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TLR4 Inhibits Spinal Gabaergic Activities via Microglial Activation in Chronic Constriction Injury Mice

Author(s): Er-liang Kong, Xiao- Zhi Wu, Yan He, Hong-qian Wang, Yan Zhang, Jin-min Zhang, Wei-feng Yu, Feixiang Wu

Neuropathic pain (NP) remains a significant clinical problem worldwide. Toll-like rec e ptor  4 (TLR4) expressed on microglia in the spinal cord exert great influence on NP induced hyperalgesia. Impaired γ-aminobutyric acid (GABAergic) neuron activities in the spinal cordare also confirmed to be associated with NP progression. However, the role of TLR4 inducedmicroglial activation on impaired spinal GABAergic neuron activities inneuropathic painconditions remains unclear. Mechanical thr esholds were measured after intrathecal injectionof TLR4 inhibitor (TAK-242) or GABAA receptor agonist (muscimol) in male C57 mice. Microglialactivation, glutamic acid decarboxylase 65 (GAD65), as well as GABA concentrations incerebrospinal fluid (CSF) were further analyzed. Spontaneous inhibitory postsynaptic current(sIPSC) of GABAergic neurons were recorded using electrophysiological test. TLR4 expressionlevel was measured after chronic constriction injury (CCI) surgery and after intrathecaladministration of a TLR4 agonist (lipopolysaccharide, LPS) in naive mice.CCI surgery and TLR4agonist LPS treatment both induced hyperalgesia, while TLR4 inhibitor TAK-242 or GABAAreceptor agonist muscimol increased the mechanical thresholds in both CCI surgery andLPS-treated mice. Furthermore, decreased GAD65 fluorescence, GABA concentrations in CSFand sIPSC in CCI and LPS mice were a lleviated by TAK-242. Moreover, TAK-242 and microg lia  activa tion inhibitor (minocycline) suppressed the enhanced microglial activation in CCI surgeryand LPS-treated mice, and GAD65 fluorescence and GABA concentrations were increased byminocycline intervention. Additionally, TLR4 expression levels were up-regulated followingCCI surgery and intrathecal administration of LPS. TLR4 suppresses spinal GABAergic neuronactivities viamicroglial activation.

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