The increased release of norepinephrine (NE) in the brain as part of the 'acute phase response' has been postulated to result from a direct action of IL-1 on the hypothalamus. To test whether the effects of IL-1α were direct, we carded out in vivo experiments using microdialysis and measured NE release in the hypothalamus using high pressure liquid chromatography (HPLC). Two groups of male Sprague Dawley rats were either injected intraperitoneally with 1 ml of IL-1 α (2 μg/ml) or had IL-1α 2 μl (100 ng/ml) infused directly into the medial hypothalamus. A significant increase in extracellular hypothalamic NE was observed in the animal group treated with IL-1α intraperitoneally and not in the controls or the group treated with IL-1α intracerebrally. One-way ANOVA showed a significant effect of drag and route of administration with the ip IL-1α treated group, differing from all other groups (vehicle ip, IL-1α ic, and vehicle ic). Therefore these findings suggest that some aspects of IL-1α actions on the HPA may be indirect requiring other intermediate steps or mediators outside the central nervous system.