The effects of inflammatory substances, bradykinin (BK), 5-HT, and histamine (HIS), on the release of calcitonin gene-related peptide (CGRP) from the peripheral terminals of sensory afferents in the rat trachea were examined ex vivo. With intralumenal perfusion, the isolated rat trachea displays low but measurable secretion of CGRP (32 ± 4.6 fmol/10 min fraction). The addition of BK (10-6 to 10-4 M) to the superfusate resulted in an immediate, concentration-dependent increase in the level of CGRP (5-30-fold increase above baseline) in the perfusates, and this effect showed a concentration-dependent tachyphylaxis. [Des-Arg10]-kallidin, a B1 receptor agonist, at concentrations of up to 10-4 M did not induce any significant increase in CGRP outflow from the rat trachea. HIS at 10-4 M caused a modest but progressive augmentation in the release of CGRP. 5-HT at 10-4 M had no effect upon the resting efflux of CGRP, but at a concentration of 10-6 M significantly enhanced the release of CGRP evoked by capsaicin (10-6 M). Similar conditioning studies carried out with HIS and BK showed no augmentation. BK-evoked CGRP efflux was significantly inhibited by [D-Arg0, Hyp3, Thi5,8, D-Phe7]-BK (B2 antagonist) and indomethacin. While [Des-Arg9, Leu8]-BK (B1 antagonist) also caused a reduction of BK-induced release, its effect did not reach statistical significance. The facilitatory effect of 5-HT on capsaicin-evoked release was not markedly affected by 5-HT, or 5-HT2 antagonists, (s)-(-)propranolol or methysergide, but was totally abolished by the 5-HT3 receptor antagonist ICS 205-930 and also by indomethacin. These data suggest that BK, acting through a B2 receptor, activates CGRP release from the peripheral terminals of capsaicin-sensitive sensory afferents. The sensitizing effect of 5-HT on the capsaicin-evoked release of CGRP may be mediated via a 5-HT3 receptor. Both actions appear to require the formation of cyclooxygenase products for their manifestation.
CITATION STYLE
Hua, X. Y., & Yaksh, T. L. (1993). Pharmacology of the effects of bradykinin, serotonin, and histamine on the release of calcitonin gene-related peptide from C-fiber terminals in the rat trachea. Journal of Neuroscience, 13(5), 1947–1953. https://doi.org/10.1523/jneurosci.13-05-01947.1993
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