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-3β/β-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 β-catenin protein expression and GSK-3β phosphorylation were detected by western blotting analysis. The levels of tumor necrosis factor-α and IL-1β were determined using an enzyme-linked immunosorbent assay. In addition, we used immunohistochemical analysis to determine the levels of GSK-3β 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-3β activation and β-catenin overexpression in the spinal dorsal horn. Moreover, intrathecal injection of ghrelin suppressed the activation of GSK-3β 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 β-catenin, via the suppression of GSK-3β activation, in the spinal cord of CCI rats.
Highlights
Neuropathic pain (NP), characterized by spontaneous pain, hyperalgesia, and allodynia, is a type of chronic pain defined as “pain caused by a lesion or disease of the somatosensory system”[1]
In the constriction injury (CCI) group, the ipsilateral thermal withdrawal latency (TWL) significantly decreased at day 3 and the mechanical withdrawal threshold (MWT) significantly decreased at day 1 (p < 0.05, n = 5), but the contralateral side showed no change compared with the sham group and the normal control rats
Continuous intrathecal injection of ghrelin for 7 days significantly increased the TWL and MWT on the ipsilateral side compared with CCI group (p = 0.05, n = 5) and these effects lasted until 14 days after CCI surgery
Summary
Neuropathic pain (NP), characterized by spontaneous pain, hyperalgesia, and allodynia, is a type of chronic pain defined as “pain caused by a lesion or disease of the somatosensory system”[1]. Ghrelin, which was first isolated from the rat stomach by Kojima in 1999, has a plethora of biological effects by interacting with growth hormone secretagogue receptor (GHSR). Emerging evidence from recent studies suggests that GHSR is expressed in some regions involved in controlling pain transmission, such as the hypothalamic arcuate nucleus, ventricular hypothalamic nucleus, hypophysis, hippocampus, and spinal cord[13]. These findings suggest that ghrelin may play an important role in pain regulation. Glycogen synthase kinase-3β (GSK-3β) is one of the limiting enzymes of glycogen synthesis It participates in various cellular signaling pathways and is a contributing factor in regulating these pathways, including the Wnt3a, NF-κB, and MAPK pathways. We hypothesized that ghrelin may mitigate NP by regulating the activation of GSK-3β and the Wnt3a/β-catenin signaling pathway
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