The undecapeptide substance P (SP) contained in primary afferent nerves is thought to mediate that part of the neurogenic inflammatory response consisting of vasodilation and plasma extravasation. This response is diminished in rats pretreated as neonates with the neurotoxin capsaicin. It is not known whether primary afferent nerves influence cellular responses of the immune response to antigenic stimulation. Using 6- to 12-wk-old Sprague-Dawley rats pretreated as neonates with capsaicin, we examined the regional lymph node response to a s.c. antigenic stimulus of sheep red blood cells. The number of cells secreting antigen-specific antibody in these animals was reduced by more than 80% using direct and indirect plaque assay methods. The reduced antibody response in capsaicin-pretreated animals was reversed by a s.c. infusion of SP given over a 4-hr period at the injection site immediately after antigen stimulation. This response had a threshold at approximately 1.0 X 10(-5) M SP. SP1-7 (1.0 X 10(-5) M) was without effect but an infusion of SP5-11 (1.0 X 10(-5) M) reversed the effects of capsaicin treatment indicating a carboxyl-terminal effect of SP. The results suggest that the reduced response of capsaicin-treated animals to an antigenic stimulus is due to an effect of capsaicin on the SP-containing primary afferent nerves rather than a toxic effect of capsaicin on the immune system.