Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting side effect of cancer treatment, often associated with degeneration of sensory axons or their terminal regions. Presence of the slow Wallerian degeneration protein (WLDS), or genetic deletion of sterile alpha and TIR motif containing protein 1 (SARM1), which strongly protect axons from degeneration after injury or axonal transport block, alleviate pain in several CIPN models. However, oxaliplatin can cause an acute pain response, suggesting a different mechanism of pain generation. Here, we tested whether the presence of WLDS or absence of SARM1 protects against acute oxaliplatin-induced pain in mice after a single oxaliplatin injection. In BL/6 and WldS mice, oxaliplatin induced significant mechanical and cold hypersensitivities which were absent in Sarm1−/− mice. Despite the presence of hypersensitivity there was no significant loss of intraepidermal nerve fibers (IENFs) in the footpads of any mice after oxaliplatin treatment, suggesting that early stages of pain hypersensitivity could be independent of axon degeneration. To identify other changes that could underlie the pain response, RNA sequencing was carried out in DRGs from treated and control mice of each genotype. Sarm1−/− mice had fewer gene expression changes than either BL/6 or WldS mice. This is consistent with the pain measurements in demonstrating that Sarm1−/− DRGs remain relatively unchanged after oxaliplatin treatment, unlike those in BL/6 and WldS mice. Changes in levels of four transcripts – Alas2, Hba-a1, Hba-a2, and Tfrc – correlated with oxaliplatin-induced pain, or absence thereof, across the three genotypes. Our findings suggest that targeting SARM1 could be a viable therapeutic approach to prevent oxaliplatin-induced acute neuropathic pain.
Highlights
Ongoing pain caused by chemotherapy-induced peripheral neurop athy (CIPN) worsens quality of life of in patients undergoing chemo therapy (Farquhar-smith, 2016)
This type of programmed axon death occurs after acute injury
Sarm1 deletion blocks the development of mechanical hypersensitivity following acute oxaliplatin treatment
Summary
Ongoing pain caused by chemotherapy-induced peripheral neurop athy (CIPN) worsens quality of life of in patients undergoing chemo therapy (Farquhar-smith, 2016). Studies in patients and animal models implicate axonal degeneration as a common process in CIPN pathology (Fukuda et al, 2017), where chemotherapeutic drugs directly or indirectly trigger a “dying back” axon degeneration that progresses in a distal-to-proximal manner. This type of programmed axon death occurs after acute injury
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