Neuroimmune Mechanisms of a Model of Chronic Back Pain in Mice and Humans

Chronic back pain (CBP) is one of the most common causes of disability with 1 in 5 people suffering worldwide. Our studies employ an innovative animal model of CBP induced by injection of urokinase-type plasminogen activator (uPa) along the ligamentous insertion region of the lumbar spine. The inflammatory agent, urokinase, is a serine protease that activates plasminogen to plasmin. Typically, the model can be induced within 10 minutes and hypersensitivity persists for 8-10 weeks. Hypersensitivity, gait disturbance, anxiety- and depression-like measures are observed in this CBP model. Here we examined neuroimmune interactions in the spinal cord and DRG from CBP compared to controls. We used flow cytometry analysis of fresh spinal cord and DRG from CBP mice. In the DRG, we observed an increase in CD45+ cells in male and female mice compared to controls. Sex differences in CBP mice DRG were observed compared to controls: males had a greater percentage of CD11b+ cells (myeloid/monocytes) than females. Tissues were also analyzed by qPCR. We obtained whole-cell electrophysiology recordings of DRG neurons from CBP and control mice. Additionally, we obtained recordings of naïve DRG neurons following application of uPA to determine cell-type specific actions. To bridge the translational gap, we also studied human DRG neurons (hDRG) obtained from ethically consented donor tissue. We applied uPA to hDRG and analyzed mRNA expression of injury or pain-associated markers such as ATF3, CCK-B or P2X4 receptor. These studies provide insights into the neuroimmune mechanisms of a model of CBP in mice and humans.