Interest in development of therapeutics targeting brain neuropeptide systems for treatment of cocaine addiction (e.g., kappa opioid agonists) is based on animal data showing interactions between the neuropeptides, brain dopamine, and cocaine. In this autopsied brain study, our major objective was to establish by radioimmunoassay whether levels of dynorphin and other neuropeptides (e.g., metenkephalin, neurotensin and substance P) are increased in the dopamine-rich caudate, putamen, and nucleus accumbens of human chronic cocaine users (n=12) vs. matched control subjects (n=17) as predicted by animal findings. Changes were limited to markedly increased dynorphin immunoreactivity in caudate (+92%), decreased caudate neurotensin (-49%), and a trend for increased dynorphin (+75%) in putamen. In other examined subcortical/cerebral cortical areas dynorphin levels were normal with the striking exception of the ventral pallidum (+346%), whereas cerebral cortical metenkephalin levels were generally decreased and neurotensin variably changed. Our finding that, in contradistinction to animal data, the other striatal neuropeptides were not increased in human cocaine users could be explained by differences in pattern and contingency between human drug users and the animal models. However, the human dynorphin observations parallel well animal findings and suggest that the dynorphin system is upregulated, manifested as elevated neuropeptide levels, after chronic drug exposure in striatum and ventral pallidum. Our postmortem brain data suggest involvement of striatal dynorphin systems in human cocaine users and should add to the interest in the testing of new dynorphin-related therapeutics for the treatment of cocaine addiction.