Substance P (SP), 40 micrograms/kg SC, induced protein leakage in the skin, muscle, trachea and esophagus of the anesthetized rat as measured by Monastral blue B labeling of small blood vessels. CRF, 30 micrograms/kg SC, injected 30 min before SP, decreased the SP-induced dye leakage. To locate where CRF might act, autoradiographic studies of [125I]-CRF binding to esophageal segments were conducted and displaceable binding of [125I]-CRF to submucosal elements in the esophageal epithelium were revealed, suggesting that CRF acts on selective sites to reduce vascular leakage.