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Reissue of RFA-NS-20-010: The purpose of this funding opportunity announcement (FOA) 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 small molecule and biologic hits/leads towards clinical trials. Applicants must have a promising hit/lead, 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, and assembly of Investigational New Drug (IND) application. 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.