Basic Research|Articles in Press

Spinal Cord Stimulation Increases Chemoefficacy and Prevents Paclitaxel-Induced Pain via CX3CL1



      Despite increasing utilization of spinal cord stimulation (SCS), its effects on chemoefficacy, cancer progression, and chemotherapy-induced peripheral neuropathy (CIPN) pain remain unclear. Up to 30% of adults who are cancer survivors may suffer from CIPN, and there are currently no effective preventative treatments.

      Materials and Methods

      Through a combination of bioluminescent imaging, behavioral, biochemical, and immunohistochemical approaches, we investigated the role of SCS and paclitaxel (PTX) on tumor growth and PTX-induced peripheral neuropathy (PIPN) pain development in T-celldeficient male rats (Crl:NIH-Foxn1rnu) with xenograft human non–small cell lung cancer. We hypothesized that SCS can prevent CIPN pain and enhance chemoefficacy partially by modulating macrophages, fractalkine (CX3CL1), and inflammatory cytokines.


      We show that preemptive SCS enhanced the antitumor efficacy of PTX and prevented PIPN pain. Without SCS, rats with and without tumors developed robust PIPN pain-related mechanical hypersensitivity, but only those with tumors developed cold hypersensitivity, suggesting T-cell dependence for different PIPN pain modalities. SCS increased soluble CX3CL1 and macrophages and decreased neuronal and nonneuronal insoluble CX3CL1 expression and inflammation in dorsal root ganglia.


      Collectively, our findings suggest that preemptive SCS is a promising strategy to increase chemoefficacy and prevent PIPN pain via CX3CL1-macrophage modulation.


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        • Colvin L.A.
        Chemotherapy-induced peripheral neuropathy: where are we now?.
        Pain. 2019; 160: S1-S10
        • Staff N.P.
        • Grisold A.
        • Grisold W.
        • Windebank A.J.
        Chemotherapy-induced peripheral neuropathy: a current review.
        Ann Neurol. 2017; 81: 772-781
        • Cata J.P.
        • Cordella J.V.
        • Burton A.W.
        • Hassenbusch S.J.
        • Weng H.R.
        • Dougherty P.M.
        Spinal cord stimulation relieves chemotherapy-induced pain: a clinical case report.
        J Pain Symptom Manage. 2004; 27: 72-78
        • Phan P.
        • Khodavirdi A.
        Successful treatment of chemotherapy-induced peripheral neuropathy (CIPN) with spinal cord stimulation (SCS).
        Cancer Res. 2007; 67: 35
        • Roybal A.E.
        • Sivanesan E.
        • Chen Y.
        Case report: dorsal root ganglion (DRG) stimulation for acute neuropathic pain from acute herpes zoster infection.
        SAGE Open Med Case Rep. 2021; 92050313X211062297
        • Luo X.
        • Huh Y.
        • Bang S.
        • et al.
        Macrophage toll-like receptor 9 contributes to chemotherapy-induced neuropathic pain in male mice.
        J Neurosci. 2019; 39: 6848-6864
        • Zhang H.
        • Li Y.
        • de Carvalho-Barbosa M.
        • et al.
        Dorsal root ganglion infiltration by macrophages contributes to paclitaxel chemotherapy-induced peripheral neuropathy.
        J Pain. 2016; 17: 775-786
        • Sivanesan E.
        • Stephens K.E.
        • Huang Q.
        • et al.
        Spinal cord stimulation prevents paclitaxel-induced mechanical and cold hypersensitivity and modulates spinal gene expression in rats.
        Pain Rep. 2019; 4: e785
        • Vallejo R.
        • Gupta A.
        • Kelley C.A.
        • et al.
        Effects of phase polarity and charge balance spinal cord stimulation on behavior and gene expression in a rat model of neuropathic pain.
        Neuromodulation. 2020; 23: 26-35
        • Stephens K.E.
        • Chen Z.
        • Sivanesan E.
        • et al.
        RNA-seq of spinal cord from nerve-injured rats after spinal cord stimulation.
        Mol Pain. 2018; 141744806918817429
        • Crowther J.E.
        • Chen G.H.
        • Legler A.
        • Gulati A.
        Spinal cord stimulation in the treatment of cancer pain: a retrospective review.
        Neuromodulation. 2022; 25: 693-699
        • Weisshaar C.L.
        • Winkelstein B.A.
        Ablating spinal NK1-bearing neurons eliminates the development of pain and reduces spinal neuronal hyperexcitability and inflammation from mechanical joint injury in the rat.
        J Pain. 2014; 15: 378-386
        • Ho Kim S.
        • Mo Chung J.
        An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat.
        Pain. 1992; 50: 355-363
        • Hai J.
        • Zhu C.Q.
        • Bandarchi B.
        • et al.
        L1 cell adhesion molecule promotes tumorigenicity and metastatic potential in non–small cell lung cancer.
        Clin Cancer Res. 2012; 18: 1914-1924
        • Gao Y.
        • Shen J.K.
        • Choy E.
        • et al.
        Pharmacokinetics and tolerability of NSC23925b, a novel P-glycoprotein inhibitor: preclinical study in mice and rats.
        Sci Rep. 2016; 625659
        • Sarabia-Estrada R.
        • Ruiz-Valls A.
        • Guerrero-Cazares H.
        • et al.
        Metastatic human breast cancer to the spine produces mechanical hyperalgesia and gait deficits in rodents.
        Spine J. 2017; 17: 1325-1334
        • Aswendt M.
        • Adamczak J.
        • Couillard-Despres S.
        • Hoehn M.
        Boosting bioluminescence neuroimaging: an optimized protocol for brain studies.
        PLoS One. 2013; 8e55662
        • Beh S.T.
        • Kuo Y.M.
        • Chang W.-S.W.
        • et al.
        Preventive hypothermia as a neuroprotective strategy for paclitaxel-induced peripheral neuropathy.
        Pain. 2019; 160: 1505-1521
        • Shechter R.
        • Yang F.
        • Xu Q.
        • et al.
        Conventional and kilohertz-frequency spinal cord stimulation produces intensity- and frequency-dependent inhibition of mechanical hypersensitivity in a rat model of neuropathic pain.
        Anesthesiology. 2013; 119: 422-432
        • Dixon W.J.
        Efficient analysis of experimental observations.
        Annu Rev Pharmacol Toxicol. 1980; 20: 441-462
        • Cheah M.
        • Fawcett J.W.
        • Andrews M.R.
        Assessment of thermal pain sensation in rats and mice using the Hargreaves test.
        Bio Protoc. 2017; 7e2506
        • Jurcak N.R.
        • Rucki A.A.
        • Muth S.
        • et al.
        Axon guidance molecules promote perineural invasion and metastasis of orthotopic pancreatic tumors in mice.
        Gastroenterology. 2019; 157: 838-850.e6
        • Pereira E.
        • Foster A.
        Appetite suppression and weight loss incidental to spinal cord stimulation for pain relief.
        Obes Surg. 2007; 17: 1272-1274
        • Lam V.K.
        • Bentzen S.M.
        • Mohindra P.
        • et al.
        Obesity is associated with long-term improved survival in definitively treated locally advanced non-small cell lung cancer (NSCLC).
        Lung Cancer. 2017; 104: 52-57
        • Zhang X.
        • Liu Y.
        • Shao H.
        • Zheng X.
        Obesity paradox in lung cancer prognosis: evolving biological insights and clinical implications.
        J Thorac Oncol. 2017; 12: 1478-1488
        • Old E.A.
        • Nadkarni S.
        • Grist J.
        • et al.
        Monocytes expressing CX3CR1 orchestrate the development of vincristine-induced pain.
        J Clin Invest. 2014; 124: 2023-2036
        • Luo X.
        • Chen O.
        • Wang Z.
        • et al.
        IL-23/IL-17A/TRPV1 axis produces mechanical pain via macrophage-sensory neuron crosstalk in female mice.
        Neuron. 2021; 109: 2691-2706.e5
        • Huang Z.Z.
        • Li D.
        • Liu C.C.
        • et al.
        CX3CL1-mediated macrophage activation contributed to paclitaxel-induced DRG neuronal apoptosis and painful peripheral neuropathy.
        Brain Behav Immun. 2014; 40: 155-165
        • Bang S.
        • Xie Y.K.
        • Zhang Z.J.
        • Wang Z.
        • Xu Z.Z.
        • Ji R.R.
        GPR37 regulates macrophage phagocytosis and resolution of inflammatory pain.
        J Clin Invest. 2018; 128: 3568-3582
        • Chen O.
        • Donnelly C.R.
        • Ji R.R.
        Regulation of pain by neuro-immune interactions between macrophages and nociceptor sensory neurons.
        Curr Opin Neurobiol. 2020; 62: 17-25
        • Latchney L.R.
        • Fallon M.A.
        • Culp D.J.
        • Gelbard H.A.
        • Dewhurst S.
        Immunohistochemical assessment of fractalkine, inflammatory cells, and human herpesvirus 7 in human salivary glands.
        J Histochem Cytochem. 2004; 52: 671-681
        • Linderoth B.
        • Gunasekera L.
        • Meyerson B.A.
        Effects of sympathectomy on skin and muscle microcirculation during dorsal column stimulation: animal studies.
        Neurosurgery. 1991; 29: 874-879
        • Amann W.
        • Berg P.
        • Gersbach P.
        • et al.
        Spinal cord stimulation in the treatment of non-reconstructable stable critical leg ischaemia: results of the European peripheral Vascular Disease Outcome Study (SCS-EPOS).
        Eur J Vasc Endovasc Surg. 2003; 26: 280-286
        • Ishida Y.
        • Kimura A.
        • Nosaka M.
        • et al.
        Essential involvement of the CX3CL1-CX3CR1 axis in bleomycin-induced pulmonary fibrosis via regulation of fibrocyte and M2 macrophage migration.
        Sci Rep. 2017; 7: 1-12
        • Wang J.
        • Pan H.
        • Lin Z.
        • et al.
        Neuroprotective effect of fractalkine on radiation-induced brain injury through promoting the M2 polarization of microglia.
        Mol Neurobiol. 2021; 58: 1074-1087
        • Panek C.A.
        • Ramos M.V.
        • Mejias M.P.
        • et al.
        Differential expression of the fractalkine chemokine receptor (CX3CR1) in human monocytes during differentiation.
        Cell Mol Immunol. 2015; 12: 669-680
        • Enam S.F.
        • Krieger J.R.
        • Saxena T.
        • et al.
        Enrichment of endogenous fractalkine and anti-inflammatory cells via aptamer-functionalized hydrogels.
        Biomaterials. 2017; 142: 52-61
        • Vitale S.
        • Cambien B.
        • Karimdjee B.F.
        • et al.
        Tissue-specific differential antitumour effect of molecular forms of fractalkine in a mouse model of metastatic colon cancer.
        Gut. 2007; 56: 365-372
        • Conroy M.J.
        • Lysaght J.
        CX3CL1 signaling in the tumor microenvironment.
        Adv Exp Med Biol. 2020; 1231: 1-12
        • Wege A.K.
        • Dreyer T.F.
        • Teoman A.
        • Ortmann O.
        • Brockhoff G.
        • Bronger H.
        CX3CL1 overexpression prevents the formation of lung metastases in trastuzumab-treated MDA-MB-453-based humanized tumor mice (HTM).
        Cancers. 2021; 13: 2459
        • Dreyer T.F.
        • Kuhn S.
        • Stange C.
        • et al.
        The chemokine CX3CL1 improves trastuzumab efficacy in HER2 low–expressing cancer in vitro and in vivo.
        Cancer Immunol Res. 2021; 9: 779-789
        • Cao L.
        • DeLeo J.A.
        CNS-infiltrating CD4+ T lymphocytes contribute to murine spinal nerve transection-induced neuropathic pain.
        Eur J Immunol. 2008; 38: 448-458
        • Costigan M.
        • Moss A.
        • Latremoliere A.
        • et al.
        T-cell infiltration and signaling in the adult dorsal spinal cord is a major contributor to neuropathic pain-like hypersensitivity.
        J Neurosci. 2009; 29: 14415-14422
        • Laumet G.
        • Edralin J.D.
        • Dantzer R.
        • Heijnen C.J.
        • Kavelaars A.
        Cisplatin educates CD8+ T cells to prevent and resolve chemotherapy-induced peripheral neuropathy in mice.
        Pain. 2019; 160: 1459-1468
        • Krukowski K.
        • Eijkelkamp N.
        • Laumet G.
        • et al.
        CD8+ T cells and endogenous IL-10 are required for resolution of chemotherapy-induced neuropathic pain.
        J Neurosci. 2016; 36: 11074-11083
        • Fan W.
        • Sdrulla A.D.
        Differential modulation of excitatory and inhibitory populations of superficial dorsal horn neurons in lumbar spinal cord by Aβ-fiber electrical stimulation.
        Pain. 2020; 161: 1650-1660
        • Jamison R.N.
        • Schein J.R.
        • Vallow S.
        • Ascher S.
        • Vorsanger G.J.
        • Katz N.P.
        Neuropsychological effects of long-term opioid use in chronic pain patients.
        J Pain Symptom Manage. 2003; 26: 913-921
        • Fan Q.
        • Gayen M.
        • Singh N.
        • et al.
        The intracellular domain of CX3CL1 regulates adult neurogenesis and Alzheimer’s amyloid pathology.
        J Exp Med. 2019; 216: 1891-1903
        • Dorandish S.
        • Williams A.
        • Atali S.
        • et al.
        Regulation of amyloid-β levels by matrix metalloproteinase-2/9 (MMP2/9) in the media of lung cancer cells.
        Sci Rep. 2021; 11: 9708
        • Rosito M.
        • Lauro C.
        • Chece G.
        • et al.
        Trasmembrane chemokines CX3CL1 and CXCL16 drive interplay between neurons, microglia and astrocytes to counteract pMCAO and excitotoxic neuronal death.
        Front Cell Neurosci. 2014; 8: 193
        • Trettel F.
        • Di Castro M.A.
        • Limatola C.
        Chemokines: key molecules that orchestrate communication among neurons, microglia and astrocytes to preserve brain function.
        Neuroscience. 2020; 439: 230-240
        • Rosito M.
        • Deflorio C.
        • Limatola C.
        • Trettel F.
        CXCL16 orchestrates adenosine A3 receptor and MCP-1/CCL2 activity to protect neurons from excitotoxic cell death in the CNS.
        J Neurosci. 2012; 32: 3154-3163
        • Tong N.
        • Perry S.W.
        • Zhang Q.
        • et al.
        Neuronal fractalkine expression in HIV-1 encephalitis: roles for macrophage recruitment and neuroprotection in the central nervous system.
        J Immunol. 2000; 164: 1333-1339
        • Hurst L.A.
        • Bunning R.A.
        • Sharrack B.
        • Woodroofe M.N.
        siRNA knockdown of ADAM-10, but not ADAM-17, significantly reduces fractalkine shedding following pro-inflammatory cytokine treatment in a human adult brain endothelial cell line.
        Neurosci Lett. 2012; 521: 52-56
        • Romera C.
        • Hurtado O.
        • Botella S.H.
        • et al.
        In vitro ischemic tolerance involves upregulation of glutamate transport partly mediated by the TACE/ADAM17-tumor necrosis factor-α pathway.
        J Neurosci. 2004; 24: 1350-1357
        • Kaur T.
        • Zamani D.
        • Tong L.
        • et al.
        Fractalkine signaling regulates macrophage recruitment into the cochlea and promotes the survival of spiral ganglion neurons after selective hair cell lesion.
        J Neurosci. 2015; 35: 15050-15061
        • Yu X.
        • Liu H.
        • Hamel K.A.
        • et al.
        Dorsal root ganglion macrophages contribute to both the initiation and persistence of neuropathic pain.
        Nat Commun. 2020; 11: 264
        • Tao X.
        • Luo X.
        • Zhang T.
        • Hershey B.
        • Esteller R.
        • Ji R.R.
        Spinal cord stimulation attenuates mechanical allodynia and increases central resolvin D1 levels in rats with spared nerve injury.
        Front Physiol. 2021; 12687046
        • Croom J.E.
        • Foreman R.D.
        • Chandler M.J.
        • Barron K.W.
        Cutaneous vasodilation during dorsal column stimulation is mediated by dorsal roots and CGRP.
        Am J Physiol. 1997; 272: H950-H957
        • Tanaka S.
        • Barron K.W.
        • Chandler M.J.
        • Linderoth B.
        • Foreman R.D.
        Low intensity spinal cord stimulation may induce cutaneous vasodilation via CGRP release.
        Brain Res. 2001; 896: 183-187
        • Baliu-Piqué M.
        • Jusek G.
        • Holzmann B.
        Neuroimmunological communication via CGRP promotes the development of a regulatory phenotype in TLR4-stimulated macrophages.
        Eur J Immunol. 2014; 44: 3708-3716
        • Jiang L.
        • Zhang W.
        • Li W.
        • Ling C.
        • Jiang M.
        Anti-inflammatory drug, leflunomide and its metabolite teriflunomide inhibit NSCLC proliferation in vivo and in vitro.
        Toxicol Lett. 2018; 282: 154-165
        • Linderoth B.
        • Foreman R.D.
        Conventional and novel spinal stimulation algorithms: hypothetical mechanisms of action and comments on outcomes.
        Neuromodulation. 2017; 20: 525-533
        • Foreman R.D.
        • Linderoth B.
        • Ardell J.L.
        • et al.
        Modulation of intrinsic cardiac neurons by spinal cord stimulation: implications for its therapeutic use in angina pectoris.
        Cardiovasc Res. 2000; 47: 367-375
        • Singh S.K.
        • Krukowski K.
        • Laumet G.O.
        • et al.
        CD8+ T cell-derived IL-13 increases macrophage IL-10 to resolve neuropathic pain.
        JCI Insight. 2022; 7e154194
        • Meier K.
        • Nikolajsen L.
        • Sørensen J.C.
        • Jensen T.S.
        Effect of spinal cord stimulation on sensory characteristics: a randomized, blinded crossover study.
        Clin J Pain. 2015; 31: 384-392
        • Kriek N.
        • Groeneweg J.G.
        • Stronks D.L.
        • De Ridder D.
        • Huygen F.J.
        Preferred frequencies and waveforms for spinal cord stimulation in patients with complex regional pain syndrome: a multicentre, double-blind, randomized and placebo-controlled crossover trial.
        Eur J Pain. 2017; 21: 507-519