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Keywords:

  • acid-sensing ion channel;
  • 2-aminoethoxydiphenyl borate;
  • camphor;
  • capsaicin;
  • N-(4-t-butylphenyl)-4-(3-chloropyridin-2-yl) tetrahydropyrazine-1(2H)-carboxamide

Abstract

Chronic cough derives from inflammatory hypersensitivity of tracheobronchial nerve endings, most of which express the polymodal capsaicin receptor-channel transient receptor potential vanilloid (TRPV) type 1 and the secretory neuropeptide calcitonin gene-related peptide (CGRP). An isolated mouse trachea preparation was established to measure chemically and thermally stimulated CGRP release as an index for sensory transduction of potential cough-inducing stimuli. TRPV1 knockout mice were employed to assess the TRPV1 contribution to tracheal responsiveness and sensitization. Graded heat-induced CGRP release depended entirely on extracellular calcium and partly on TRPV1; knockout mice showed 60% less CGRP release at 45°C (for 5 min) than wild-types. This heat response was facilitated by the TRPV1 agonist ethanol and the TRPV1–3 agonist 2-aminoethoxydiphenyl borate, effects that were reduced or absent in TRPV1−/−, respectively. The TRPV1 antagonists ruthenium red and N-(4-t-butylphenyl)-4-(3-chloropyridin-2-yl) tetrahydropyrazine-1(2H)-carboxamide were ineffective on the basal heat response. A step increase of temperature from 22 to 40°C caused a TRPV1-independent CGRP release that was doubled by bradykinin in wild-types but not TRPV1−/−. Proton stimulation resulted in a bell-shaped concentration–response curve with threshold at pH 6.7 and a maximum at pH 5.7; responses were greatly reduced but not abolished in TRPV1−/−. Coadministration of amiloride (30 μm), the blocker of acid-sensing ion channels, was ineffective in both TRPV1 genotypes. The data suggest that tracheal acid sensing mainly involves TRPV1 but not acid-sensing ion channels, whereas noxious heat responsiveness partly depends and (inflammatory) sensitization to heat largely depends on the capsaicin receptor in tracheal nerve endings. Lowering of their heat threshold to near body temperature may sustain hypersensitivity and neurogenic inflammation of the upper airways.