Capsaicin was applied locally to the sciatic or saphenous nerve, and the effects on axoplasmic transport, neurogenic plasma extravasation, and thermal pain were studied. Capsaicin (10 mg/ml) led to a complete block of axoplasmic transport of immunoreactive substance P (I-SP) and somatostatin (I-SRIF) in rat sciatic nerve without affecting the transport of noradrenaline or acetylcholinesterase. Inhibition of I-SP transport was also found in sciatic nerves of guinea-pig, cat and rabbit. In contrast, one or two weeks after systemic capsaicin treatment (125 mg/kg s.c.), orthograde transport of I-SP was the same in control and capsaicin-treated rats. After local capsaicin application to the sciatic nerve, a decrease of I-SP was found not only in skin and sciatic nerve distal to the site of application, but also in dorsal root ganglia, dorsal roots and the dorsal half of the spinal cord segments L 4-5. This was accompanied by a loss of acid phosphatase activity in the substantia gelatinosa supplied by sciatic nerve afferents. Plasma extravasation by mustard oil was reduced in the skin of the hind paw with a time course identical to the I-SP depletion. The response to noxious heat (hot plate test) was, however, abolished earlier. These results indicate that capsaicin applied to a peripheral nerve inhibits axoplasmic transport in sensory but not in adrenergic or cholinergic neurons, which leads to long-term biochemical and functional changes of the entire sensory neuron. In addition, capsaicin appears to inhibit impulse propagation in certain populations of sensory neurons.