Cough Reflex Induced by Microinjection of Citric Acid Into the Larynx of Guinea Pigs: New Coughing Model

We have addressed the hypothesis that the opposing effects of bronchopulmonary C-fiber activation on cough are attributable to the activation of C-fiber subtypes. Coughing was evoked in anesthetized guinea pigs by citric acid (0.001–2 M) applied topically in 100-µl aliquots to the tracheal mucosa. In control preparations, citric acid evoked 10 ± 1 coughs cumulatively. Selective activation of the pulmonary C fibers arising from the nodose ganglia with either aerosols or continuous intravenous infusion of adenosine or the 5-HT3 receptor-selective agonist 2-methyl-5-HT nearly abolished coughing evoked subsequently by topical citric acid challenge. Delivering adenosine or 2-methyl-5-HT directly to the tracheal mucosa (where few if any nodose C fibers terminate) was without effect on citric acid-evoked cough. These actions of pulmonary administration of adenosine and 2-methyl-5-HT were accompanied by an increase in respiratory rate, but it is unlikely that the change in respiratory pattern caused the decrease in coughing, as the rapidly adapting receptor stimulant histamine also produced a marked tachypnea but was without effect on cough. In awake guinea pigs, adenosine failed to evoke coughing but reduced coughing induced by the nonselective C-fiber stimulant capsaicin. We conclude that bronchopulmonary C-fiber subtypes in guinea pigs have opposing effects on cough, with airway C fibers arising from the jugular ganglia initiating and/or sensitizing the cough reflex and the intrapulmonary C fibers arising from the nodose ganglia actively inhibiting cough upon activation.

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Capsazepine inhibits cough induced by capsaicin and citric acid but not by hypertonic saline in guinea pigs

Journal of Applied Physiology ◽

10.1152/jappl.1995.79.4.1082 ◽

1995 ◽

Vol 79 (4) ◽

pp. 1082-1087 ◽

Cited By ~ 128

Author(s):

U. G. Lalloo ◽

A. J. Fox ◽

M. G. Belvisi ◽

K. F. Chung ◽

P. J. Barnes

Keyword(s):

Citric Acid ◽

Hypertonic Saline ◽

Guinea Pigs ◽

Specific Inhibitor ◽

Inhibitory Effect ◽

Sensory Nerves ◽

Cough Reflex ◽

Acidic Solutions ◽

Nasal Irritation ◽

Cough Response

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.

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Suppressive effect of pectic polysaccharides from Cucurbita pepo L. var. Styriaca on citric acid-induced cough reflex in guinea pigs

Fitoterapia ◽

10.1016/j.fitote.2010.11.006 ◽

2011 ◽

Vol 82 (3) ◽

pp. 357-364 ◽

Cited By ~ 19

Author(s):

Gabriela Nosáľová ◽

Ľubica Prisenžňáková ◽

Zuzana Košťálová ◽

Anna Ebringerová ◽

Zdenka Hromádková

Keyword(s):

Citric Acid ◽

Guinea Pigs ◽

Cucurbita Pepo ◽

Suppressive Effect ◽

Pectic Polysaccharides ◽

Cough Reflex

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Metabolism of Citric Acid in Scorbutic Guinea Pigs

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)69447-5 ◽

1960 ◽

Vol 235 (4) ◽

pp. 902-905

Author(s):

Sachchidananda Banerjee ◽

Haobam Devendra Singh

Keyword(s):

Citric Acid ◽

Guinea Pigs

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Selective inhibitors for phosphodiesterase 3 and 4 in antigen-induced increase of cough reflex sensitivity in guinea pigs

Pulmonary Pharmacology & Therapeutics ◽

10.1016/j.pupt.2006.05.004 ◽

2007 ◽

Vol 20 (5) ◽

pp. 543-548 ◽

Cited By ~ 7

Author(s):

Masaki Fujimura ◽

Qi Liu

Keyword(s):

Guinea Pigs ◽

Selective Inhibitors ◽

Cough Reflex Sensitivity ◽

Cough Reflex ◽

Phosphodiesterase 3

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Effect Of Repeated Cough Induced By Citric Acid Exposures On Cough Sensitivity And Airway Pathology In Guinea Pigs

10.1164/ajrccm-conference.2011.183.1_meetingabstracts.a5542 ◽

2011 ◽

Author(s):

Hitoshi Nakaji ◽

Akio Niimi ◽

Hirofumi Matsuoka ◽

Toshiyuki Iwata ◽

Hisako Matsumoto ◽

...

Keyword(s):

Citric Acid ◽

Guinea Pigs ◽

Airway Pathology

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Protease-activated receptor-2 activation exaggerates TRPV1-mediated cough in guinea pigs

Journal of Applied Physiology ◽

10.1152/japplphysiol.01558.2005 ◽

2006 ◽

Vol 101 (2) ◽

pp. 506-511 ◽

Cited By ~ 61

Author(s):

Raffaele Gatti ◽

Eunice Andre ◽

Silvia Amadesi ◽

Thai Q. Dinh ◽

Axel Fischer ◽

...

Keyword(s):

Citric Acid ◽

Sensory Neurons ◽

Guinea Pigs ◽

Transient Receptor Potential ◽

Inflammatory Diseases ◽

Receptor Potential ◽

Chronic Obstructive ◽

Transient Receptor Potential Vanilloid ◽

Independent Manner ◽

Protease Activated Receptor 2

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.

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Mast cells in citric acid-induced cough of guinea pigs

Toxicology and Applied Pharmacology ◽

10.1016/j.taap.2004.05.012 ◽

2005 ◽

Vol 202 (1) ◽

pp. 18-24 ◽

Cited By ~ 2

Author(s):

Yih-Loong Lai ◽

Tai-Yin Lin

Keyword(s):

Citric Acid ◽

Mast Cells ◽

Guinea Pigs

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Prostaglandin E2 sensitizes the cough reflex centrally via EP3 receptor-dependent activation of NaV 1.8 channels

Respiratory Research ◽

10.1186/s12931-021-01889-4 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Al-Shaimaa A. Al-Kandery ◽

Muddanna S. Rao ◽

Ahmed Z. El-Hashim

Keyword(s):

Citric Acid ◽

Nucleus Tractus Solitarius ◽

Whole Body ◽

Prostaglandin E ◽

Cough Reflex ◽

Trpv1 Antagonist ◽

Underlying Mechanisms ◽

Set Up ◽

Guinea Pig Model ◽

Ep3 Receptor

Abstract Background Cough hypersensitivity is a major characteristic feature associated with several types of cough, including chronic cough, but its underlying mechanisms remain to be fully understood. Inflammatory mediators, such as prostaglandin E2 (PGE2), have been implicated in both peripheral induction and sensitization of the cough reflex. In this study, using a conscious guinea pig model of cough, we investigated whether PGE2 can sensitize the cough reflex via central actions and, if so, via which mechanisms. Methods All drugs were administered by intracerebroventricular (i.c.v.) route and whole-body plethysmograph set-up was used for both induction, using aerosolized citric acid (0.2 M), and recording of cough. Immunohistochemistry was performed to confirm the expression of NaV 1.8 channels in the nucleus tractus solitarius (nTS). Results We show that both PGE2 and the non-selective EP1/EP3 agonist, sulprostone, dose-dependently enhanced the citric acid-induced cough (P ≤ 0.001, P ≤ 0.01, respectively). Pretreatment with the EP1 antagonist, ONO-8130, did not affect the sulprostone-induced cough sensitization, whilst the EP3 antagonist, L-798,106, dose-dependently inhibited this effect (P ≤ 0.05). Furthermore, treatment with either the EP2 agonist, butaprost or the EP4 agonist, L-902,688, had no effect on cough sensitization. Additionally, pretreatment with either the TRPV1 antagonist, JNJ-17203212 or the TRPA1 antagonist, HC-030031, alone or in combination, nor with the NaV 1.1, 1.2, 1.3, 1.4, 1.6 and 1.7 channel blocker, tetrodotoxin, had any effect on the cough. In contrast, pretreatment with the NaV 1.8 antagonist, A-803467, dose-dependently inhibited this effect (P ≤ 0.05). Furthermore, NaV 1.8 channels were shown to be expressed in the nTS. Conclusion Collectively, our findings show that PGE2 sensitizes the cough reflex centrally via EP3 receptor-dependent activation of NaV 1.8 but independently of TRPV1,TRPA1 and TTX-sensitive sodium channel activation. These results indicate that PGE2 plays an important role in central sensitization of the cough reflex and suggest that central EP3 receptors and/or NaVv 1.8 channels may represent novel antitussive molecular targets. Graphical Abstract

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972. A Mycobacterium tuberculosis Secreted Lipid Triggers Cough Through a Neuronal Cough Receptor

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz359.074 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S33-S33

Author(s):

Paxton Cruz ◽

Cody Ruhl ◽

Michael Shiloh

Keyword(s):

Mycobacterium Tuberculosis ◽

Disease Transmission ◽

Guinea Pigs ◽

Cough Reflex ◽

Nociceptive Neurons ◽

Active Pulmonary Tuberculosis ◽

Neuronal Receptor ◽

Musculoskeletal Systems ◽

Cough Receptor

Abstract Background A hallmark symptom of active pulmonary tuberculosis vital for disease transmission is cough. The current paradigm for tuberculosis-related cough is that it results from airway damage or irritation. However, there is limited experimental data to support this theory, and whether Mycobacterium tuberculosis (Mtb) induces cough to facilitate its own transmission has not been explored. The cough reflex is a complex and coordinated event involving both the nervous and musculoskeletal systems initiated by particulate or chemical molecules activating nociceptive neurons, which sense pain or irritation. This activation induces a signaling cascade ultimately resulting in a cough. Respiratory nociceptive neurons innervate the airway of humans and most mammals and thus are poised to respond to noxious molecules to help protect the lung from damage. Because Mtb is a lung pathogen, cough is a primary mechanism of Mtb transmission, and respiratory nociceptive neurons activate cough, we hypothesized that Mtb produces molecules that stimulate cough thereby facilitating its spread from infected to uninfected individuals. We previously identified a cough molecule produced by Mtb, and in this work characterize its neuronal receptor using genetics, biochemistry, and pharmacology. Methods We used an in vitro neuronal activation bioassay to study Mtb cough-inducing molecules. We also used a biochemical assay to identify the cough receptor. Finally, we used gene silencing, biochemistry, and pharmacologic inhibition to validate and characterize the activity of the newly discovered cough receptor. Results We isolated a complex lipid produced by Mtb that activates nociceptive neurons. Both an organic Mtb extract and the purified molecule alone were sufficient to induce cough in a conscious guinea pig cough model and guinea pigs infected with wild-type Mtb cough much more frequently than guinea pigs infected with Mtb strains unable to produce nociceptive molecules. Using genetics, biochemistry, and pharmacology techniques, we identified and validated a cough receptor for the Mtb lipid expressed on nociceptive neurons. Conclusion We conclude that Mtb produces a molecule that activates nociceptive neurons and induces cough through a specific neuronal receptor. These findings have significant implications for our understanding of Mtb transmission. Disclosures All Authors: No reported Disclosures.

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