Previously, we have shown that intracisternal (i.c.) administration of beta-endorphin suppresses brain and liver DNA synthesis in rat pups. This finding is consistent with the view that endogenous CNS beta-endorphin plays an important role in controlling postnatal growth. Recent evidence suggests that brain CCK8, the sulfated carboxyterminal octapeptide fragment of cholecystokinin, may function physiologically as an endogenous opioid antagonist. We now report that CCK8 injected i.c. together with beta-endorphin effectively prevented beta-endorphin from inhibiting brain and liver DNA synthesis in 10-day-old rats. CCK8 blocked the liver DNA effect of beta-endorphin via actions within the brain, as subcutaneous administration of CCK8 was ineffective. In contrast to CCK8, i.c. administration of CCK8U (the unsulfated form of CCK8) together with beta-endorphin did not prevent beta-endorphin from inhibiting liver DNA synthesis, and only slightly reversed the brain DNA effect. The results obtained support a role for endogenous brain CCK8 in the modulation of tissue DNA responses to CNS beta-endorphin and possibly to other endogenous opioids. If so, interference with brain CCK function could disrupt tissue growth. Thus, normal mammalian development may require a close functional interaction between the cholecystokinin and beta-endorphin systems in the brain.