Neuroimmune mechanisms of a mouse model of chronic back pain

Goins, A. E.; Zurek, N. A.; Holguin, C.; Gravelle, A.; Goyal, S.; Noor, S.; Demeter, J. B.; Koch, M. R.; de la Pena, J. B.; Westlund, K. N.; Alles, S. R. A.

doi:10.1101/2024.12.13.628454

bioRxiv · 10.1101/2024.12.13.628454

Neuroimmune mechanisms of a mouse model of chronic back pain

Goins, A. E.·Zurek, N. A.·Holguin, C.·Gravelle, A.·Goyal, S.·Noor, S.·Demeter, J. B.·Koch, M. R.·de la Pena, J. B.·Westlund, K. N.·Alles, S. R. A.

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Abstract

Chronic back pain (CBP) is the leading cause of disability affecting 1 in 10 people worldwide. Symptoms are marked by persistent lower back pain, reduced mobility, and heightened cold sensitivity. Here, we utilize a mouse model of CBP induced by injecting urokinase-type plasminogen activator (uPA), a proinflammatory agent in the fibrinolytic pathway, between the L2/L3 lumbar vertebrae. We identified neuroimmune interactions contributing to uPA-induced CBP (henceforth, uPA-CBP) in mouse dorsal root ganglia (DRG), where nociceptive neurons reside. Flow cytometric data reveal that uPA-CBP increases CD45+CD11b+ cells in the DRG, a population characteristically implicated in other chronic pain models1. Blocking colony stimulating factor 1 receptor (CSF1R) signaling using PLX5622 partially reduced pain, suggesting CD45+CD11b+ macrophage involvement. Whole-cell patch-clamp electrophysiology data indicated DRG neuron hyperexcitability in CBP mice compared to controls. RNA sequencing revealed upregulation of pain- and inflammation-related genes involved in leukocyte migration. Together, these findings underscore the importance of the DRG neuroimmune axis in mediating chronic back pain. HighlightsO_LIuPA-CBP induces gait changes, mechanical and thermal sensitivity compared to shams C_LIO_LIuPA-CBP mice show increased CD45+CD11b+ cells in DRG compared to shams C_LIO_LIuPA-CBP mice show neuronal excitability in DRG neurons compared to shams C_LIO_LIPain behaviors are alleviated by pharmacologically blocking CSF1R signaling C_LIO_LIDysregulation of inflammation- and ion channel-related genes in uPA-CBP DRG C_LI

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Goins, A. E., Zurek, N. A., Holguin, C., Gravelle, A., Goyal, S., Noor, S., Demeter, J. B., Koch, M. R., de la Pena, J. B., Westlund, K. N., Alles, S. R. A.. 2024-12-17. Neuroimmune mechanisms of a mouse model of chronic back pain. https://doi.org/10.1101/2024.12.13.628454

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