Interleukin-1 alpha (IL-1 alpha) and interleukin-1 beta (IL-1 beta) are thought to be endogenous pyrogens, i.e., to mediate fever production; warm-sensitive (W) and cold-sensitive (C) neurons in the preoptic area (POA) are presumed to be the ultimate targets of endogenous pyrogens. The recent purification of an IL-1 receptor antagonist (IL-1ra) has provided a means for verifying the presumptive action of IL-1 on these neurons. This study was undertaken, therefore, to investigate whether IL-1ra may block the IL-1 alpha and IL-1 beta effects on the firing rates (FR) of W and C neurons in guinea pig POA slices. Human recombinant (hr) IL-1 beta (500 ng/ml) reduced the FR of 26 W neurons and increased those of 3 C neurons recorded; it had no effect on 8 thermally insensitive neurons. hrIL-1 alpha (200-600 ng/ml) did not change the FR of any neuron. IL-Ira (0.01-0.5 mg/ml) had no effect by itself on the FR of all the neurons, but it blocked the hrIL-1 beta-induced FR changes of 24 of the 26 W and of all 3 C neurons when given before the cytokine. The lowest effective dose was 0.05 mg/ml. These results support the hypothesis, therefore, that POA thermosensitive neurons may be direct targets of IL-1 beta and that it may be an endogenous pyrogen acting on these units to induce fever production.