Cellular sites of enkephalin gene expression were investigated using the technique of in situ hybridization in the normal striatum and in the denervated striatum of monkeys depleted of dopamine by pretreatment with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Animals received MPTP by either (a) intravenous injection to induce generalized parkinsonism, or (b) infusion into one carotid artery to induce unilateral parkinsonism. The animals which received systemic injections of MPTP were found to have an essentially total loss of nigral dopamine cells whereas the intracarotid MPTP treatment was found to destroy approximately 95% of the dopamine neurons in the ipsilateral substantia nigra. A double-stranded cDNA probe encoding the human preproenkephalin (PPE) gene was isotopically labelled with 35S and used to detect PPE mRNA within striatal tissue sections. Application of this radiolabelled cDNA probe to lightly fixed striatal sections from both groups of animals revealed an increase in expression of PPE mRNA within denervated striatal enkephalinergic neurons relative to control tissue. An increase in the number of detectable enkephalinergic mRNA-positive neurons relative to control tissue was also noted. These results suggest that the nigral dopaminergic neurons tonically inhibit PPE gene expression in the striatum.