DESCRIPTION: Chronic pain is a critical limiting factor that delays rehabilitation after injury. Since currently available treatments are inadequate, the development of new therapeutics is a national healthcare priority. Years of animal experimentation have generated a multitude of mechanistic observations that explain the initiation and continuation of pain at a cellular and molecular level but new therapies have not emerged from this effort. Two key limitations are the nonspecific effects of typical small molecule drugs, and the inability to limit dangerous side effects caused by off-target actions when agents are delivered systemically. We have devised a solution that employs recombinant adeno-associated viral (AAV) vectors to express small analgesic peptides (called peptide aptamers) in sensory neurons following injection of the vector into the dorsal root ganglion (DRG). Substantial data show that injection at the level of the DRG is safe in animals and humans. This approach also employs only minute doses of agent, and restricts effects to the targeted peripheral sensory neurons of that segment. The peptide aptamers are designed to interfere with assembly, trafficking, or function of critical molecular targets that regulate peripheral sensory transduction and dorsal horn (DH) synaptic function, resulting in highly selective peripheral modulation of sensory neuron performance. This final feature is critical since genesis and perpetuation of chronic pain clearly involves plasticity in peripheral receptors and DH pain- transmitting synapses. The overall objective of this project is to define a novel strategy, AAV-delivered analgesic peptide aptamers, for modulating intracellular protein interactions of specific nociceptive pathways selectively in primary sensory neurons, and to test the efficacy of this approach as a molecular therapeutic tool for treating chronic pain. The proposed studies will test proof-of-concept on modulation of two critical pain signaling nodes, the N-type Ca2+ channel (CaV2.2) and the Transient Receptor Potential Vanilloid 1 (TRPV1) channel. Successful completion of the proposed research will set the stage for development of an entirely novel and functionally potent mode of segmental chronic pain therapy, and thereby convert the vast backlog of mechanistic discovery into practical treatments.