Pain is a sensation realized by every individual at some point in his or her lives. Different causes of pain result in treatment by administration of drugs ranging from aspirin to morphine as the current standard of care. Morphine targets the opioid receptors as its “on-target” mechanism of action. Unfortunately, prolonged treatment of pain with morphine causes many adverse effects such as addiction, tolerance, nausea, sedation, respiratory depression, constipation, and others. Thus, understanding the different mechanisms for pain perception, discovery of new molecular targets to treat pain with minimal undesired side effects, and the discovery and development of new therapeutic agents for the alleviation of pain is an on going effort by the scientific community world- wide. The goal of this research project is to characterize the unexplored human opioid receptor N-terminal domain peptides as a new chemotype for the treatment of pain and how they modulate opioid receptor pharmacology. The impact of the anticipated results on the medicinal chemistry and pain research fields could advance the existing paradigms for ligand design strategies for opioid peptide based therapeutics, GPCR based therapeutics, as well as provide novel tools to probe the molecular mechanisms of pain management.