Cellular immune mechanisms underlying chronic post-surgical pain in adolescents

About This Grant

SUMMARY Chronic postsurgical pain (CPSP), pain persisting for more than 3 months post-surgery, affects 14.5-38% of children and adolescents in the U.S. undergoing major surgery. CPSP has significant consequences, including depression, disability, opioid misuse and healthcare costs. Preliminary data suggest that immune dysregulation and neuroimmune interactions play a role in CPSP pathogenesis, with proinflammatory cytokines contributing to the chronification of pain while IL-6, IL-8 and IL-13 may have protective effects, with potential for development of management strategies. However, cellular immune mechanisms that underly CPSP are not well understood and lack of a translational immune ex-vivo model presents a critical gap in translational research, hindering prevention and treatment of CPSP. This study aims to elucidate the mechanistic links between immune signatures and sensory neuron excitability in CPSP pathogenesis. This research will leverage banked serum and peripheral blood mononuclear cell samples from pediatric surgical patients and will be the first to employ induced pluripotent stem cell (iPSC)-derived sensory neurons, to model immune- neural interactions in CPSP. This will enable novel investigation of immune-neural interactions involved in CPSP development, integrating experimental, clinical, immunology and neurobiology data through rigorous analyses. The central hypothesis is that serum from CPSP patients is inherently proinflammatory, promoting immune cell dysregulation and sensitizing nociceptive sensory neurons. This hypothesis will be tested by the following specific aims: Aim 1 will examine immune mechanisms contributing to CPSP by comparing in vitro cytokine responses and immune cell differentiation of control peripheral blood mononuclear cells PBMCs exposed to serum from CPSP vs. non-CPSP patients. We will correlate these with in vivo longitudinal immune profiles from surgical subjects. Aim 2 will investigate how CPSP vs. non-CPSP patient serum modulates excitability of ex vivo iPSC-derived sensory neurons. Using calcium imaging, we will assess responses to noxious stimuli in and correlate excitability with experimental (pressure pain threshold) and clinical pain phenotypes. Combining in vivo and in vitro data to elucidate immune-sensory neuron interactions with patient- banked samples offers a unique opportunity to gain insight into cellular models of CPSP, providing a robust, powerful, human-specific platform for linking immune signals to pain mechanisms. Identifying key cytokine and immune cell signatures that differentiate CPSP patients will guide future development of immune-targeted treatments and personalized pain management strategies. This translational study will provide foundational insights into the immune-neural mechanisms of CPSP, enabling the development of predictive biomarkers and novel therapeutic strategies. The proposed research will establish a platform for future R01 studies focused on iPSC-based CPSP modeling and mechanism based therapeutic interventions.