Injection of morphine (10 mg/kg) induced a complex immediate-early gene response in the rat forebrain, as detected with immunocytochemistry. The c-Fos protein was induced consistently in the dorsomedial caudate-putamen, the nucleus accumbens, and in midline and intralaminar nuclei of the thalamus. In some rats induction was also seen in the parietal and insular cortex and in lateral regions of the caudate-putamen. Induction was detectable, although weak, at 30 min, was maximal at 2 h, and was undetectable 3 h after injection. JunB was induced in the same regions of the caudate-putamen as found for c-Fos, but was not induced in the nucleus accumbens or thalamus. In the caudate-putamen, JunB induction was still present 3 h injection. A considerably smaller induction of c-Jun was noted in the dorsomedial caudate-putamen and in deep neocortex. Expression of JunD was inhibited in intralaminar and midline thalamic nuclei. Increases in numbers of cells immunoreactive for a Jun-related antigen (Jra) were found in the caudate-putamen and nucleus accumbens. These results indicate a complex immediate-early gene response to acute morphine, suggesting that morphine activates or inhibits specific neurons and circuits in the forebrain.