Ketamine Depresses Toll-Like Receptor 3 Signaling in Spinal Microglia in a Rat Model of Neuropathic Pain

Abstract

Reports suggest that microglia play a key role in spinal nerve ligation (SNL)-induced neuropathic pain, and toll-like receptor 3 (TLR3) has a substantial role in the activation of spinal microglia and the development of tactile allodynia after nerve injury. In addition, ketamine application could suppress microglial activation in vitro, and ketamine could inhibit proinflammatory gene expression possibly by suppressing TLR-mediated signal transduction. Therefore, the present study was designed to disclose whether intrathecal ketamine could suppress SNL-induced spinal microglial activation and exert some antiallodynic effects on neuropathic pain by suppressing TLR3 activation. Behavioral results showed that intrathecal ketamine attenuated SNL-induced mechanical allodynia, as well as spinal microglial activation, in a dose-dependent manner. Furthermore, Western blot analysis displayed that ketamine application downregulated SNL-induced phosphorylated-p38 (p-p38) expression, which was specifically expressed in spinal microglia but not in astrocytes or neurons. Besides, ketamine could reverse TLR3 agonist (polyinosine-polycytidylic acid)-induced mechanical allodynia and spinal microglia activation. It was concluded that intrathecal ketamine depresses TLR3-induced spinal microglial p-p38 mitogen-activated protein kinase pathway activation after SNL, probably contributing to the antiallodynic effect of ketamine on SNL-induced neuropathic pain.

Depressing Interleukin-1� Contributed to the Synergistic Effects of Tramadol and Minocycline on Spinal Nerve Ligation-Induced Neuropathic Pain

“…The cutoff time was 30 s. Each rat was tested 30 min before drug administration as control performance and then once a day for 4 days during the drug administration. The time that the animal remained on the rotarod was recorded and expressed as a percentage of that animal's own mean control performance [27]. …”

Paeoniflorin Attenuates Inflammatory Pain by Inhibiting Microglial Activation and Akt-NF-κB Signaling in the Central Nervous System

“…Microglia is resident macrophages in the CNS and exerts important functions in maintaining homeostasis in the CNS [6,7]. Activation of microglia occurs in most pathological processes, which is often accompanied by morphologic change and production of cytotoxic molecules, and upregulation of phagocytosis and immune surface antigens [8][9][10].…”

Toll-like receptors in central nervous system injury and disease: A focus on the spinal cord

“…Stimulation of spinal TLR3 by i.t. administration of poly I:C to male rats resulted in the development of mechanical allodynia which was followed by microglial activation (Mei et al, 2011). The investigations of Liu et al (2012) suggested that TLR3 is critical for central sensitization-driven pain hypersensitivity.…”