iodoresiniferatoxin and Cough

Nerve growth factor (NGF) is an important mediator of airway hyper-responsiveness and hyperalgesia but its role in cough is unknown.. In this study the effects of NGF on the cough reflex and airway calibre were investigated in guinea pigs. The involvement of the tropomyosin-related kinase A (TrkA) receptor and transient receptor potential vanilloid-1 (TRPV1), and the p38 mitogen-activated protein kinase (MAPK)-dependent pathway in any NGF-induced effects on cough and airway obstruction was also assessed.. Guinea pigs were placed in a transparent whole-body plethysmograph box. Cough was assessed visually, acoustically and by analysis of the airflow signal. Airway obstruction was measured using enhanced pause (Penh) as an index.. Exposure of guinea pigs to NGF did not induce a cough response nor a significant airway obstruction. However, exposure of guinea pigs to NGF immediately before citric acid inhalation resulted in a significant increase in the citric acid-induced cough and airway obstruction compared with vehicle-treated animals. Pretreatment with the TrkA receptor antagonist, K252a, or the TRPV1 antagonist, iodoresiniferatoxin, significantly inhibited the NGF-enhanced cough and airway obstruction. Exposure to NGF also increased p38 MAPK phosphorylation, but pretreatment with the p38 MAPK inhibitor, SB203580, did not affect either the NGF-enhanced cough or airway obstruction despite preventing the NGF-induced elevation in p38 MAPK phosphorylation.. The data show that NGF can enhance both cough and airway obstruction via a mechanism that involves the activation of the TrkA receptor and TRPV1 but not the p38 MAPK-dependent pathway.

Topics: Airway Obstruction; Animals; Carbazoles; Citric Acid; Cough; Diterpenes; Enzyme Inhibitors; Female; Guinea Pigs; Imidazoles; Indole Alkaloids; Male; Nerve Growth Factors; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Pyridines; Receptor, trkA; TRPV Cation Channels

Topics: Animals; Antitussive Agents; Cough; Diterpenes; Receptors, Drug; TRPV Cation Channels

Iodo-resiniferatoxin (I-RTX) has recently been described as an ultra potent antagonist of the transient receptor potential vanilloid-1 (TRPV1).. The ability of I-RTX to inhibit cough induced by inhalation of two putative TRPV1 stimulants (capsaicin and citric acid) was tested in non-anaesthetised guinea pigs.. Pretreatment with I-RTX either intraperitoneally (0.03-0.3 micromol/kg) or by aerosol (0.1-3 microM) reduced the number of coughs produced by inhalation of citric acid (0.25 M) and capsaicin (30 microM) in a dose dependent manner. Capsazepine (CPZ) also reduced citric acid and capsaicin induced cough, but the activity of I-RTX was 10-100 times more potent than CPZ in all the experimental conditions tested.. I-RTX is a novel and potent antitussive drug which inhibits cough mediated by agents possibly acting via TRPV1 activation.

Topics: Animals; Antitussive Agents; Cough; Diterpenes; Guinea Pigs; Ion Channels; Male; Receptors, Drug; TRPV Cation Channels