Inhibition of SARM1 Reduces Neuropathic Pain in a Spared Nerve Injury Rodent Model

Introduction/Aims: The function of the sterile alpha and toll/interleukin receptor motif-containing protein 1 (SARM1) in neuropathic pain development has not yet been established. This protein has a central role in regulating axon degeneration and its depletion delays this process. This study aims to demonstrate the effects of SARM1 deletion on the development of neuropathic pain. Methods: Thirty-two wild-type (WT) or SARM1 knockout (KO) rats underwent spared nerve injury (SNI) or sham surgery. Mechanical allodynia was assessed by electronic Von Frey and cold hyperalgesia by the acetone test. Nociception was evaluated at the baseline, Day-1, Day-2, Week-1, Week-2, Week-3, and Week-4 time points. Nerve sections were examined by immunohistochemistry (IHC). Results: WT Injury rats were more sensitive to pain than WT Sham at all postoperative time points, validating the pain model. Injured SARM1 KO rats only demonstrated a difference in mechanical or cold nociception from KO Sham at Week 3. Injured KO rats demonstrated a clear trend of decreased sensitivity compared to WT Injury nociception, reaching significance at Week 4 (p = 0.044). Injured KO rats showed attenuated sensitivity to cold allodynia relative to WT at Week 2 (p = 0.019). IHC revealed decreased macrophages in spared sural nerves of injured KO animals at 2 and 4 weeks, and the proximal portion of tibial/peroneal nerves at Week 2. Discussion: This study demonstrates that SARM1 KO rats are less sensitive to mechanical and cold nociception than WT rats in an SNI model with decreased inflammatory response. Given these results, inhibition of SARM1 should be further investigated in the treatment of neuropathic pain.