Mechanisms of Capsaicin- and Citric-Acid-Induced Cough Reflexes in Guinea Pigs

Abstract

Abstract. Previously, we developed a novel coughing model that evoked coughs via citric acid microinjection into the larynx of unanesthetized, unrestrained guinea pigs. Here, we compared the effects of capsaicin and citric acid administration into the larynx using this model. Inhalation of capsaicin (30 µM) or citric acid (0.4 M) for 5 min induced cough mimetic responses over a 10-min observation period (mean ± S.E.M.: 8.85 ± 1.60 and 10.40 ± 1.17 coughs, respectively, n = 18). Microinjection of 0.4 M citric acid into the larynx (20 µl in total in 10 aliquots of 2 µl at 30-s intervals) induced 27.29 ± 2.69 coughs over a 10-min observation period, whereas microinjection of 3 mM capsaicin evoked a maximum of 8.32 ± 1.82 coughs (n = 18). Desensitization of C-fibers by capsaicin (100 mg / kg, s.c.) abolished the coughs evoked upon inhalation or microinjection of capsaicin and inhalation of citric acid, but had no significant effect on those induced by microinjection of citric acid. These results indicate that there were fewer nonmyelinated C-fiber afferents in the larynx area than in other regions (bronchi or alveoli). Consequently, citric acid microinjected into the larynx may induce the cough reflex by stimulating other fibers (for example, Aδ-fibers), rather than C-fibers. In contrast, inhaled citric acid predominantly stimulated C-fibers, and hardly affected Aδ-fibers.

Comparison of the incidence and severity of cough induced by sufentanil and fentanyl: a prospective, randomised, double‐blind study

“…Citric acid initiates the cough reflex by stimulation of C-fibres in the airway [13]. Sufentanil and fentanyl preparations are available as citrate salts; there is a possibility that, when sufentanil and fentanyl are injected intravenously, their citrate component may stimulate the pulmonary chemoreflex.…”

Effects of Eppikahangeto, a Kampo Formula, and Ephedrae herba Against Citric Acid-Induced Laryngeal Cough in Guinea Pigs

“…The difference between the results of Miyata (8) and our present study might reflect the antitussive character of the Kampo medicine and / or the difference of the methods. Tanaka and Maruyama described that the microinjection of citric acid stimulates both Aδ-fiber and C-fiber (12), whereas its inhalation stimulates only C-fiber (26). Therefore, there is the possibility that EPP may influence Aδ-fiber rather than C-fiber.…”

Mechanistic studies of acid-evoked coughing in anesthetized guinea pigs

“…In conscious guinea pigs, citric acid-evoked coughing is inhibited by the capsaicin receptor transient receptor potential vanilloid type 1 (TRPV1) antagonists capsazepine and iodo-resiniferatoxin or the TRPV1 channel blocker Ruthenium Red, and can also be inhibited by neurokinin 1 (NK 1 ), NK 2 , and/or NK 3 receptor antagonists (1,2,7,18,34,54,55). The acid-evoked coughing is mimicked by inhalation of the TRPV1 receptor agonists capsaicin, resiniferatoxin, and anandamide in both animals and human subjects, and prior capsaicin desensitization abolishes citric acid-evoked coughing in awake guinea pigs (10,25,35,50). Because the only tachykinin-containing nerves innervating the airways of normal, uninflamed guinea pigs are capsaicinsensitive C fibers (21, 32 49, 56), these data provide overwhelming evidence that acid-evoked coughing in conscious guinea pigs is dependent on activation of capsaicin-sensitive, tachykinin-containing vagal afferent C fibers innervating the airways.…”