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. 2025 Aug 5;50(8):675-684.
doi: 10.1136/rapm-2024-105433.

Spinal cord stimulation attenuates paclitaxel-induced gait impairment and mechanical hypersensitivity via peripheral neuroprotective mechanisms in tumor-bearing rats

Ahmed Olalekan Bakare  1 , Kimberly Stephens  2   3 , Karla R Sanchez  1 , Vivian Liu  4 , Lei Zheng  5 , Vasudha Goel  6 , Yun Guan  1   7 , Eellan Sivanesan  8
Affiliations

Spinal cord stimulation attenuates paclitaxel-induced gait impairment and mechanical hypersensitivity via peripheral neuroprotective mechanisms in tumor-bearing rats

Ahmed Olalekan Bakare et al. Reg Anesth Pain Med. .

Abstract

Background: Taxanes such as paclitaxel (PTX) induce dose-dependent chemotherapy-induced peripheral neuropathy (CIPN), which is associated with debilitating chronic pain and gait impairment. Increased macrophage-related proinflammatory activities have been reported to mediate the development and maintenance of neuropathic pain. While spinal cord stimulation (SCS) has been used for a number of pain conditions, the mechanisms supporting its use for CIPN remain to be elucidated. Thus, we aimed to examine whether SCS can attenuate Schwann cell-mediated and macrophage-mediated neuroinflammation in the sciatic nerve of Rowlette Nude (RNU) rats with PTX-induced gait impairment and mechanical hypersensitivity.

Methods: Adult male tumor-bearing RNU rats were used for this study examining PTX treatment and SCS. Gait and mechanical hypersensitivity were assessed weekly. Cytokines, gene expression, macrophage infiltration and polarization, nerve morphology and Schwann cells were examined in sciatic nerves using multiplex immunoassay, bulk RNA sequencing, histochemistry and immunohistochemistry techniques.

Results: SCS (50 Hz, 0.2 milliseconds, 80% motor threshold) attenuated the development of mechanical hypersensitivity (20.93±0.80 vs 12.23±2.71 grams, p<0.0096) and temporal gait impairment [swing (90.41±7.03 vs 117.27±9.71%, p<0.0076), and single stance times (94.92±3.62 vs 112.75±7.27%, p<0.0245)] induced by PTX (SCS+PTX+Tumor vs Sham SCS+PTX+Tumor). SCS also attenuated the reduction in Schwann cells, myelin thickness and increased the concentration of anti-inflammatory cytokine interleukin (IL)-10. Bulk RNA sequencing revealed differential gene expression after SCS, with 607 (59.2%) genes upregulated while 418 (40.8%) genes were downregulated. Notably, genes related to anti-inflammatory cytokines and neuronal growth were upregulated, while genes related to proinflammatory-promoting genes, increased M2γ polarization and decreased macrophage infiltration and Schwann cell loss were downregulated.

Conclusion: SCS may attenuate PTX-induced pain and temporal gait impairment, which may be partly attributed to decreases in Schwann cell loss and macrophage-mediated neuroinflammation in sciatic nerves.

Keywords: cancer pain; neurotoxicity syndromes; pain management; peripheral nerve injuries; spinal cord stimulation.

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Conflict of interest statement

Competing interests: AOB, KES, KRS, VL, VG and ES have no conflicts of interest to declare. LZ receives grant support from Bristol-Meyer Squibb, Merck, Astrazeneca, iTeos, Amgen, NovaRock, Inxmed, and Halozyme. LZ is a paid consultant/Advisory Board Member at Biosion, Alphamab, NovaRock, Ambrx, Akrevia/Xilio, QED, Natera, Novagenesis, Snow Lake Capitals, BioArdis, Amberstone Biosciences, Tempus, Pfizer, Tavotek Lab, ClinicalTrial Options, LLC, and Mingruizhiyao. LZ holds shares at Alphamab, Amberstone, and Mingruizhiyao. YG receives research funding from Medtronic, Inc and TissueTech, Inc.

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