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

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

Stacey Anne Gould et al. Exp Neurol. 2021 Apr.

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 (WLD^S), 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 WLD^S or absence of SARM1 protects against acute oxaliplatin-induced pain in mice after a single oxaliplatin injection. In BL/6 and Wld^S 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 Wld^S 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 Wld^S 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.

Keywords: Axon degeneration; Cold hypersensitivity; Mechanical hypersensitivity; Neuropathic pain; Oxaliplatin; SARM1; WLD(S).

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