Interleukin-1 (IL-1) induces anorexia via direct action in the brain, and its participation in the pathogenesis of cancer-associated anorexia has been hypothesized. Because the functional ablation of the ventromedial nucleus of hypothalamus (VMH), where IL-1 receptors have been detected, reverses cancer-associated anorexia in tumor-bearing (TB) rats, we hypothesize that cancer anorexia involves the direct effect of IL-1 on the VMH. To test this hypothesis, we investigated whether the intra-VMH injection of the IL-1 receptor antagonist (IL-1ra) improves food intake in anorectic TB rats. Sixteen Fischer rats (approximately 300 g/BW) were injected s.c. with 10(6) trypan-blue viable methylcholanthrene sarcoma cells, and then individually caged. Chow and water were freely available, and food intake was recorded throughout the study. Normal food intake was measured in 8 more rats, injected s.c. with normal saline. Tumor developed in all rats. When TB rats became anorectic, they were randomly assigned to either treatment or control groups. Using stereotaxic techniques, 25 ng of IL-1ra dissolved in normal saline (TB-IL-1ra; n = 8), or an equal volume of normal saline (TB-NS; n = 8) was injected bilaterally into the VMH. After surgery, rats were caged and changes in food intake recorded. At study's end, rats were sacrificed and brains removed for histological confirmation of injection sites. In the TB-NS group, food intake decreased with the occurrence of anorexia. In contrast, the intra-VMH injection of IL-1ra reduced the severity of cancer anorexia, significantly improving food intake in TB-IL-1ra rats. Data indicate that centrally acting IL-1 plays a significant role in the development of cancer anorexia.