Using in situ hybridization, we have shown that the κ-opioid receptor agonist enadoline (CI-977) and the non-competitive NMDA receptor antagonist dizocilpine (MK-901) induced the immediate early gene c-fos in dorsal medial thalamic nuclei. Dizocilpine, and not enadoline, also induced c-fos in the posterior cingulate cortex and retrosplenial cortex. Enadoline's stimulation of c-fos mRNA was dose and time dependent and completely inhibited by pretreatment with naltrexone. Morphine did not stimulate c-fos in the thalamus. It is suggested that the stimulation of c-fos with enadoline represents a specific κ-opioid receptor effect.