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Protection against oxaliplatin-induced mechanical and thermal hypersensitivity in Sarm1−/− mice

Research output: Contribution to journalArticlepeer-review

Stacey Anne Gould, Matthew White, Anna L. Wilbrey, Erzsébet Pór, Michael Philip Coleman, Robert Adalbert

Original languageEnglish
Article number113607
JournalExperimental Neurology
Volume338
DOIs
PublishedApr 2021

Bibliographical note

Funding Information: This work was supported by the United Kingdom Medical Research Council project grant ( MR/L003813/1 ); Biotechnology and Biological Sciences Research Council Institute Strategic Programme Grant ; and the John and Lucille van Geest Foundation . Publisher Copyright: © 2021 The Author(s) Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

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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.

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