This program project grant is designed to develop new modalities of treatment and new mechanisms for the relief from pain and addiction. During the first 2 years of this Program Project the P.I.'s have discovered several new classes of opioid ligands that strongly suggest several new possibilities for obtaining non-addictive opioid analgesics, and possibly new modalities for the treatment of those already addicted who wish to withdraw from addiction. In this section of the grant we have successfully shown that halogenation substitution can dramatically alter the level of peptide drug accumulated in the brain and also affects the peripheral analgesic potency. We have also described in vivo regional distribution of peptide drugs in the brain after i.v. administration and developed a new pro-drug concept for DPDPE. Coupled to our success with determining the optimal route delivering the delta ligand DPDPE to the CNS we are now in the position to address several new hypotheses as follows: 1. Structural lipophilic and hydrogen bonding alterations/modifications in delta selective ligands will lead to improvements in regional brain (CNS) accumulation. 2. Pro-drugs can be used to enhance peptide drug delivery to specific tissue depots (i.e. small intestine versus CNS). 3. In Vitro bovine brain endothelial cell assays can help predict in vivo blood brain barrier penetration. 4. There is a peptide drug structure dependency to the specific route of peripheral drug administration. Our main Specific Aim is to use our extensive research experience in chemical and biological assay development coupled to our past two years of success in describing peptide drug absorption, distribution, metabolism and excretion (ADME) and apply it to new lipophilic and pro-drug peptide ligands. By using both in vivo brain distribution coupled to the in vitro bovine brain endothelial cell model we will also be able to determine the specific peptide drug structural requirements for optimal BBB penetration. Since we have successfully shown that certain modifications to stable peptide analogues alter CNS accumulation we are confident that we can continue to use our integrated, analytical, enzymatic, metabolic, distribution and stability techniques to determine the most optimal peptide drug structure for clinical application.