Genetic and neural circuit mechanisms responsible for the acute to chronic pain transition

Chronic postsurgical pain (CPSP) is a potentially devastating outcome from an otherwise successful surgical procedure. It affects millions of patients every year, with pain lasting for months to years, resulting in patient suffering and economic hardship. Attempts to prevent CPSP have largely been unsuccessful, with no change in the incidence despite increased use of regional and multimodal analgesia. This illustrates that there is much we still don’t understand about what causes the transition from acute to chronic pain and that further research is needed to understand the mechanism of this transition and to identify ways to prevent and treat it. Descending pain facilitatory circuits via cells in the rostroventral medulla have been proposed as a key mechanism in the acute to chronic pain transition. However, it is unclear if this is a defining feature or just one of many mechanisms responsible for central sensitization. We have identified three strains of consomic rats that develop persistent pain-like behaviors following a hind paw incision; both male and female SS-5BN rats, and male but not female SS-6BN and SS-13BN rats. This indicates that genes on Brown Norway (BN) chromosomes 5, 6 and 13 lead to CPSP-like behaviors when substituted into the Dahl salt-sensitive (SS) rat genetic background. We will use these strains to test the hypothesis that a defining feature of the acute to chronic pain transition is the recruitment of pain faciliatory “on” cells in the RVM. Our overall objective is to use these consomic strains to identify and link the effects of gene(s) to ion channel and receptor profiles, and to physiological pathways (descending pain modulation) which result in changes in our behavioral endpoints (mechanical nociceptor thresholds), thus leading to a greater understanding of the mechanisms responsible for the acute to chronic pain transition. This will be accomplished in three projects: Project 1 will test the hypothesis that the recruitment of pain facilitatory rostral ventromedial medulla (RVM) neurons drives the acute to chronic pain transition in SS-5BN, SS-6BN and SS-13BN rats using a Targeted Recombination in Active Populations (TRAP) approach for targeted expression of inhibitory DREADDs in a select subpopulation of RVM neurons; Project 2 will use a cell-based high-content phenotypic- screening platform to elucidate the cell-specific combinations (constellations) of key signaling proteins that define specific cell types. Differences in these profiles between the strains will be used to help identify pathways underlying the pain-like phenotypes exhibited by SS-5BN, SS-6BN and SS-13BN rats; Project 3 will use congenic SS-13BN rats to narrow chromosomal regions to help identify the gene polymorphism(s) responsible for this strain’s CPSP-like behaviors. We expect our studies to provide a better mechanistic understanding of the acute to chronic pain transition and may identify genetic or biochemical biomarkers that will guide future research on the causes of chronic postsurgical pain. Project Number: 1R35GM164170-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Norman Taylor | Institution: UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH, SALT LAKE CITY, UT | Award Amount: $454,300 | Activity Code: R35 | Study Section: Maximizing Investigators' Research Award - D Study Section[MRAD] View on NIH RePORTER: https://reporter.nih.gov/project-details/11329514