The mechanism of cough associated with upper respiratory infection (URI) is poorly understood. This paper reports a study of the role of altered sensitivity of capsaicin-sensitive airway nerves. In a prospective study, baseline (B) capsaicin-induced cough and methacholine-induced airway responsiveness were measured in 103 healthy volunteers. During the following year, 31 subjects reattended for challenge testing during URI (I) and after recovery (R). The log concentration of capsaicin required to elicit two coughs (C2) was significantly lower during infection than recovery but not baseline [median (interquartile range) B = 0.59 (0.28-1.20), I = 0.27 (0-0.89), R = 0.89 (0.28-1.49)]. Log C5 (concentration causing five coughs) was lower during infection than baseline and recovery [B = 1.79 (1.20-2.70), I = 1.49 (0.89-2.08), R = 1.79 (1.20-2.40)]. FEV1 and PC15 methacholine values were unchanged during infection compared to baseline. Subjects with dry cough (n = 14) had lower C5 values during infection than both baseline and recovery, and lower C2 values during infection than recovery; in these subjects, increase in capsaicin sensitivity correlated with cough severity score. Subjects with productive cough or no cough showed no consistent changes during infection. Twenty-six control subjects who reattended without URI showed no change in capsaicin sensitivity. Upper respiratory infection may cause cough as a result of increased sensitivity of capsaicin-sensitive afferent airway nerves without affecting airway calibre or responsiveness.
The effect of inhaled capsaicin, the irritant extract of pepper, on airway tone has been studied in humans. Inhaled capsaicin (2.4 X 10(-10) and 2.4 X 10(-9) mol) caused a dose-dependent fall in specific airways conductance (maximum fall 28 +/- 19 and 38 +/- 19%, respectively; means +/- SD, n = 17). This was maximal within 20 s of exposure and lasted for less than 60 s. There was no difference in the magnitude or duration of bronchoconstriction between normal, smoking, or asthmatic subjects. Capsaicin also caused coughing and retrosternal discomfort. On repeated exposure to capsaicin, there was no evidence for a reduced response (tachyphylaxis). Ipratropium bromide (0.25 mg by inhalation) significantly (P less than 0.05) reduced the bronchoconstriction (maximum falls 34 +/- 14 and 15 +/- 9% after saline and ipratropium bromide, respectively; means +/- SD n = 6), indicating that it was dependent on a cholinergic vagal reflex rather than on local release of substance P from nerves in the airway. Inhaled sodium cromoglycate (10 mg by nebulizer or 40 mg as a dry powder), however, had no significant effect on the bronchoconstrictor response. Capsaicin may be a useful tool for investigating nonmyelinated nerve reflexes in human airways.
1Neuropeptides released from sensory nerves may account for cutaneous flare and wheal following local trauma. In 28 normal subjects we have studied the effects of four sensory neuropeptides given by intradermal injection on the forearm or back. 2 All peptides caused a flare distant from the site of injection, presumably due to an axon reflex. Substance P (SP) was the most potent (geometric mean dose causing 50% ofmaximum flare, 4.2 pmol). Neurokinin A (NKA) was the next most potent with neurokinin B (NKB) and calcitonin gene-related peptide (CGRP) the least. The distant flare response to SP, NKA and NKB was maximal at 5 min and disappeared within 2 h. 3 CGRP caused a local erythema over the site of injection at doses above 0.5 pmol which at higher doses lasted for up to 12 h. 4 SP, NKA and NKB caused wheals at doses above 5 pmol with SP and NKB being the most potent. CGRP (up to 250 pmol) did not consistently cause wheal formation. There was no significant effect of coinjection ofCGRP upon the response to SP although there was a tendency for an enhancement ofthe wheal response. 5 The H,-histamine antagonist terfenadine (60mg orally) significantly inhibited the wheal and distant flare response to histamine (5 nmol) and NKA, but not that caused by NKB. The distant flare of CGRP was also reduced but the local erythema was unaltered. 6 Aspirin (600 mg orally) significantly inhibited the distant flare response to SP, NKA and CGRP, but not that caused by NKB or histamine; the local erythema induced by CGRP was unaffected by aspirin. Aspirin also inhibited the wheal formed by NKA but not the wheal induced by the other substances. 7 These results suggest that tachykinins cause a distant flare response partially via the release of histamine and cyclo-oxygenase products, but cause a wheal by a direct effect on the skin microvasculature. The order of potency SP > NKB > NKA suggests that an SPp or NK, receptor is involved in the wheal response. CGRP by contrast has a direct vasodilator effect which is very prolonged.
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