We previously reported that desflurane induced airway contraction via antidromic tachykinin release from sensory C-fibers. Here, we investigated the effect of desflurane on airway lung resistance (R(L)) using specific receptor antagonists in C-fibers. Young guinea pigs were anesthetized and their tracheas were cannulated with an endotracheal tube via a tracheotomy. A Fleisch pneumotachograph and a differential transducer were used to monitor respiratory flow rate, intrapleural pressure, and airway pressure, and R(L) was calculated and recorded. A transient receptor potential A1 (TRPA1) or a transient receptor potential V1 (TRPV1) selective antagonist of sensory C-fibers, i.e., HC030031 or BCTC, was administered before the exposure to desflurane. In an additional experiment, tachykinin receptor of airway smooth muscles was antagonized only by the neurokinin-2 receptor antagonist MEN-10376 before the exposure to desflurane. HC030031 completely inhibited both the first and the second contractile responses induced by desflurane, whereas BCTC had little effect. MEN-10376 also significantly and substantially diminished the contractile response. Desflurane contracts the airway in untreated guinea pigs mainly by activating irritant gas receptor TRPA1 of afferent C-fibers, resulting in the release of contractile tachykinins such as neurokinin A.