Enkephalin (ENK) and Dynorphin (DYN) are opioid peptides present in neurons of various brain regions including the striatum. Some of these neurons are controlled by dopamine D1 and D2 receptors. Studies have been performed to explore how these neurons are expressed developmentally, and to investigate the effects of cocaine on the expression of these peptides in the fetal monkey brain. Eighteen-day pregnant monkeys were treated with 3 mg/kg cocaine or physiological saline, 4x/day until days 60 or 70 of pregnancy. Fetal brains were dissected into 6 or 7 regions. In day 60 control fetuses (n=3) all brain regions showed approximately equal amounts of DYN mRNA. By day 70, DYN gene expression was significantly increased particularly in the striatal block and the diencephalon. ENK gene expression was higher than DYN in all brain regions in both days 60 and 70 fetal monkeys. Moreover, in the day 70 fetuses, ENK mRNA was also expressed in the prefrontal cortex (PFC). In the day 60 fetal monkeys, chronic cocaine treatment caused a significant increase in the mRNA expression of both DYN and ENK in the rostral forebrain tissue block. By day 70, fetal brain DYN mRNA was significantly increased in the striatal tissue block and significantly decreased in the midbrain block of cocaine-treated fetuses. Cocaine treatment had the most significant effect on ENK gene expression in the day 70 fetal monkeys (n=3, each group). At this time in gestation, ENK mRNA levels were significantly increased both in the most rostral tissue block (PFC) and in the striatal area of cocaine-treated fetal monkeys, and significantly decreased in the midbrain region . These results suggest that the development of opioid neurons may be critical during the day 45-70 stage, and that prolonged exposure to cocaine can alter gene expression of developing opioid neurons.