To investigate the physiological role of the substance P innervation(SPI) in the nasal mucosa from inhaled irritant macromolecules, SPI was selecitvely stimulated by capsaicin and the degree of horseradish peroxidase (HRP) permeability across the epithelium of the nasal mucosa of the rat was evaluated by the enzyme immunoassay, or the electron microscopic histochemistry. The serum level of HRP were reduced significantly in capsaicin administered rats along the time course with quantitative analysis. Control rats showed heavy permeation of HRP across the epithelium, but capssaicin administered rat showed weak permeation of HRP across the epithelium in histochemical electron microscopy. In conclusion, selective stimulation of SPI of the rat nasal mucosa with capsaicin decreased the epithelial absorption permeability to HRP without compromising the epithelial integrity. These findings imply that the major role of capsaicin sensitive nerve in the nasal mucosa is to protect the permeation of inhaled irritant macromolecules.