Neurons in the striatum that project to the substantia nigra contain the opioid peptide dynorphin. Stimulation of D1 dopamine receptors results in increased expression of mRNA encoding dynorphin as well as expression of immediate-early genes such as c-fos in these neurons. Levels of dynorphin vary in different regions of the normal rat striatum, being highest in ventral and medial striatum. In a prior study, we have shown that both regional and temporal patterns of c-fos induction following treatment with the indirect dopamine receptor agonist cocaine are inversely related to those of dynorphin expression. These results suggested that dynorphin is involved in regulating the responsiveness of these neurons to dopamine input. In the present experiments, we examined such a potential role for dynorphin by analyzing the influence of the dynorphin (kappa opioid receptor) agonist spiradoline on immediate-early gene induction by cocaine, and we determined that this immediate-early gene response is mediated by D1 dopamine receptors located in the striatum. As a marker of neuron activation, expression of c-fos and zif 268 immediate-early genes was assessed with quantitative in situ hybridization histochemistry. Results showed that 1) intrastriatal infusion of the D1 dopamine receptor antagonist SCH-23390 (2.5-250 pmol) resulted in a dose-dependent blockade of immediate-early gene induction by cocaine (30 mg/kg); 2 systemic administration of the kappa opioid receptor agonist spiradoline (0.5-10.0 mg/kg) decreased cocaine-induced expression of c-fos and zif 268 mRNAs in striatum in a dose-dependent manner; 3) intrastriatal infusion of spiradoline (1-50 nmol) also suppressed immediate-early gene induction by cocaine, demonstrating that kappa opioid receptors located in the striatum mediate such an effect; and 4) systemic and intrastriatal administration of spiradoline also affected immediate-early gene expression in cortex. These results demonstrate that, in striatum, immediate-early gene induction by cocaine is a D1 dopamine receptor-mediated process that is inhibited by activation of kappa opioid receptors. Therefore, these findings suggest that the striatal dynorphin opioid system acts directly and/or indirectly to inhibit dopamine input to striatonigral neurons through kappa opioid receptor-mediated processes in the striatum.