection coincided, the cough was positively identified. Sound and sound waveforms were also recorded and filtered for further analysis. Body movements were observed by operator. Manual versus automated counts were compared. Seven types of airflow signals were identified by integrating manual and automated monitoring. Observation of mouse movements and analysis of sound waveforms alone did not produce meaningful data. Mouse cough numbers decreased significantly after all above drugs treatment. The Bland-Altman and consistency analysis between automatic and manual counts was 0.968 and 0.956. The study suggests that the mouse is able to present with cough, which could be detected by sound monitoring and respiratory airflow waveform changes.

Topics: Animals; Capsaicin; Codeine; Cough; Female; Mice; Mice, Inbred BALB C; Plethysmography, Whole Body; Pulmonary Ventilation; Respiratory Sounds; Sodium Chloride

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

Cough initiated from the trachea and larynx in anaesthetized guinea-pigs is mediated by capsaicin-insensitive, mechanically sensitive vagal afferent neurones. Tachykinin-containing, capsaicin-sensitive C-fibres also innervate the airways and have been implicated in the cough reflex. Capsaicin-sensitive nerves act centrally and synergistically to modify reflex bronchospasm initiated by airway mechanoreceptor stimulation. The hypothesis that polymodal mechanoreceptors and capsaicin-sensitive afferent nerves similarly interact centrally to regulate coughing was addressed in this study. Cough was evoked from the tracheal mucosa either electrically (16 Hz, 10 s trains, 1-10 V) or by citric acid (0.001-2 m). Neither capsaicin nor bradykinin evoked a cough when applied to the trachea of anaesthetized guinea-pigs, but they substantially reduced the electrical threshold for initiating the cough reflex. The TRPV1 receptor antagonist capsazepine prevented the increased cough sensitivity induced by capsaicin. These effects of topically applied capsaicin and bradykinin were not due to interactions between afferent nerve subtypes within the tracheal wall or a direct effect on the cough receptors, as they were mimicked by nebulizing 1 mg ml(-1) bradykinin into the lower airways and by microinjecting 0.5 nmol capsaicin into nucleus of the solitary tract (nTS). Citric acid-induced coughing was also potentiated by inhalation of bradykinin. The effects of tracheal capsaicin challenge on cough were mimicked by microinjecting substance P (0.5-5 nmol) into the nTS and prevented by intracerebroventricular administration (20 nmol h(-1)) of the neurokinin receptor antagonists CP99994 or SB223412. Tracheal application of these antagonists was without effect. C-fibre activation may thus sensitize the cough reflex via central mechanisms.

Topics: Administration, Inhalation; Animals; Bradykinin; Bronchial Spasm; Capsaicin; Citric Acid; Cough; Guinea Pigs; Lung; Male; Mechanoreceptors; Microinjections; Nerve Fibers, Unmyelinated; Neurons, Afferent; Nociceptors; Reflex; Substance P; Tachykinins

1. Endogenous neuronal lipid mediator anandamide, which can be synthesized in the lung, is a ligand of both cannabinoid (CB) and vanilloid receptors (VR). The tussigenic effect of anandamide has not been studied. The current study was designed to test the direct tussigenic effect of anandamide in conscious guinea-pigs, and its effect on VR1 receptor function in isolated primary guinea-pig nodose ganglia neurons. 2. Anandamide (0.3-3 mg.ml(-1)), when given by aerosol, induced cough in conscious guinea-pigs in a concentration dependent manner. When guinea-pigs were pretreated with capsazepine, a VR1 antagonist, the anandamide-induced cough was significantly inhibited. Pretreatment with CB1 (SR 141716A) and CB2 (SR 144528) antagonists had no effect on anandamide-induced cough. These results indicate that anandamide-induced cough is mediated through the activation of VR1 receptors. 3. Anandamide (10-100 micro M) increased intracellular Ca(2+) concentration estimated by Fluo-4 fluorescence change in isolated guinea-pig nodose ganglia cells. The anandamide-induced Ca(2+) response was inhibited by two different VR1 antagonists: capsazepine (1 micro M) and iodo-resiniferatoxin (I-RTX, 0.1 micro M), indicating that anandamide-induced Ca(2+) response was through VR1 channel activation. In contrast, the CB1 (SR 141716A, 1 micro M) and CB2 (SR 144528, 0.1 micro M) receptor antagonists had no effect on Ca(2+) response to anandamide. 4. In conclusion, these results provide evidence that anandamide activates native vanilloid receptors in isolated guinea-pig nodose ganglia cells and induces cough through activation of VR1 receptors.

Topics: Aerosols; Animals; Arachidonic Acids; Calcium; Camphanes; Capsaicin; Cells, Cultured; Consciousness; Cough; Dronabinol; Endocannabinoids; Excitatory Amino Acid Antagonists; Guinea Pigs; Male; Nodose Ganglion; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Rimonabant

Acidic solutions mimick many of the effects of capsaicin (Cap), including pain, bronchoconstriction, cough, and sensory neuropeptide release. Evidence from the use of the Cap antagonist capsazepine suggests that in some cases protons act at the Cap receptor. In the present study, we have investigated whether cough evoked by Cap and citric acid (CA) is mediated specifically via the Cap receptor on airway sensory nerves. We have examined the effects of capsazepine on Cap-, CA-, and hypertonic saline-induced cough and also on CA-induced nasal irritation in awake guinea pigs. Capsazepine was nebulized for 5 min before cough challenges with Cap for 5 min and CA for 10 min. Control animals were pretreated with vehicle alone. Capsazepine (100 microM) inhibited the cough response to 30 microM Cap from 0.77 +/- 0.14 coughs/min in control animals to 0.23 +/- 0.08 coughs/min (P < 0.05) and to 80 microM Cap from 1.4 +/- 0.23 to 0.3 +/- 0.11 coughs/min (P < 0.01). There was no effect, however, of lower concentrations of capsazepine (5 and 10 microM) against Cap-evoked cough. At a concentration of 100 microM, capsazepine also inhibited the coughing induced by 0.25 M CA from 1.8 +/- 0.26 to 0.93 +/- 0.31 coughs/min (P < 0.05) but not that induced by 0.5 M CA. Nasal irritation induced by 0.25 M CA, but not by 0.5 M CA, was also inhibited by capsazepine from 2.47 +/- 0.37 to 0.75 +/- 0.31 nose wipes/min (P < 0.05). This inhibitory effect of capsazepine did not appear to reflect a nonspecific suppression of the cough reflex, since cough evoked by exposure to hypertonic (7%) saline for 10 min was unaffected by pretreatment with capsazepine (100 microM). These data show that capsazepine is a specific inhibitor of Cap- and CA-induced cough in guinea pigs. Moreover, they suggest that low pH stimuli evoke cough and nasal irritation by an action at the Cap receptor, either directly or through the release of an intermediate agent.

Topics: Animals; Antitussive Agents; Bronchodilator Agents; Capsaicin; Citrates; Citric Acid; Cough; Guinea Pigs; Irritants; Male; Protons; Saline Solution, Hypertonic; Terbutaline