PROJECT SUMMARY (Human Tissue Procurement and Processing Core) Despite advances in our understanding of nociception in animal models, pain targets in mice have experienced decades of difficulty in translation to novel effective and safe treatments for patients with chronic pain. The lack of translation between mouse and human pain treatments has highlighted limitations of animal models of pain. Recent advances in applying single-cell genomics and physiology directly to human tissue positions our field to make important new advances in pain biology with improved opportunities for clinical translation. The Human Tissue Procurement and Processing Core will be responsible for obtaining high-quality tissue from post-mortem donors and chronic pain patients with informed consent. The experience of most forms of neuropathic pain begins with abnormal firing of peripheral nociceptors, whose cell bodies are in the dorsal root ganglia or trigeminal ganglia. These ganglia reside outside of the central nervous system and would make ideal pain therapeutic targets if they could be inhibited selectively. We thus propose to extract dorsal root ganglia, trigeminal ganglia and distal sciatic nerve from post-mortem human donors using an established rapid autopsy program at Massachusetts General Hospital. This IRB-approved protocol is already underway and has collected samples from > 25 donors, a selection of which were successfully processed for single-nucleus genomic assays. The Core will build upon these established tissue procurement and processing protocols in collaboration with other U19 Centers. To characterize molecular changes that occur in patients with chronic pain, patients with chronic phantom limb secondary to symptomatic neuromas will have their neuromas procured during muscle reinnervation surgery. This protocol is IRB approved and already enrolling. Fresh and frozen samples will be made available to Center investigators for single-cell genomic assays. The Core will also maintain a tissue bank of deidentified frozen tissues for distribution to Center investigators and investigators across the PRECISION Human Pain Network.