The effect of sensory nerve C fiber network degeneration on airways permeability and responsiveness was studied in guinea pigs. Degeneration of the C fiber sensory network was produced by injecting capsaicin in solvent (total dose 50 mg/kg) into neonatal animals (n = 29) with littermate animals (n = 30) treated with solvent alone serving as controls. Sensory nerve depletion was established by comparing tracheal strips from both groups of animals in vitro. When the animals reached between 400 and 500 g body weight, airways permeability to fluorescein isothiocyanate dextran (FITC-D) and airways responsiveness to a graded dose of aerosolized histamine were measured. The data show that degeneration of the C fiber network had no effect on the airways responsiveness to histamine. They also show that degeneration of the C fiber network produced a significant (P less than or equal to .01) increase in airways reactivity [0.36 +/- 0.08 cm H2O/mL s-1 (mean +/- SEM)] following cigarette smoke exposure compared with control (0.11 +/- 0.04) or control-smoke-exposed animals (0.10 +/- 0.02). Degeneration of the C fiber network did not affect the increased permeability seen following cigarette smoke exposure (capsaicin pretreated 39.8 +/- 9.1 and control pretreated 28.4 +/- 7.9 (micrograms)(min)/mg). We conclude that degeneration of the C fiber network is associated with increased rather than decreased airways responsiveness in guinea pigs exposed to cigarette smoke.