Opioids have been found to modulate the function of the immune system by regulating the biochemical and proliferative properties of its cellular components. The interaction of opioid and immune systems, however, is not unidirectional, but rather, bidirectional in nature. In the CNS, one cellular target of immune system activation is the astrocytes, glial cells known to synthesize proenkephalin. We have recently shown that these cells also express the messenger RNA transcripts for the opioid receptors mu, delta and kappa, raising the question of the functional significance of this opioid peptide and the related receptors in the astrocytes. That is, why do astrocytes express proenkephalin and opioid receptors, and are these molecules responsive to a factor to which the astrocytes could be exposed in vivo? Furthermore, do these molecules respond to this factor in a region-specific fashion? In the present study, in order to characterize the astrocytic opioid response to an immune factor, we examined the concomitant regulation of mu, delta, kappa and proenkephalin messenger RNAs by interleukin-1beta (1 ng/ml=60 pM, 24 h) in primary astrocyte-enriched cultures derived from the rat (post-natal day 1-2) cortex, striatum, cerebellum, hippocampus and hypothalamus. Interleukin-1beta treatment was found to increase by 55-75% the level of mu receptor messenger RNA in striatal, cerebellar and hippocampal cultures, but not in cultures derived from the cortex or hypothalamus. However, the cytokine had no effect on the level of delta receptor messenger RNA in any of the five cultures examined. In marked contrast to its stimulatory effects on mu receptor messenger RNA levels and its lack of an effect on 6 receptor messenger RNA expression, interleukin-1beta reduced to 10-30% of control levels the kappa receptor messenger RNA levels in all cultures. Interleukin-1beta had no effect on the level of proenkephalin messenger RNA in cortical, striatal, cerebellar and hypothalamic cultures, but did significantly decrease the expression of proenkephalin messenger RNA in hippocampal cultures to 40% of the control level. Therefore, interleukin-1beta differentially regulated opioid receptor messenger RNA in astrocyte-enriched cultures in a manner dependent upon both the receptor type and the brain region from which the culture was derived. The cytokine also differentially regulated proenkephalin messenger RNA in a region-dependent fashion. These findings suggest a capacity for astrocytes to differentially regulate opioid peptide and receptor messenger RNAs in response to an immune factor, supporting the potential existence of a novel immune-opioid system interaction in the CNS.