The effect of cytokines and neuropeptides on neuroimmune functions has not been completely elucidated and recent evidence suggests an important role for these molecules linking the neuroimmune system and inflammatory events. The aim of this study was to analyse the effect of substance P (SP) on a pure population of hypothalamic brain mast cell (BMC). A pure population of BMC challenged with 10(-8) M SP gave 78% histamine release (HR) and secreted 600 pg/ml of tumor necrosis factor-alpha (TNF-alpha) as determined by ELISA. The production of TNF-alpha mRNA, measured by a competitive RT-PCR, was 14 times higher than that in unstimulated cells. The secretion of histamine and TNF-alpha from BMC after stimulation with SP supports the hypothesis that these mediators could induce an initial response in neuroinflammatory diseases.