Spinal cord stimulation prevents paclitaxel-induced mechanical and cold hypersensitivity and modulates spinal gene expression in rats

Eellan Sivanesan; Kimberly E Stephens; Qian Huang; Zhiyong Chen; Neil C Ford; Wanru Duan; Shao-Qui He; Xinyan Gao; Bengt Linderoth; Srinivasa N Raja; Yun Guan

doi:10.1097/PR9.0000000000000785

Spinal cord stimulation prevents paclitaxel-induced mechanical and cold hypersensitivity and modulates spinal gene expression in rats

Pain Rep. 2019 Sep 12;4(5):e785. doi: 10.1097/PR9.0000000000000785. eCollection 2019 Sep-Oct.

Authors

Eellan Sivanesan¹, Kimberly E Stephens^{1

2

3}, Qian Huang¹, Zhiyong Chen¹, Neil C Ford¹, Wanru Duan¹, Shao-Qui He¹, Xinyan Gao¹, Bengt Linderoth⁴, Srinivasa N Raja¹, Yun Guan^{1

5}

Affiliations

¹ Department of Anesthesiology and Critical Care Medicine, School of Medicine, The Johns Hopkins University, Baltimore, MD, USA.
² Department of Pharmacology and Molecular Sciences, School of Medicine, The Johns Hopkins University, Baltimore, MD, USA.
³ Center for Epigenetics, School of Medicine, The Johns Hopkins University, Baltimore, MD, USA.
⁴ Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
⁵ Department of Neurological Surgery, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.

Abstract

Introduction: Paclitaxel-induced peripheral neuropathy (PIPN) is a common dose-limiting side effect of this cancer treatment drug. Spinal cord stimulation (SCS) has demonstrated efficacy for attenuating some neuropathic pain conditions.

Objective: We aim to examine the inhibitory effect of SCS on the development of PIPN pain and changes of gene expression in the spinal cord in male rats after SCS.

Methods: We examined whether traditional SCS (50 Hz, 6-8 h/session daily for 14 consecutive days) administered during paclitaxel treatment (1.5 mg/kg, i.p.) attenuates PIPN-related pain behavior. After SCS treatment, we performed RNA-seq of the lumbar spinal cord to examine which genes are differentially expressed after PIPN with and without SCS.

Results: Compared to rats treated with paclitaxel alone (n = 7) or sham SCS (n = 6), SCS treatment (n = 11) significantly inhibited the development of paclitaxel-induced mechanical and cold hypersensitivity, without altering open-field exploratory behavior. RNA-seq showed that SCS induced upregulation of 836 genes and downregulation of 230 genes in the spinal cord of paclitaxel-treated rats (n = 3) as compared to sham SCS (n = 5). Spinal cord stimulation upregulated immune responses in paclitaxel-treated rats, including transcription of astrocyte- and microglial-related genes, but repressed transcription of multiple gene networks associated with synapse transmission, neuron projection development, γ-aminobutyric acid reuptake, and neuronal plasticity.

Conclusion: Our findings suggest that traditional SCS may attenuate the development of pain-related behaviors in PIPN rats, possibly by causing aggregate inhibition of synaptic plasticity through upregulation and downregulation of gene networks in the spinal cord.

Keywords: Chemotherapy-induced peripheral neuropathy; Neuropathic pain; RNA-sequencing; Rat; Spinal cord stimulation.

Abstract

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