LIPOXIN A(4) ATTENUATES RADICULAR PAIN POSSIBLY BY INHIBITING SPINAL ERK, JNK AND NF-kappa B/P65 AND CYTOKINE SIGNALS, BUT NOT P38, IN A RAT MODEL OF NON-COMPRESSIVE LUMBAR DISC HERNIATION

摘要

Inflammatory response induced by protrused nucleus pulposus (NP) has been shown to play a crucial role in the process of radicular pain. Lipoxins represent a unique class of lipid mediators that have anti-inflammatory and proresolving action. The present study was undertaken to investigate if intrathecal lipoxin A(4) (LXA(4)) could alleviate mechanical allodynia in the rat models of application of NP to the L5 dorsal root ganglion (DRG). Non-compressive models of application of NP to L5 DRG were established and intrathecal catheterization for drug administration was performed in rats. Daily intrathecal injection of vehicle or LXA(4) (10 ng or 100 ng) was performed for three successive days post-operation. Mechanical thresholds were tested and the ipsilateral lumbar (L4-L6) segment of spinal dorsal horns were removed for the determination of tumor necrosis factor-alpha (TNF-alpha), IL-1 beta, transforming growth factor-beta 1 (TGF-beta 1) and IL-10 expression and NF-kappa B/p65, extracellular signal-regulated kinase (ERK), C-Jun N-terminal kinase (JNK) and P38 expression. Application of NP to DRG in rats induced mechanical allodynia, increased the expression of pro-inflammatory factors (TNF-alpha and IL-1 beta), NF-kappa B/p65, the phosphorylated-ERK (p-ERK), -JNK (p-JNK) and -P38 (p-p38) and decreased the expression of anti-inflammatory cytokines (TGF-beta 1 and IL-10) in the ipsilateral lumbar (L4-L6) segment of spinal dorsal horns. Intrathecal injection of LXA(4) alleviated the development of neuropathic pain, inhibited the upregulation of pro-inflammatory cytokines (TNF-alpha and IL-1 beta), upregulated the expression of anti-inflammatory cytokines (TGF-beta 1 and IL-10) and attenuated the activation of NF-kappa B/p65, p-ERK, p-JNK, but not p-p38, in a dose-dependent manner. In this study, we have demonstrated that LXA(4) potently alleviate radicular pain in a rat model of non-compressive lumbar disc herniation. The anti-inflammatory and pro-resolution properties of LXA(4) have shown a great promise for the management of radicular pain caused by intervertebral disc herniation. (C) 2015 IBRO. Published by Elsevier Ltd. All rights reserved.