The purpose of this notice of funding opportunity (NOFO) is to support preclinical optimization and development of safe, effective, and non-addictive small molecule and biologic therapeutics to treat pain. The goal of the program is to accelerate the optimization and development of promising early therapeutic molecules and to facilitate readiness for the Early Phase Pain Investigation Clinical Network (EPPIC-Net) or other Phase II clinical studies. Applicants must have a promising biologic or small molecule starting point for optimization, robust biological rationale for the intended approach, and identified assays for optimization of the agent. The scope of this program includes optimization and early development activities, IND-enabling studies, development of a pharmacodynamic/target engagement biomarker, assembly and filing of an Investigational New Drug (IND) application and Phase I clinical testing. This is a milestone-driven phased cooperative agreement program involving participation of NIH program staff in the development of the project plan and monitoring of research progress.