Spinal Cord Stimulation Enhances Microglial Activation in the Spinal Cord of Nerve-Injured Rats
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ORIGINAL ARTICLE
Spinal Cord Stimulation Enhances Microglial Activation in the Spinal Cord of Nerve-Injured Rats Bin Shu1,2 • Shao-Qiu He1
•
Yun Guan1,3
Received: 30 April 2020 / Accepted: 23 July 2020 Ó Shanghai Institutes for Biological Sciences, CAS 2020
Abstract 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 lg–100 lg), which inhibits microglial activation, dosedependently attenuated the mechanical hypersensitivity. Pretreatment with low-dose minocycline (1 lg, 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.
& Yun Guan [email protected] 1
Department of Anesthesiology and Critical Care Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA
2
Present Address: Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
3
Department of Neurological Surgery, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA
Keywords Spinal cord stimulation Microglia Neuropathic pain Spinal cord Rat
Introduction Glial cells, including both macroglia and microglia, account for *70% of the cells in the central nervous system (CNS) [1]. These cells play important roles in maintaining homeostasis, supporting and protecting neurons, and synthesizing and releasing various neuromodulators that affect neuronal excitability. Microglia, the resident innate immune cells of the CNS, show remarkable morphological and functional plasticity to environmental changes, injuries, and neurologic disorders [2–4]. Both quiescent and activated microglia have been isolated from the CNS by immunomagnetic separation [3]. The isolated microglia retain properties similar to those in vivo, and hence are suitable for use in ex vivo investigations [2, 3]. The phenotypes of isolated microglia also correlate with two major phenotypic profiles characterized mostly by in vitro studies. The classically activated M1-like state is associated with the release of pro-inflammatory cytokines [e.g., tumor necrosis factor (TNF)-a, interleukin (IL)-1b, and IL-6], which are thought to enhance pain transmission
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