Paclitaxel is one of the most extensively used anti-cancer agents, however, its use is often limited by severe hypersensitivity reactions, including respiratory distress, bronchospasm and hypotension, which can occur despite pre-medication with dexamethasone and histamine H₁ and H₂ antagonists. The present study was designed to determine the mechanisms of paclitaxel hypersensitivity. In rats, paclitaxel (15 mg/kg, i.v.) caused a marked increase in pulmonary vascular permeability and edema. The arterial PaO₂ decreased, while PaCO₂ increased, transiently after paclitaxel injection. The paclitaxel-induced pulmonary vascular hyperpermeability was blocked by dexamethasone but not by histamine H₁ or H₂ antagonists. Paclitaxel increased the vascular permeability in lungs of mast cell-deficient rats Ws/Ws (-/-) to almost the similar extent as that elicited in wild-type rats. On the other hand, the paclitaxel-induced pulmonary vascular hyperpermeability was reversed by sensory denervation with capsaicin or pretreatment with LY303870 and SR48968, NK₁ and NK₂ antagonists, respectively. Consistent with these findings, a marked elevation of sensory neuropeptides such as substance P, neurokinin A and calcitonin gene-related peptide was observed in rat bronchoalveolar lavage fluid after paclitaxel injection. These findings suggest that sensory nerves rather than mast cells are implicated in the etiology of paclitaxel hypersensitivity.