Substance P-immunoreactivity (SP-IR) in the guinea-pig ureter was found to be totally depleted after systemic capsaicin pretreatment. Removal of the inferior mesenteric ganglion (IMG) led to a total depletion of SP-IR from the rostral third of the ureter and to a partial depletion from the caudal third. Electrical stimulation of the IMG caused Evans blue extravasation mainly in the rostral third of both ureters, whereas stimulation of the right pelvic nerve caused Evans blue extravasation in the caudal third of the ureters on both sides. The responses to nerve stimulation were absent in capsaicin-pretreated animals. Furthermore, capsaicin caused release of SP-IR from ureter slices in vitro, this release was not inhibited by tetrodotoxin. Potassium (60 and 120 mM) also released SP-IR. It is concluded that SP-IR in the ureter is contained in capsaicin-sensitive sensory neurons reaching the ureter via both parasympathetic (caudal part) and sympathetic nerves (rostral part). Activation of these neurons by capsaicin leads to a peripheral release of SP-IR which most likely increases vascular permeability.