Ghrelin Alleviates Neuropathic Pain Through GHSR-1a–Mediated Suppression of the p38 MAPK/NF-κB Pathway in a Rat Chronic Constriction Injury Model

Abstract

Neuropathic pain is related to the sustained activation of neuroglial cells and the production of proinflammatory cytokines in the spinal dorsal horn. Ghrelin, the endogenous ligand for growth hormone secretagogue receptor 1a (GHSR-1a), has been shown to inhibit the activation of microglia and the release of proinflammatory cytokines. The purpose of this study was to investigate the role of ghrelin/GHSR-1a signaling in neuropathic pain and to understand the associated mechanisms. A rat model of neuropathic pain was established by chronic constriction injury (CCI) of the sciatic nerve. Hyperalgesia and allodynia were evaluated by observing the mechanical withdrawal threshold and the thermal withdrawal latency. The expression levels of ghrelin and GHSR-1a were detected by semiquantitative reverse transcriptase-polymerase chain reaction and Western blot analysis. The levels of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α were detected using an enzyme-linked immunosorbent assay. The expression levels of p-p38 mitogen-activated protein kinases (p38 MAPK) and nuclear factor-κB (NF-κB) p65 were determined by Western blot and immunohistochemistry analysis. Both ghrelin and GHSR-1a were expressed in the spinal dorsal horns of normal rats and were not significantly different from that of sham rats. However, rats in the CCI model group developed severe hyperalgesia and allodynia, as well as significantly downregulated expression of ghrelin and GHSR-1a. Compared with CCI model rats, intrathecal injection of ghrelin clearly delayed thermal hyperalgesia and mechanical allodynia at 3, 5, and 7 days after CCI; reduced the levels of IL-1β, IL-6, and tumor necrosis factor-α; and inhibited the phosphorylation of p38 MAPK and the activation of NF-κBp65 in the spinal dorsal horn. In addition, the effect of ghrelin could be blocked by [D-Lys]-GHRP-6, a GHSR-1a antagonist. Our present study demonstrated that ghrelin alleviated neuropathic pain through a GHSR-1a-mediated suppression of the p38 MAPK/NF-κB pathway.