ABSTRACT
Ghrelin has been shown to alleviate neuropathic pain by inhibiting the release of proinflammatory cytokines. The purpose of this study was to investigate the role of GSK-3ß/ß-catenin signaling in mediating the effect of ghrelin on neuropathic pain and to understand the associated mechanisms. Chronic constriction injury (CCI) of the sciatic nerve was used to establish a rat model of neuropathic pain. Hyperalgesia and allodynia were evaluated by observing the mechanical withdrawal threshold and the thermal withdrawal latency. Wnt3a and ß-catenin protein expression and GSK-3ß phosphorylation were detected by western blotting analysis. The levels of tumor necrosis factor-α and IL-1ß were determined using an enzyme-linked immunosorbent assay. In addition, we used immunohistochemical analysis to determine the levels of GSK-3ß phosphorylation in the dorsal horn of the spinal cord. Intrathecal delivery of ghrelin effectively ameliorated CCI-induced mechanical allodynia and thermal hyperalgesia at 7 and 14 days and reduced the levels of tumor necrosis factor-α. Ghrelin inhibited CCI-induced GSK-3ß activation and ß-catenin overexpression in the spinal dorsal horn. Moreover, intrathecal injection of ghrelin suppressed the activation of GSK-3ß in the spinal dorsal horn of CCI rats, as assessed by immunohistochemical analysis. Our data indicated that ghrelin could markedly alleviate neuropathic pain by inhibiting the expression of ß-catenin, via the suppression of GSK-3ß activation, in the spinal cord of CCI rats.
Subject(s)
Ghrelin/administration & dosage , Hyperalgesia/drug therapy , Neuralgia/drug therapy , Sciatic Nerve/injuries , Animals , Disease Models, Animal , Gene Expression Regulation/drug effects , Glycogen Synthase Kinase 3 beta/metabolism , Humans , Hyperalgesia/etiology , Hyperalgesia/pathology , Injections, Spinal , Male , Neuralgia/etiology , Neuralgia/pathology , Nociception/drug effects , Phosphorylation/drug effects , Rats , Spinal Cord Dorsal Horn/drug effects , Spinal Cord Dorsal Horn/pathology , beta Catenin/metabolismABSTRACT
BACKGROUND AND OBJECTIVES: Pulsed radiofrequency (PRF) is a minimal neurodestructive interventional pain therapy. However, its analgesic mechanism remains largely unclear. We aimed to investigate the peripheral and spinal mechanisms of PRF applied either adjacent to the ipsilateral L5 dorsal root ganglion (PRF-DRG) or PRF to the sciatic nerve (PRF-SN) in the neuropathic pain behavior induced by chronic constriction injury (CCI) in rats. METHODS: On day 0, CCI or sham surgeries were performed. Rats then received either PRF-DRG, PRF-SN, or sham PRF treatment on day 4. Pain behavioral tests were conducted before surgeries and on days 1, 3, 5, 7, 9, 11, 13, and 14. After the behavioral tests, the rats were sacrificed. The venous blood or sciatic nerve samples were collected for ELISAs and the dorsal horns of the L4-L6 spinal cord were collected for western blot examination. RESULTS: The mechanical allodynia and the thermal hyperalgesia has been relieved by a single PRF-DRG or PRF-SN application. In addition, the analgesic effect of PRF-DRG was superior to PRF-SN on CCI-induced neuropathic pain. Either PRF-DRG or PRF-SN reversed the enhancement of interleukin 1ß (IL-1ß) and tumor necrosis factor alpha (TNF-α) levels in the blood of CCI rats. PRF-DRG or PRF-SN also downregulated spinal ß-catenin expression. CONCLUSIONS: PRF treatment either to DRG or to sciatic nerve reduced neuropathic pain behavior, and reduced peripheral levels of pro-inflammatory cytokines and spinal ß-catenin expression in CCI rats. PRF to DRG has a better analgesic effect than PRF to the nerve.
