Brain cytokines, induced by various inflammatory challenges, have been linked to sickness behaviors, including fatigue. However, the relationship between brain cytokines and fatigue after exercise is not well understood. Delayed recovery of running performance after muscle-damaging downhill running is associated with increased brain IL-1beta concentration compared with uphill running. However, there has been no systematic evaluation of the direct effect of brain IL-1beta on running performance after exercise-induced muscle damage. This study examined the specific role of brain IL-1beta on running performance (either treadmill or wheel running) after uphill and downhill running by manipulating brain IL-1beta activity via intracerebroventricular injection of either IL-1 receptor antagonist (ra; downhill runners) or IL-1beta (uphill runners). Male C57BL/6 mice were assigned to the following groups: uphill-saline, uphill-IL-1beta, downhill-saline, or downhill-IL-1ra. Mice initially ran on a motor-driven treadmill at 22 m/min and -14% or +14% grade for 150 min. After the run, at 8 h (wheel cage) or 22 h (treadmill), uphill mice received intracerebroventricular injections of IL-1beta (900 pg in 2 microl saline) or saline (2 microl), whereas downhill runners received IL-1ra (1.8 microg in 2 microl saline) or saline (2 microl). Later (2 h), running performance was measured (wheel running activity and treadmill run to fatigue). Injection of IL-1beta significantly decreased wheel running activity in uphill runners (P<0.01), whereas IL-1ra improved wheel running in downhill runners (P<0.05). Similarly, IL-1beta decreased and Il-1ra increased run time to fatigue in the uphill and downhill runners, respectively (P<0.01). These results support the hypothesis that increased brain IL-1beta plays an important role in fatigue after muscle-damaging exercise.