Several lines of evidence have indicated that interferon-alpha (IFN-alpha) induces a variety of central actions; e.g., fever anorexia, slow wave sleep and depression. However, little is known about the cellular mechanisms by which IFN-alpha affects neuronal activity. In the present article, the effects of recombinant human IFN-alpha on N-methyl-D-aspartate (NMDA)-induced responses of rat medial preoptic (MPO) neurons were examined by means of slice patch method as an in vitro model of neural-immune interactions. The results suggest that IFN-alpha suppresses the NMDA responses through its action on opioid receptors and the production of free radicals such as hydroxyl radicals and nitric oxide (NO) due to the neuron-glial cell interactions.