The aim of the present study is to explore the role of immunosuppression mediated by substance P (SP) in spinal dorsal horn (SDH) in the pathogenesis of the autoimmune diseases. The experimental allergic neuritis (EAN), experimental allergic encephalomyelitis (EAE) and adjuvant arthritis (AA) animal models were established in the guinea pigs and Wistar rats, respectively. The effects of alteration of SP activity in SDH on immune responses and the pathogenesis of the autoimmune diseases were observed. The results showed that decreasing activity of SP in SDH by pretreatment of capsaicin or intrathecal SP antagonist could enhance cellular and humoral immune responses and aggravate the autoimmune diseases, while intrathecal SP agonist could suppress the immunity and alleviate clinical signs. The contents of SP in SDH was elevated dramatically at the peak of immune responses. These results suggest that SDH SP might participate in the pathogenesis of the autoimmune diseases. The increase of SP contents in SDH may inhibit the immune system via unknown pathway and ease clinical severity of the autoimmune disease, where SP might act as neurotransmitter in the immunoregulation of the negative feedback. To elevate SP content in SDH might be beneficial to the autoimmune diseases.