MRL-LPR MICE DISPLAY ALTERED NOCICEPTION: A POSSIBLE MODEL FOR LUPUS PERIPHERAL NEUROPATHY

PV015 / #269 Poster Topic: AS02 - Animal Models Background/Purpose Affective disorders and cognitive abnormalities, as well as other neuropsychiatric SLE (NPSLE) manifestations, occur in 20-40% of lupus patients. Of the 19 ACR case definitions for NPSLE, 7 involve the peripheral nervous system. Treatment options for patients with NPSLE remain limited, nonspecific, and mostly non-evidenced based. Furthermore, many patients do not respond to treatment, and face significant neuropsychiatric disability. Our understanding of NPSLE is unfortunately not as advanced as for other lupus manifestations, hampered by the difficulty in obtaining human brain tissue. Therefore, animal models have added importance in investigating disease mechanisms and identifying novel therapeutic targets, especially for manifestations of disease shared between animal models and human SLE. MRL-lpr mice spontaneously develop high-titer anti-DNA and other nuclear autoantibodies, proliferative glomerulonephritis, and inflammatory skin disease, as well as depressive-like behavior and cognitive abnormalities at a young age.[1] However, while peripheral neuropathy is common in human lupus patients, whether MRL/lpr mice display peripheral nervous system disease has not been carefully studied. Our goal was to determine if MRL/lpr mice display altered nociception, and could potentially be used to model lupus-associated peripheral neuropathy. Methods A previous study by Yan et al[2] demonstrated that female MRL/lpr mice exhibit thermal hyperalgesia and mechanical allodynia. Thermal sensitivity was measured based upon the withdrawal response of the hind paws to increased temperature generated by a radiant heat beam device. Hyperalgesia was demonstrated in 13-week-old animals, but withdrawal latencies did not change between 10 and 12 weeks and were similar to those in control mice. To better evaluate altered sensory function and develop an assay to easily monitor the effects of potential therapeutic interventions, we enhanced the standard testing protocol by incrementally raising the temperature from 40 to 52 °C within a 180-second time frame. The test focuses on observing paw licking, which signifies the behavioral reaction to the thermal stimulus. This careful modulation allowed us to accurately record the latency, or response time, for the mice to lick their fore and hind paws. Results We compared female MRL/lpr mice to age and sex-matched control mice from the background MRL strain (separate cohorts of 8-12 week old mice). We found that already at 8 weeks of age, MRL/lpr mice exhibit a notable increase in thermal hyperalgesia (ie, decreased latency until withdrawal) (102±4.02 seconds, n=8) compared to the control MRL strain (126±2.34, n=7), a significant difference in the mean latencies of hind paw licking responses between the 2 experimental groups (p=0.02, Wilcoxon signed-rank test). Similar thermal hyperalgesia responses were observed in the MRL/lpr strain also at 10 and 12 weeks. Ongoing studies are focused on identifying the earliest detectable heightened sensitivity, and exploring how standard treatment with cyclophosphamide and other immunosuppressives influences the nociceptive response in this lupus-prone strain. Conclusions MRL-lpr mice display heightened temperature sensitivity. Altered nociception in this strain may represent an early and sensitive tool to detect NPSLE, and if confirmed, may serve to model the involvement of the peripheral nervous system in this disease. References: [1.] Polis B. Autoimmunity 2024;57(1):2330387. [2.] Yan X. J Neurochem 2017;140(6):963-76.