Background/Purpose: Of the 19 ACR case definitions for NPSLE, seven involve the peripheral nervous system. MRL/lpr mice spontaneously develop anti-dsDNA antibodies, nephritis, and skin disease, as well as depressive-like behavior and cognitive abnormalities (Polis B, Autoimmunity, 57,2024). However, while peripheral neuropathy is common in human lupus (Florica B, Sem Arth Rheum, 203,2011), whether MRL/lpr mice display peripheral nervous system disease has not been carefully studied.

Methods: To better evaluate sensory function and develop an assay to easily monitor the effects of therapeutic interventions, we enhanced traditional rodent nociception testing by incrementally raising the temperature from 40 to 52°C within 180 seconds. The test focuses on 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 animals to lick their fore- and hind paws. Female MRL/lpr, and age and sex matched congenic control MRL mice, were tested at 6, 8, and 12 weeks of age.Rota-Rod testing was performed using Stanford’s laboratory protocol. Time to fall and speed at fall were both measured for analysis. Female MRL/lpr and age and sex matched congenic control MRL mice were tested at 15 weeks of age. A standard open field test was done where the animals were left to explore the field for 5 minutes in minimum abrasive conditions. The total time spent in the center zone and the total distance traveled by each mouse were measured. Female MRL/lpr and age and sex matched congenic control MRL mice were tested at 15 weeks of age.

Results: Nociception: We found that already at 6 weeks of age, while there is no difference in anti-dsDNA antibody levels or other characteristic clinical or serologic signs of disease activity, MRL/lpr mice exhibited a notable increase in thermal hyperalgesia, as seen by a decreased mean latency until hind paw-licking responses (withdrawal): 82.69+/-15.03 seconds (n=13) compared to the control MRL strain 122+/-15.15 (n=9) (Figure 1) (p < 0.0001, Unpaired t-test). Similar thermal hyperalgesia responses were observed in MRL/lpr mice also at 8-9 weeks (p < 0.0001, Figure 1), and 12 weeks of age (data not shown). Similar testing using a cold plate approach is in process.Rota-rod: No significant differences were observed in the time to fall/speed at fall between the MRL/lpr mice (n=6) and the MRL strain (n=7)(Figure 2), a finding not supporting a difference in proprioception between these strains.Open Field: MRL/lpr showed a significant decrease in total distance traveled in the open field (1348+/-140.1, n=7) compared to the MRL strain (1995+/-263.3, n=7 (p < 0.0001, Unpaired t test), a result not supporting locomotor hyperactivity in the MRL/lpr strain. There was no significant difference observed in the cumulative time spent in the center zone (Figure 3).

Conclusion: MRL/lpr mice display significantly heightened temperature sensitivity already at 6 weeks of age, before many other disease manifestations are evident. Altered nociception may represent an early and sensitive tool to detect peripheral neuronal involvement in this strain, and if confirmed may serve to model the involvement of the peripheral nervous system in SLE.

Figure 1: Top: Hindpaw licking latency at 6 weeks of age. Bottom: Hindpaw licking latency at 8-9 weeks of age. LPRF, female MRL/lpr mice; MPJF, female MRL/+ mice.

Figure 2: Top: Time in seconds until the mouse fell off the apparatus. Bottom: Speed recorded at the time of the fall. MPJ and LPR, female MRL/+ and MRL/lpr mice at 15 weeks of age, respectively.

Figure 3: Bottom: Cumulative time spent in center zone shown in %. Top: Total distance traveled in cm. LPR and MPJ, female MRL/lpr and MRL/+ mice at 15 weeks of age, respectively.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/mrl-lpr-mice-display-altered-nociception-a-new-model-for-lupus-peripheral-neuropathy/