Changes in the levels of enkephalin and substance P messenger RNA expression were examined in the striatum following dopamine depletion resulting from unilateral injection of 6-hydroxydopamine into the substantia nigra. In response to striatal dopamine depletion, the levels of enkephalin messenger RNA were elevated, whereas substance P messenger RNA was decreased within all regions of the striatum. Examination of the striatal peptide messenger RNAs between one and 21 days after the injection of 6-hydroxydopamine revealed a temporal dissociation between changes in enkephalin and substance P messenger RNAs. Within one day of the 6-hydroxydopamine injection, substance P messenger RNA was significantly decreased by 30% at all levels of the striatum. This decrease was maintained for up to 21 days after the lesion. In contrast, striatal enkephalin messenger RNA was not significantly elevated until three days following the injection of 6-hydroxydopamine, after which there was a gradual increase up to 21 days. In order to correlate alterations in peptide messenger RNA expression with 6-hydroxydopamine-induced changes in striatal dopamine innervation, tissue punches from the striatum were examined for dopamine content at one, two, three and seven days after the lesion. One day after the lesion, striatal dopamine levels were significantly increased by 47%. In contrast, within two days tissue dopamine content was reduced by 77% compared to control levels. A further decrease of 90% or more was observed at three and seven days after the lesion. Taken together, these data demonstrate a temporal dissociation between changes in enkephalin and substance P messenger RNA levels following 6-hydroxydopamine-induced striatal dopamine depletions. This temporal dissociation may reflect a differential response of enkephalin and substance P messenger RNAs to alterations in dopamine release and subsequent receptor activation.