Striatal expression of preproenkephalin and preprotachykinin messenger RNA was studied in normal controls and in patients with Parkinson's disease using in situ hybridization histochemistry. In controls, preproenkephalin messenger RNA was expressed in a population of medium-sized neurons of mean cross-sectional area 165 microns 2, accounting for 66% of striatal medium-sized neurons, whereas preprotachykinin messenger RNA was expressed in a population of medium-sized neurons of mean cross-sectional area 204 microns 2 (23% larger than those expressing enkephalin, P < 0.05), accounting for 58% of medium-sized striatal neurons. Much lower levels of both preproenkephalin messenger RNA and preprotachykinin messenger RNA were expressed by large neurons in the globus pallidus and substantia nigra reticulata. In addition, preproenkephalin messenger RNA was expressed at low levels by neurons in the subthalamic nucleus. In Parkinson's disease cases, there was a statistically significant increase in preproenkephalin messenger RNA expression in the body of the caudate (109% increase, P < 0.05) and in the intermediolateral putamen (55% increase, P < 0.05) due to an increase in the level of gene expression per neuron rather than an increase in the number of neurons expressing preproenkephalin messenger RNA. Similar increases were observed in other putaminal subregions and in the putamen as a whole, but these did not reach statistical significance. No change in preprotachykinin messenger RNA expression was detected. These findings demonstrate selective up-regulation of a striatal neuropeptide system in Parkinson's disease compatible with increased activity of the "indirect" striatopallidal pathway, which is thought to play a crucial role in the pathophysiology of akinesia and rigidity in this condition.