Substance P, a neuropeptide contained in visceral sensory nerves, has a dual afferent/efferent functions and is also known to play a major role in the production of pro-inflammatory cytokines by leukocytes (e.g. macrophages). We recently reported that burn injury-induced changes in the cellular localization of Substance P, its cognate receptor and the metalloprotease responsible for degradation of Substance P, is augmented by the presence of ethanol relative to other treatment groups. Coincident with ethanol-induced changes in Substance P cellular localization is increased protein levels for IL-6. This enhanced presence of IL-6 ileal tissue may be dependent on Substance P release. Current studies are expanding these observations by determining whether modulation of Substance P play a role in the increased levels of pro-inflammatory cytokine, IL-6. This research may suggest new therapeutic approaches to gastrointestinal system-induced septicemia after a combination of ethanol and burn injury.