To develop and validate a novel model of central sensitization from peripheral, chronic low-dose lipopolysaccharide (LPS) injections in mice.

Chronic pain is increasingly understood as a central disorder, driven by mechanisms beyond peripheral damage. While the exact mechanism driving chronification is not yet known, central sensitization (CS) is thought to be vital. Literature has previously shown that neuroinflammation and glial cell activation are involved; however, it is unclear whether systemic inflammation from the periphery alone can contribute to CS. Current pain studies often use spinal cord ligation or inflammatory agent injections in the paw. However, we wanted to examine the potential for low-dose, chronic lipopolysaccharide (LPS) injections in the periphery to cause alterations in pain threshold, mimicking CS.

In this proof-of-concept study, 8 young-adult C57BL/6J mice (5 female) were injected intraperitoneally (I.P.) once a week with 0.5 mg/kg of vaccine-grade LPS from Escherichia coli 0111:B4 (n=6) or sterile-grade saline (n=2) for 4 weeks, following an LPS-injection protocol our team has used which demonstrated peripheral LPS induced neutrophil infiltration into the brain. Von Frey mechanical sensitivity testing (VFT) was performed pre-injection and after the second week post-injection. As a preliminary study, we will complete the remaining weeks of injections and subsequent VFT, then harvest the brain for IHC-P to observe glial cell reactivity by morphology.

At the time of abstract submission, two injections were completed. The LPS cohort exhibits a decreased 50% withdrawal threshold (Sidak’s test, p<0.05), whereas no statistically significant difference is observed in the saline group (p>0.05). To the team’s knowledge, no studies have yet demonstrated decreased mechanical sensitivity thresholds following chronic low-dose LPS injections.

This proof-of-concept study suggests that low-dose systemic inflammation may be capable of causing CS-like changes in the central nervous system that are demonstrated as decreased pain thresholds.