Previous studies have shown that interleukin-1 (IL-1) can excite the magnocellular neurosecretory cells (MNCs) of the hypothalamus. However it is not known if IL-1 can have direct IL-1 receptor type 1 (IL-1R1)-mediated effects on MNCs, and little is known about the cellular mechanisms by which IL-1 influences electrical activity in these cells. Here we used patch-clamp recordings to examine the effects of IL-1 on acutely isolated rat MNCs. We found that IL-1 directly excites MNCs in a dose-dependent manner and that this response can be blocked by an inhibitor of the IL-1R1. Voltage clamp analysis of the current evoked by IL-1 revealed a linear current-voltage relationship between -90 and -20 mV, and a reversal potential near -35 mV. This value was not affected by reducing the concentration of chloride ions in the external solution, indicating the involvement of a non-selective cation conductance. The effects of IL-1 were inhibited by Na-salicylate, an inhibitor of cyclooxygenase. Moreover the effects of IL-1 were mimicked and occluded by prostaglandin E₂ (PGE₂), and were inhibited by AH-23848, an antagonist of the EP₄ receptor. The current evoked by IL-1 was also abolished by 100 µM Gd³⁺, but was significantly larger when examined in cells pre-shrunk by negative pressure applied via the recording pipette. IL-1 alone did not cause changes in cell volume, or in the mechanosensitivity of MNCs. We conclude that IL-1 directly excites MNCs via an IL-1R1-mediated induction of PGE₂ synthesis and EP₄ receptor-dependent autocrine upregulation of the nonselective cation conductance that underlies osmoreception.