1 Rats were pretreated with capsaicin (50 mg/kg, s.c.) on the 2nd, 10th, or 20th day of life. Three months later immunoreactive substance P (I-SP) was determined in skin, sensory nerves and the central nervous system. Neurogenic plasma extravasation was also examined.2 Pretreatment at the age of 2 or 10 days resulted in a decrease (26 to 69%) of I-SP in skin, saphenous and vagus nerve, dorsal roots, dorsal half of the spinal cord, and medulla oblongata. The I-SP content of the ventral half of the spinal cord, of midbrain, hypothalamus, striatum, cortex, and cerebellum remained unchanged. Neurogenic plasma extravasation was inhibited by more than 80%.3 In contrast to this irreversible effect of capsaicin on newborn rats, pretreatment of 20 day old rats led to reversible depletion of I-SP and to reversible impairment of neurogenic plasma extravasation.4 Capsaicin pretreatment of adult rats caused a marked depletion of I-SP in the skin of the hind paw and an impairment of neurogenic plasma extravasation. A similar decrease of I-SP was seen after chronic denervation of the skin.5 Intra-arterial infusion of substance P (threshold dose 5 x 10(-13) mol/min) or physalaemin induced dose-dependent plasma extravasation. Somatostatin, vasoactive intestinal polypeptide, caerulein and the enkephalin-analogue FK 33-824 were ineffective in doses 100 fold higher.6 The results indicate that the action of capsaicin on substance P neurones is restricted to primary sensory neurones. Since in every case a decreased substance P content of the skin was associated with impaired neurogenic plasma extravasation, it is suggested that release of substance P is involved in neurogenic plasma extravasation.