Inhibition of SARM-1 Reduces Neuropathic Pain in a Spared Nerve Injury Rodent Model
Christopher G Herbosa, BS1, Ronald Perez, BS1, Daniel A Hunter, RA2, Christopher J Dy, MD MPH, FACS1 and David M Brogan, MD, MSc1, 1Washington University School of Medicine, St. Louis, MO, 2Department of Surgery, Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, Saint Louis, MO
Introduction: The SARM-1 protein has been shown to play an essential role in regulating axonal degeneration and its depletion halts this destructive process. Because Wallerian degeneration may contribute to the development of neuropathic pain, we hypothesize that loss of SARM-1 function will decrease neuropathic pain in a spared nerve injury model.
Materials & Methods: Thirty-two wild type (WT) or SARM-1 knockout (KO) rats underwent spared nerve injury (SNI) with peroneal and tibial nerve ligation and transection or sham surgery with no nerve injury (eight per group). Neuropathic pain was assessed using an electronic Von Frey aesthesiometer applied to the sural nerve distribution of injured and uninjured paws and the required force to stimulate withdrawal was recorded in grams. Nociception was evaluated at baseline and after surgery at predetermined timepoints (day-1, day-3, week-1, week-2, week-3, and week-4). A separate acetone test to detect cold allodynia was also completed. Nerve samples were qualitatively examined by light microscopy. Results were analyzed by one-way ANOVA followed by Tukey honesty significant difference tests for multiple comparisons.
Results: Injured SARM-1 KO rats demonstrated a clear trend of more reduced sensitivity to nociceptive stimulation in a neuropathic pain model than the WT Injury cohort, which reached significance at week-4 (13.0±6.0 vs. 27.5±11.5, p=0.044) (Figure 1A). Injured SARM-1 KO rats also showed less sensitivity to cold allodynia than WT Injury rats at week-2 and week-4 (p=0.002, p=0.002) (Figure 1B). WT Injury rats demonstrated greater sensitivity to pain than WT Sham at all timepoints (day-1, day-3, week-1, week-2, week-3, and week-4), validating the pain model (p=0.028, 0.002, 0.005, <0.001, 0.002, <0.001) (Figure 1A). WT injury rats similarly showed greater reactivity to cold allodynia than WT sham at day-3, week-2, week-3, and week-4 (p=0.021, 0.003, 0.006, <0.001) (Figure 1B). However, KO Injury rats demonstrated no difference in pain or cold sensitivity compared to the sham cohorts at any timepoint. Light microscopy suggests reduced demyelination in KO rats compared to WT at site of nerve injury (Figures 2A, 2B).
Conclusions: This experiment demonstrates that SARM-1 KO rats are less sensitive to nociception and cold allodynia than WT rats following SNI. Our results suggest that reduced axonal degeneration in the SARM1 KO genotype may lessen the severity of neuropathic pain.
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