Microglia can modulate spinal nociceptive transmission. Yet, their role in spinal cord stimulation (SCS)-induced pain inhibition is unclear. Here, we examined how SCS affects microglial activation in the lumbar cord of rats with chronic constriction injury (CCI) of the sciatic nerve. Male rats received conventional SCS (50 Hz, 80% motor threshold, 180 min, 2 sessions/day) or sham stimulation on days 18–20 post-CCI. SCS transiently attenuated the mechanical hypersensitivity in the ipsilateral hind paw and increased OX-42 immunoreactivity in the bilateral dorsal horns. SCS also upregulated the mRNAs of M1-like markers, but not M2-like markers. Inducible NOS protein expression was increased, but brain-derived neurotrophic factor was decreased after SCS. Intrathecal minocycline (1 μg–100 μg), which inhibits microglial activation, dose-dependently attenuated the mechanical hypersensitivity. Pretreatment with low-dose minocycline (1 μg, 30 min) prolonged the SCS-induced pain inhibition. These findings suggest that conventional SCS may paradoxically increase spinal M1-like microglial activity and thereby compromise its own ability to inhibit pain.
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Watkins LR, Hutchinson MR, Ledeboer A, Wieseler-Frank J, Milligan ED, Maier SF. Norman Cousins Lecture. Glia as the “bad guys”: implications for improving clinical pain control and the clinical utility of opioids. Brain Behav Immun 2007, 21: 131–146.
Crain JM, Nikodemova M, Watters JJ. Microglia express distinct M1 and M2 phenotypic markers in the postnatal and adult central nervous system in male and female mice. J Neurosci Res 2013, 91: 1143–1151.
Nikodemova M, Watters JJ. Efficient isolation of live microglia with preserved phenotypes from adult mouse brain. J Neuroinflammation 2012, 9: 147.
Inoue K, Tsuda M. Microglia in neuropathic pain: cellular and molecular mechanisms and therapeutic potential. Nat Rev Neurosci 2018, 19: 138–152.
Mika J, Zychowska M, Popiolek-Barczyk K, Rojewska E, Przewlocka B. Importance of glial activation in neuropathic pain. Eur J Pharmacol 2013, 716: 106–119.
Ledeboer A, Sloane EM, Milligan ED, Frank MG, Mahony JH, Maier SF, et al. Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation. Pain 2005, 115: 71–83.
Chen G, Luo X, Qadri MY, Berta T, Ji RR. Sex-Dependent Glial Signaling in Pathological Pain: Distinct Roles of Spinal Microglia and Astrocytes. Neurosci Bull 2018, 34: 98–108.
Tsuda M. Modulation of Pain and Itch by Spinal Glia. Neurosci Bull 2018, 34: 178–185.
Kumar K, Taylor RS, Jacques L, Eldabe S, Meglio M, Molet J, et al. Spinal cord stimulation versus conventional medical management for neuropathic pain: a multicentre randomised controlled trial in patients with failed back surgery syndrome. Pain 2007, 132: 179–188.
Barchini J, Tchachaghian S, Shamaa F, Jabbur SJ, Meyerson BA, Song Z, et al. Spinal segmental and supraspinal mechanisms underlying the pain-relieving effects of spinal cord stimulation: an experimental study in a rat model of neuropathy. Neuroscience 2012, 215: 196–208.
Foreman RD, Linderoth B. Neural mechanisms of spinal cord stimulation. Int Rev Neurobiol 2012, 107: 87–119.
Sivanesan E, Maher DP, Raja SN, Linderoth B, Guan Y. Supraspinal Mechanisms of Spinal Cord Stimulation for Modulation of Pain: Five Decades of Research and Prospects for the Future. Anesthesiology 2019, 130: 651–665.
Huang Q, Duan W, Sivanesan E, Liu S, Yang F, Chen Z, et al. Spinal Cord Stimulation for Pain Treatment After Spinal Cord Injury. Neurosci Bull 2019, 35: 527–539.
Sdrulla AD, Guan Y, Raja SN. Spinal Cord Stimulation: Clinical Efficacy and Potential Mechanisms. Pain Pract 2018, 18: 1048–1067.
Yang F, Xu Q, Cheong YK, Shechter R, Sdrulla A, He SQ, et al. Comparison of intensity-dependent inhibition of spinal wide-dynamic range neurons by dorsal column and peripheral nerve stimulation in a rat model of neuropathic pain. Eur J Pain 2014, 18: 978–988.
Shechter R, Yang F, Xu Q, Cheong YK, He SQ, Sdrulla A, 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.
Guan Y. Spinal cord stimulation: neurophysiological and neurochemical mechanisms of action. Curr Pain Headache Rep 2012, 16: 217–225.
Vallejo R, Kelley CA, Gupta A. Modulation of neuroglial interactions using differential target multiplexed spinal cord stimulation in an animal model of neuropathic pain. Mol Pain 2020, 16: 1744806920918057.
Sato KL, Johanek LM, Sanada LS, Sluka KA. Spinal cord stimulation reduces mechanical hyperalgesia and glial cell activation in animals with neuropathic pain. Anesth Analg 2014, 118: 464–472.
Sivanesan E, Stephens KE, Huang Q, Chen Z, Ford NC, Duan W, et al. Spinal cord stimulation prevents paclitaxel-induced mechanical and cold hypersensitivity and modulates spinal gene expression in rats. Pain Rep 2019, 4: e785.
Stephens KE, Chen Z, Sivanesan E, Raja SN, Linderoth B, Taverna SD, et al. RNA-seq of spinal cord from nerve-injured rats after spinal cord stimulation. Mol Pain 2018, 14: 1744806918817429.
Vallejo R, Tilley DM, Cedeno DL, Kelley CA, DeMaegd M, Benyamin R. Genomics of the Effect of Spinal Cord Stimulation on an Animal Model of Neuropathic Pain. Neuromodulation 2016, 19: 576–586.
Bennett GJ, Xie YK. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 1988, 33: 87–107.
Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 1994, 53: 55–63.
Dixon WJ. Efficient analysis of experimental observations. Annu Rev Pharmacol Toxicol 1980, 20: 441–462.
Yang F, Xu Q, Shu B, Tiwari V, He SQ, Vera-Portocarrero LP, et al. Activation of cannabinoid CB1 receptor contributes to suppression of spinal nociceptive transmission and inhibition of mechanical hypersensitivity by Abeta-fiber stimulation. Pain 2016, 157: 2582–2593.
Mestre C, Pelissier T, Fialip J, Wilcox G, Eschalier A. A method to perform direct transcutaneous intrathecal injection in rats. J Pharmacol Toxicol Methods 1994, 32: 197–200.
Liu S, Huang Q, He S, Chen Z, Gao X, Ma D, et al. Dermorphin [D-Arg2, Lys4] (1–4) amide inhibits below-level heat hypersensitivity in mice after contusive thoracic spinal cord injury. Pain 2019, 160: 2710–2723.
He SQ, Xu Q, Tiwari V, Yang F. Oligomerization of MrgC11 and μ-opioid receptors in sensory neurons enhances morphine analgesia. Sci Signal 2018, 11(535):eaao3134. https://doi.org/10.1126/scisignal.aao3134.
Ji RR, Befort K, Brenner GJ, Woolf CJ. ERK MAP kinase activation in superficial spinal cord neurons induces prodynorphin and NK-1 upregulation and contributes to persistent inflammatory pain hypersensitivity. J Neurosci 2002, 22: 478–485.
Zhuang ZY, Gerner P, Woolf CJ, Ji RR. ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model. Pain 2005, 114: 149–159.
Woolf CJ, Mannion RJ. Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 1999, 353: 1959–1964.
Burke NN, Kerr DM, Moriarty O, Finn DP, Roche M. Minocycline modulates neuropathic pain behaviour and cortical M1-M2 microglial gene expression in a rat model of depression. Brain Behav Immun 2014, 42: 147–156.
Ji RR, Berta T, Nedergaard M. Glia and pain: Is chronic pain a gliopathy? Pain 2013, 154: S10–S28.
Raghavendra V, Tanga F, DeLeo JA. Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy. J Pharmacol Exp Ther 2003, 306: 624–630.
Tilley DM, Cedeño DL, Kelley CA, Benyamin R, Vallejo R. Spinal Cord Stimulation Modulates Gene Expression in the Spinal Cord of an Animal Model of Peripheral Nerve Injury. Reg Anesth Pain Med 2016, 41: 750–756.
Trang T, Beggs S, Wan X, Salter MW. P2X4-receptor-mediated synthesis and release of brain-derived neurotrophic factor in microglia is dependent on calcium and p38-mitogen-activated protein kinase activation. J Neurosci 2009, 29: 3518–3528.
Coull JA, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K, et al. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 2005, 438: 1017–1021.
Stiller CO, Cui JG, O’Connor WT, Brodin E, Meyerson BA, Linderoth B. Release of gamma-aminobutyric acid in the dorsal horn and suppression of tactile allodynia by spinal cord stimulation in mononeuropathic rats. Neurosurgery 1996, 39: 367–374; discussion 374–365.
Cui JG, O’Connor WT, Ungerstedt U, Linderoth B, Meyerson BA. Spinal cord stimulation attenuates augmented dorsal horn release of excitatory amino acids in mononeuropathy via a GABAergic mechanism. Pain 1997, 73: 87–95.
Colonna M, Butovsky O. Microglia Function in the Central Nervous System During Health and Neurodegeneration. Annu Rev Immunol 2017, 35: 441–468.
Wes PD, Holtman IR, Boddeke EW, Moller T, Eggen BJ. Next generation transcriptomics and genomics elucidate biological complexity of microglia in health and disease. Glia 2016, 64: 197–213.
Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O’Keeffe S, et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. 2014, 34: 11929–11947.
Cao H, Zhang YQ. Spinal glial activation contributes to pathological pain states. Neurosci Biobehav Rev 2008, 32: 972–983.
Song ZP, Xiong BR, Guan XH, Cao F, Manyande A, Zhou YQ, et al. Minocycline attenuates bone cancer pain in rats by inhibiting NF-kappaB in spinal astrocytes. Acta Pharmacol Sin 2016, 37: 753–762.
Guasti L, Richardson D, Jhaveri M, Eldeeb K, Barrett D, Elphick MR, et al. Minocycline treatment inhibits microglial activation and alters spinal levels of endocannabinoids in a rat model of neuropathic pain. Mol Pain 2009, 5: 35.
Nie H, Zhang H, Weng HR. Minocycline prevents impaired glial glutamate uptake in the spinal sensory synapses of neuropathic rats. Neuroscience 2010, 170: 901–912.
Cho IH, Lee MJ, Jang M, Gwak NG, Lee KY, Jung HS. Minocycline markedly reduces acute visceral nociception via inhibiting neuronal ERK phosphorylation. Mol Pain 2012, 8: 13.
Pu S, Xu Y, Du D, Yang M, Zhang X, Wu J, et al. Minocycline attenuates mechanical allodynia and expression of spinal NMDA receptor 1 subunit in rat neuropathic pain model. J Physiol Biochem 2013, 69: 349–357.
Meyerson BA, Linderoth B. Mode of action of spinal cord stimulation in neuropathic pain. J Pain Symptom Manage 2006, 31: S6–12.
Tilley DM, Lietz CB, Cedeno DL, Kelley CA, Li L, Vallejo R. Proteomic Modulation in the Dorsal Spinal Cord Following Spinal Cord Stimulation Therapy in an In Vivo Neuropathic Pain Model. Neuromodulation 2020. https://doi.org/10.1111/ner.13103.
We thank Claire F. Levine, MS, ELS (Scientific Editor, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University), for editing the manuscript and Medtronic, Inc. (Minneapolis, MN, USA) for generously providing the rodent electrodes for spinal cord stimulation. This work was supported by a grant from the Neurosurgery Pain Research Institute at the Johns Hopkins University and subsidized by the National Institutes of Health (Bethesda, Maryland, USA) (NS110598). The efforts of B.S. were supported by an award from the China Scholarship Council for Chinese PhD candidates to study abroad.
Conflict of interest
Dr. Yun Guan received research grant support from Medtronic, Inc., Minneapolis, MN. However, none of the authors has a commercial interest in the material presented in this paper. There are no other relationships that might lead to a conflict of interest in the current study. The authors declare no competing interests.
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Shu, B., He, S. & Guan, Y. Spinal Cord Stimulation Enhances Microglial Activation in the Spinal Cord of Nerve-Injured Rats. Neurosci. Bull. (2020). https://doi.org/10.1007/s12264-020-00568-6
- Spinal cord stimulation
- Neuropathic pain
- Spinal cord