Inadequate treatment of pain is an important and urgent problem, which needs to be addressed. Although opioids are still the drugs of choice for the treatment of severe pain, they are generally accompanied by undesired secondary effects like tolerance and dependence. Several pharmacological studies have suggested the role of substance P, in pain transmission. It has been observed that co-administration of neurokinin-1 receptor antagonists and morphine augmented the acute effects of morphine and also prevented morphine tolerance. In addition there are also reports that genetically modified mice lacking the NK-1 receptors do not develop tolerance to morphine. We are designing and synthesizing novel chimeric peptides that act as agonists at mu/delta opioid receptors and as antagonists at NK-1 receptors. Chimeras will include structures with prearranged opioid ligand agonist pharmacophore motifs with adjacent substance P antagonist pharmacophores. In this present study we have synthesized a series of chimeric bifunctional peptides, acting as agonists at the opioid receptors and antagonists at the neurokinin-1 receptors. Most of these peptides show excellent biological activities in vitro. Preliminary in vivo studies show them to be active in the neuropathic pain model. Results from binding assays, functional assays and SAR studies will be presented. Tyr-DAla-Gly-Phe-Gly-TrpOBn(CF₃)₂; Tyr-DAla-Gly-Phe-Ala-TrpOBn(CF₃)₂;Tyr-Pro-Trp-Phe-Gly-TrpOBn(CF₃)₂. Supported by grants from the U.S Public Health Service and from National Institute on Drug Abuse.