This study compared the effects of unilateral and bilateral 6-hydroxydopamine-induced lesions of the nigrostriatal dopaminergic neurons on substance P and enkephalin expression in the rat striatum and its main target structures by means of quantitative in situ hybridization and immunocytochemistry. In animals with bilateral lesion, substance P mRNA levels were decreased in the striatum, and this was matched by parallel reductions in substance P immunoreactivity in the striatum and in the striatonigral terminals at substantia nigra level in both hemispheres. These changes were similar to those observed ipsilaterally to unilateral lesion. In contrast, whereas increased striatal enkephalin immunoreactivity and mRNA levels and decreased immunoreactivity in the globus pallidus were observed on the lesioned side after unilateral lesion, no significant change in these enkephalin markers occurred in animals with bilateral lesion. These data suggest that the effects of dopamine deafferentation on substance P expression in the striatonigral system may be due primarily to removal of direct dopamine influence, whereas the effects on enkephalin expression in the striatopallidal system may involve complex interhemispheric adaptive mechanisms. The present finding that bilateral dopamine lesion does not simply reproduce the effects of unilateral lesion but creates a new functional state may have a critical bearing on the understanding and treatment of Parkinson's disease.