Immersion of the hind paws of anesthetized rats in hot water for 5 min induced massive plasma protein leakage as indicated by extravasation of Evans blue dye in the skin. The threshold temperature which caused noticeable plasma extravasation was 45 degrees C, a maximal response was obtained between 55 degrees C and 60 degrees C. Pretreatment of rats 2 days after birth with 50 mg kg-1 capsaicin significantly reduced the Evans blue extravasation induced by hot water at 50 degrees C and 60 degrees C, whereas guanethidine pretreatment 24 h before the experiment caused a significantly increased response at 40 degrees C, 45 degrees C and 50 degrees C. When Evans blue was injected between 10 and 120 min after immersion of the paw in hot water, a significant extravasation of the dye was no longer detectable. However, the weight of the paw as well as the weight of the piece of skin taken for Evans blue quantification increased during this period indicating the progressive development of oedema in the skin and underlying tissues. In rats treated with capsaicin as neonates, the increase in paw weight after immersion in water of 50 degrees C for 5 min was significantly delayed during the first hour, but there was no difference after two hours. In rats pretreated with D-Arg1,D-Pro2-,D- Trp7 ,9, Leu11 -substance P, a substance P (SP) antagonist, the Evans blue extravasation was significantly reduced. However, the response, which remained in rats treated with capsaicin as neonates was not blocked by the SP-antagonist. 6 It is concluded that activation of peripheral branches of sensory SP neurones contributes to the initial massive protein extravasation and to the subsequent rate of development of oedema following heat injury. Release of histamine did not significantly contribute to this response at the lower temperatures, although the response was reduced by histamine receptor blocking drugs at 55 degrees and 60 degrees C. Decreasing the sympathetic vasoconstrictor tone by guanethidine resulted in an increased response.