Atopic dermatitis can be exacerbated or induced by scratching or psychological stress; both cause the release of substance P (SP) from sensory nerves. Therefore, SP may have an etiological role in mechanisms underlying AD. Here, we show that administration of SP during the primary immune response (PIR) imprinted long-lasting pro-inflammatory immunity, resulting in exacerbation of the secondary immune response (SIR) in the absence of further SP. Five days after sensitization with dinitrofluorobenzene (DNFB), challenge with DNFB together with SP ("SP-Group") resulted in an increased PIR (as evaluated by ear swelling and granulocyte infiltration) compared to DNFB only ("Control-Group"). On day 26, after inflammation completely subsided, a second challenge with DNFB only (without SP) caused an increased SIR in the "SP-Group" compared to controls. Pretreatment on day 5 with spantide, an SP receptor antagonist, prevented increased ear swelling in the "SP-Group" not only on day 5 (PIR) but also on day 26 (SIR). In contrast, spantide treatment on day 26 did not affect the SIR. Adoptive transfer experiments suggested that CD8(+) T cells were involved in mediating enhanced SIR in animals pretreated on day 5 with SP. The present study offers a novel experimental approach to an uninvestigated facet of the pro-inflammatory effect of SP, i.e., exacerbation of inflammation via a long-term and indirect influence on CD8(+) T lymphocytes.