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

Raffaele Gatti, Eunice Andre, Silvia Amadesi, Thai Q. Dinh, Axel Fischer, Nigel W. Bunnett, Selena Harrison, Pierangelo Geppetti, Marcello Trevisani

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)506-511
Number of pages6
JournalJournal of Applied Physiology
Issue number2
StatePublished - 2006


  • Citric acid
  • Hypertonic saline
  • Indomethacin
  • Protein kinase
  • Resiniferatoxin
  • Transient receptor potential vanilloid 1

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)


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