ABSTRACT Diabetes affects 25.8 million people in the USA. Neuropathic pain is a debilitating affliction present in 26% of diabetic patients, with substantial impact on the quality of life. Despite this significant impact and prevalence, current therapies for neuropathic pain are only partially effective and the molecular mechanisms underlying neuropathic pain in diabetes are not well understood. Our long-term goal is to elucidate the molecular mechanisms responsible for PDN in order to provide targets for the development of therapeutic agents for the effective treatment of this syndrome. The objective of this application is to identify the molecular cascade linking CXCR4/SDF-1 chemokine signaling to DRG nociceptor hyper-excitability, neuropathic pain, and small fiber degeneration. The study will achieve the following specific aims. Aim 1: Determine the ion-channel current profile of the nociceptor hyper-excitable state produced by CXCR4/SDF-1 signaling in PDN. Aim 2. Determine the gene expression profile of the nociceptor hyper-excitable state produced by CXCR4/SDF-1 signaling in PDN. Aim 3. Determine the specific features of nociceptor mitochondrial dysfunction produced by CXCR4/SDF-1 signaling in PDN. The overall impact of this proposal is a better understanding of the molecular underpinnings of neuropathic pain and small fiber degeneration associated with diabetes. Furthermore, the proposed research will have a positive impact by identifying unique molecular targets for mechanism-based therapeutic development in PDN.