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

Abstract

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.

The Inhibition of Spinal Astrocytic JAK2-STAT3 Pathway Activation Correlates with the Analgesic Effects of Triptolide in the Rat Neuropathic Pain Model

“…Intrathecal implantation was performed as described in our previous studies [13, 28, 29] by inserting polyethylene (PE) tubing through which the drug was directly injected into the subarachnoid space of the lumbar enlargement. After surgery, neurologically normal rats were injected with 2% lidocaine (10  μ L) through the intrathecal catheter to confirm that the PE tubing was in the subarachnoid space.…”

“…The results of our previous studies have demonstrated that the activation of microglia and astrocytes in the SDH is critical in the induction and maintenance of NP [3, 11, 12]. Specifically, astrocytes play a vital role in the maintenance of NP; the astrocyte-specific cytotoxin L- α -aminoadipate (LAA) can effectively relieve late-phase mechanical allodynia by interrupting the “cross-talk” between neurons and astrocytes [3, 13, 14]. In addition, accumulating evidence showed that the activation of astrocytes depends on the phosphorylation state of the janus kinase (JAK) signal transducers and activators of transcription 3 (STAT3) signalling pathway [15, 16].…”

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

“…The range of monofilaments (1,479-28,840 mg) produced a logarithmically graded slope when interpolating a 50% response threshold of stimulus intensity (expressed as log 10 ) [22]. The behavioral responses were used to calculate the 50% paw withdrawal threshold, by fitting a gaussian integral psychometric function using a maximum-likelihood fitting method, as described in detail previously [21,23]. This fitting method allowed parametric statistical analysis.…”

Ketamine Inhibits Lipopolysaccharide-Induced Astrocytes Activation by Suppressing TLR4/NF-?B Pathway

“…Recent in vitro and vivo studies demonstrated that ketamine inhibited astrocyte activation and blunted LPS-induced astrocyte TNF-alpha production [10][11][12]. However, the detailed mechanisms underlying the antiin�lammatory effects of ketamine in astrocytes stimulated by LPS have not been clearly revealed.…”