Sex-specific neuroimmune pathophysiological signatures in a mouse model of chronic back pain

Chronic back pain (CBP) affects one in ten people worldwide, limiting mobility, productivity, and quality of life. Current treatments are often inadequate, partly due to an incomplete understanding of their mechanisms. This study explores pathophysiological contributions to CBP at the level of the DRG using the urokinase-type plasminogen activator (uPA) mouse model (uPA-CBP). We observed sustained mechanical hypersensitivity resembling clinical features of CBP in both male and female uPA-CBP mice with notable sex-specific effects on cold and heat sensitivity as well as gait and spontaneous pain behaviors. Whole-cell patch clamp electrophysiological recordings of lumbar DRG from male and female uPA-CBP mice reveal increased excitability compared to sham controls including a higher prevalence of multi- vs. single-firing and spontaneous activity. Analysis of action potential waveform, depolarizing spontaneous fluctuations (DSFs), and intrinsic properties revealed sex-specific differences in uPA-CBP compared to sham mice. Flow cytometry revealed increased CD45+CD11b+ myeloid cells in males and elevated CD45+CD3+CD4+ T cells in females. RNA sequencing identified upregulation of genes involved in immune response as well as sex-specific transcriptomic changes related to immune, glial, and neuronal functions and crosstalk, together suggesting altered DRG neuroimmune interactions in uPA-CBP. These findings highlight sex-specific neuroimmune pathophysiological changes in a model of CBP and uncover new potential targets for the development of analgesics for treatment. PERSPECTIVE: This study highlights sex-specific pathophysiological changes in behavioral profiles in a mouse model of CBP attributed to differential electrophysiological, transcriptomic, and immune cell profiles at the level of the DRG. We uncover new potential targets along the neuroimmune axis for the development of analgesics for treatment of CBP.