Inhibiting astrocytic activation: a novel analgesic mechanism of ketamine at the spinal level?

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.

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“…The dosages of ketamine and poly I:C used in the present study were in accordance with previous research [2,21,32] and our pilot experiment.…”

Section: Intrathecal Implantation and Drug Administrationsupporting

confidence: 57%

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

et al. 2011

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“…As observed in our previous study, inhibiting astrocytic activation is probably a novel analgesic mechanism of ketamine [37]. Some opioid receptors (μ, κ and δ subtypes) and toll like receptors (TLRs) are expressed on astrocytes.…”

Section: Discussionmentioning

confidence: 73%

Combining Ketamine with Astrocytic Inhibitor as a Potential Analgesic Strategy for Neuropathic Pain. Ketamine, Astrocytic Inhibitor and Pain

Mei

Wang

et al. 2010

Mol Pain

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BackgroundNeuropathic pain is an intractable clinical problem. Intrathecal ketamine, a noncompetitive N--methyl-D-aspartate receptor (NMDAR) antagonist, is reported to be useful for treating neuropathic pain in clinic by inhibiting the activity of spinal neurons. Nevertheless, emerging studies have disclosed that spinal astrocytes played a critical role in the initiation and maintenance of neuropathic pain. However, the present clinical therapeutics is still just concerning about neuronal participation. Therefore, the present study is to validate the coadministration effects of a neuronal noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine and astrocytic cytotoxin L-α-aminoadipate (LAA) on spinal nerve ligation (SNL)-induced neuropathic pain.ResultsIntrathecal ketamine (10, 100, 1000 μg/kg) or LAA (10, 50, 100 nmol) alleviated SNL-induced mechanical allodynia in a dose-dependent manner respectively. Phosphorylated NR1 (pNR1) or glial fibrillary acidic protein (GFAP) expression was down-regulated by intrathecal ketamine (100, 1000 μg/kg) or LAA (50, 100 nmol) respectively. The combination of ketamine (100 μg/kg) with LAA (50 nmol) showed superadditive effects on neuropathic pain compared with that of intrathecal administration of either ketamine or LAA alone. Combined administration obviously relieved mechanical allodynia in a quick and stable manner. Moreover, down-regulation of pNR1 and GFAP expression were also enhanced by drugs coadministration.ConclusionsThese results suggest that combining NMDAR antagonist ketamine with an astrocytic inhibitor or cytotoxin, which is suitable for clinical use once synthesized, might be a potential strategy for clinical management of neuropathic pain.

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“…Drugs and normal saline were injected intrathecally over 30 s, followed by a 10 μl flush of normal saline. The dosages of ketamine used in the present study were chosen based on previous research [18,21] and pilot experiments.…”

Section: Methodsmentioning

confidence: 99%

“…A number of studies have been carried out to elucidate the mechanisms underlying this analgesic effect, but without satisfying output. Previous study [21] showed that both intraperitoneal and intrathecal ketamine inhibit SNL-induced allodynia; however, intrathecal but not intraperitoneal ketamine suppresses SNL-induced astrocytic activation as reflected by down-regulated glial fibrillary acidic protein (GFAP) expression. These results suggest that intraperitoneal ketamine could alleviate SNL-induced neuropathic pain via classical "neuronal-based" mechanisms but, in addition, "astrocyte-related" mechanisms may also be important in underlying the anti-allodynic effect of intrathecal ketamine.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of spinal astrocytic c-Jun N-terminal kinase (JNK) activation correlates with the analgesic effects of ketamine in neuropathic pain

Mei

Zhang

Wang

et al. 2011

J Neuroinflammation

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BackgroundWe have previously reported that inhibition of astrocytic activation contributes to the analgesic effects of intrathecal ketamine on spinal nerve ligation (SNL)-induced neuropathic pain. However, the underlying mechanisms are still unclear. c-Jun N-terminal kinase (JNK), a member of mitogen-activated protein kinase (MAPK) family, has been reported to be critical for spinal astrocytic activation and neuropathic pain development after SNL. Ketamine can decrease lipopolysaccharide (LPS)-induced phosphorylated JNK (pJNK) expression and could thus exert its anti-inflammatory effect. We hypothesized that inhibition of astrocytic JNK activation might be involved in the suppressive effect of ketamine on SNL-induced spinal astrocytic activation.MethodsImmunofluorescence histochemical staining was used to detect SNL-induced spinal pJNK expression and localization. The effects of ketamine on SNL-induced mechanical allodynia were confirmed by behavioral testing. Immunofluorescence histochemistry and Western blot were used to quantify the SNL-induced spinal pJNK expression after ketamine administration.ResultsThe present study showed that SNL induced ipsilateral pJNK up-regulation in astrocytes but not microglia or neurons within the spinal dorsal horn. Intrathecal ketamine relieved SNL-induced mechanical allodynia without interfering with motor performance. Additionally, intrathecal administration of ketamine attenuated SNL-induced spinal astrocytic JNK activation in a dose-dependent manner, but not JNK protein expression.ConclusionsThe present results suggest that inhibition of JNK activation may be involved in the suppressive effects of ketamine on SNL-induced spinal astrocyte activation. Therefore, inhibition of spinal JNK activation may be involved in the analgesic effects of ketamine on SNL-induced neuropathic pain.

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Inhibiting astrocytic activation: a novel analgesic mechanism of ketamine at the spinal level?

Cited by 31 publications

References 54 publications

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

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

Combining Ketamine with Astrocytic Inhibitor as a Potential Analgesic Strategy for Neuropathic Pain. Ketamine, Astrocytic Inhibitor and Pain

Inhibition of spinal astrocytic c-Jun N-terminal kinase (JNK) activation correlates with the analgesic effects of ketamine in neuropathic pain

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