Abstract In situ hybridization histochemistry was used to analyse the expression of the messenger RNAs encoding for enkephalin, substance P and dynorphin in the striatum of normal rats, rats subjected to a unilateral 6-hydroxydopamine lesion of the mesostriatal dopamine pathway and lesioned rats bearing intrastriatal transplants of fetal nigral neurons. About half of the rats in each group received twice-daily subcutaneous injections of 5 mg/kg apomorphine and the other half received control injections of saline, for nine days. Three hours after the last injection, the rats were killed by decapitation. Cryostat sections through the striatum were incubated with, 35 S-labeled oligodeoxyribonucleotide probes hybridizing with preproenkephalin, preprotachykinin or prodynorphin messenger RNA. One additional series of sections was incubated with [ 3H]GBR 12935 in order to label dopamine uptake sites. Quantitative evaluation of the hybridization signal was performed both at the macroscopic level (autoradiographic film analysis) and at the cellular level (optical density of silver grains over identified cells). The grafted nigral neurons reversed the lesion-induced up-regulation of preproenkephalin messenger RNA in the whole striatal complex. By contrast, the graft-induced effect on the lesion-induced down-regulation of preprotachykinin messenger RNA was restricted to the region of the host striatum where the graft-derived dopamine fibers exhibited their densest distribution (up to 0.5 mm from the border of the grafts). However, following chronic treatment with apomorphine, preprotachykinin messenger RNA expression approached control levels in a wider portion of the grafted striata (up to 1 mm from the border of the grafts). Basal prodynorphin messenger RNA expression, which was also down-regulated in the lesioned striata, was only partially restored by the transplants. Repeated injections of apomorphine enhanced prodynorphin messenger RNA in the lesioned striata to levels several fold higher than normal. This massive increase in prodynorphin messenger RNA expression was completely prevented by the transplants over a large volume of the host striatum (> 1 mm from the graft-host border), but a trend towards an abnormally high prodynorphin messenger RNA expression was still present in peripheral striatal areas that were not reached by graft-derived dopamine fibers. The present results indicate that fetal nigral neurons transplanted to the 6-hydroxydopamine-lesioned striatum have differential effects on the activity of enkephalin-containing (i.e. mainly striatopallidal) and substance P- or dynorphin-containing (i.e. mainly striatonigral) neurons. An inhibitory control over the activity of striatopallidal neurons is completely restored by the grafts, even in non-reinnervated striatal regions, suggesting that neurohumoral mechanisms underlie this effect. A facilitatory control over the activity of striatonigral neurons is restored by the grafts only in the densely reinnervated portion of the host striatum, which indicates that synaptic transmission is likely to mediate this effect. The ability of the grafts to prevent an abnormal up-regulation of prodynorphin messenger RNA expression by apomorphine indicates, however, that graft-derived dopamine release is also sufficient to induce a complete and widespread normalization of dopamine receptor sensitivity on striatonigral neurons.