The long-term goal of this research is to elucidate the role that CNS opioid peptides and opioid receptors play in the regulation of postnatal growth and neurobehavioral development. We have identified, in the developing rat, important growth-regulating events that are suppressed by central administration of beta-endorphin-(1-31) (BE; an opioid peptide naturally synthesized in the brain and pituitary), including ornithine decarboxylase activity (ODC; a growth-controlling enzyme), DNA synthesis (an index of cell replication), and insulin metabolism/function (a trophic hormone necessary for normal perinatal maturation). BE biochemical/endocrine effects are age specific in that they are only observed in preweanling rats. These observations suggest that endogenous CNS BE may function to modulate growth via inhibitory actions on these trophic parameters. The evidence obtained supports our original hypothesis that BE, synthesized in the brain, may play a prime role in controlling postnatal development. We propose to carefully characterize the nature of BE's influences on ODC activity and DNA synthesis. Only through detailed examination of the molecular, biochemical, endocrine and neural mechanisms involved in BE's actions can its role in development be better understood.
The specific aims are: 1. To establish whether centrally-administered BE changes brain and liver ODC activity by altering the kinetic properties of ODC (Vmax/Km), and if so, to assess whether the changes reflect alterations in the intracellular levels of ODC inhibitors/activators or ODC mRNA. 2. To identify, in the brain, the specific opioid receptor types through which BE acts to influence ODC/DNA both central and peripheral tissues. By using highly selective opioid receptor antagonist/agonists we will determine the relative participation of mu, delta and epsilon receptors in BE's effects. 3. To test the hypothesis that CCK-8 (a cholecystokinin fragment naturally formed in the brain, thought to act physiologically as an endogenous """"""""antiopioid"""""""") is able to inhibit ODC/DNA effects of BE. In addition, we will use highly potent and selective antagonists of the recently identified brain cholecystokinin receptor subtypes CCK-A and CCK-B to define the roles these receptors play in ODC/DNA effects of CCK-8. If CCK-8 antagonizes BE :actions, it would be an exciting finding as it would suggest that CNS opioid and antiopioid systems interact and balance each other to promote normal development. 4. To ascertain whether the effects of centrally-administered BE on ODC/DNA in peripheral tissues are mediated by pituitary hormones, by the autonomic nervous system or by descending neuronal pathways in the spinal cord. The results from these studies should help to establish a definitive role for CNS BE in the regulation of postnatal development. The new knowledge may be fundamentally important for understanding normal and addictive physiology/endocrinology. It could also prove very useful in designing therapeutic agents of clinical benefit associated with developmental alterations resulting from disturbances of the body's natural opioid peptides or from maternal opiate abuse.
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