{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T15:31:53Z","timestamp":1787585513206,"version":"build-2736575974"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,10,10]],"date-time":"2019-10-10T00:00:00Z","timestamp":1570665600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,10,10]],"date-time":"2019-10-10T00:00:00Z","timestamp":1570665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81603198"],"award-info":[{"award-number":["81603198"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>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-3\u03b2\/\u03b2-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 \u03b2-catenin protein expression and GSK-3\u03b2 phosphorylation were detected by western blotting analysis. The levels of tumor necrosis factor-\u03b1 and IL-1\u03b2 were determined using an enzyme-linked immunosorbent assay. In addition, we used immunohistochemical analysis to determine the levels of GSK-3\u03b2 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-\u03b1. Ghrelin inhibited CCI-induced GSK-3\u03b2 activation and \u03b2-catenin overexpression in the spinal dorsal horn. Moreover, intrathecal injection of ghrelin suppressed the activation of GSK-3\u03b2 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 \u03b2-catenin, via the suppression of GSK-3\u03b2 activation, in the spinal cord of CCI rats.<\/jats:p>","DOI":"10.1038\/s41598-019-51140-w","type":"journal-article","created":{"date-parts":[[2019,10,10]],"date-time":"2019-10-10T10:40:39Z","timestamp":1570704039000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Effects of ghrelin on pGSK-3\u03b2 and \u03b2-catenin expression when protects against neuropathic pain behavior in rats challenged with chronic constriction injury"],"prefix":"10.1038","volume":"9","author":[{"given":"Zhiyou","family":"Peng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leiqiong","family":"Zha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meijuan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunze","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuejiao","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiying","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,10,10]]},"reference":[{"issue":"10","key":"51140_CR1","doi-asserted-by":"publisher","first-page":"2204","DOI":"10.1016\/j.pain.2011.06.017","volume":"152","author":"TS Jensen","year":"2011","unstructured":"Jensen, T. S. et al. A new definition of neuropathic pain. Pain. 152(10), 2204\u20135 (2011).","journal-title":"Pain."},{"issue":"1","key":"51140_CR2","doi-asserted-by":"publisher","first-page":"85","DOI":"10.3111\/13696998.2012.729548","volume":"16","author":"PC Langley","year":"2013","unstructured":"Langley, P. C., Van Litsenburg, C., Cappelleri, J. C. & Carroll, D. The burden associated with neuropathic pain in Western Europe. J Med Econ. 16(1), 85\u201395 (2013).","journal-title":"J Med Econ."},{"key":"51140_CR3","doi-asserted-by":"publisher","first-page":"S35","DOI":"10.1007\/s40122-017-0087-0","volume":"6","author":"G Cruccu","year":"2017","unstructured":"Cruccu, G. & Truini, A. A review of Neuropathic Pain: From Guidelines to Clinical Practice. Pain Ther. 6, S35\u2013S42 (2017).","journal-title":"Pain Ther."},{"issue":"12","key":"51140_CR4","doi-asserted-by":"publisher","first-page":"767","DOI":"10.1038\/nrm3470","volume":"13","author":"C Niehrs","year":"2012","unstructured":"Niehrs, C. The complex world of WNT receptor signalling. Nat Rev Mol Cell Biol. 13(12), 767\u201379 (2012).","journal-title":"Nat Rev Mol Cell Biol."},{"issue":"5","key":"51140_CR5","doi-asserted-by":"publisher","first-page":"2268","DOI":"10.1172\/JCI65364","volume":"123","author":"YK Zhang","year":"2013","unstructured":"Zhang, Y. K. et al. WNT signaling underlies the pathogenesis of neuropathic pain in rodents. J Clin Invest. 123(5), 2268\u201386 (2013).","journal-title":"J Clin Invest."},{"issue":"3","key":"51140_CR6","doi-asserted-by":"publisher","first-page":"4727","DOI":"10.3892\/mmr.2015.3972","volume":"12","author":"W Feng","year":"2015","unstructured":"Feng, W., Teng, R. N., Zhao, Y., Gao, J. & Chu, H. C. Epigenetic modulation of Wnt signaling contributes to neuropathic pain in rats. Mol Med Rep. 12(3), 4727\u20134733 (2015).","journal-title":"Mol Med Rep."},{"issue":"2","key":"51140_CR7","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1080\/14728222.2018.1420781","volume":"22","author":"V Fernandes","year":"2018","unstructured":"Fernandes, V. et al. Cellular and molecular mechanisms driving neuropathic pain: recent advancements and challenges. Expert Opin Ther Tar. 22(2), 131\u2013142 (2018).","journal-title":"Expert Opin Ther Tar."},{"issue":"12","key":"51140_CR8","doi-asserted-by":"publisher","first-page":"2572","DOI":"10.1097\/j.pain.0000000000000366","volume":"156","author":"S Liu","year":"2015","unstructured":"Liu, S. et al. Wnt\/Ryk signaling contributes to neuropathic pain by regulating sensory neuron excitability and spinal synaptic plasticity in rats. Pain. 156(12), 2572\u20132584 (2015).","journal-title":"Pain."},{"key":"51140_CR9","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/j.neulet.2016.10.004","volume":"634","author":"W Xu","year":"2016","unstructured":"Xu, W., Zhu, M., Yuan, S. & Yu, W. Spinal CXCL5 contributes to nerve injury-induced neuropathic pain via modulating GSK-3beta phosphorylation and activity in rats. Neurosci Lett. 634, 52\u201359 (2016).","journal-title":"Neurosci Lett."},{"key":"51140_CR10","doi-asserted-by":"publisher","first-page":"174480691770937","DOI":"10.1177\/1744806917709372","volume":"13","author":"Qing Ou Yang","year":"2017","unstructured":"Yang, Q. O. et al. Ryk receptors on unmyelinated nerve fibers mediate excitatory synaptic transmission and CCL2 release during neuropathic pain induced by peripheral nerve injury. Molecular Pain. 13 (2017).","journal-title":"Molecular Pain"},{"issue":"6762","key":"51140_CR11","doi-asserted-by":"publisher","first-page":"656","DOI":"10.1038\/45230","volume":"402","author":"M Kojima","year":"1999","unstructured":"Kojima, M. et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 402(6762), 656\u201360 (1999).","journal-title":"Nature."},{"issue":"6","key":"51140_CR12","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1016\/j.molmet.2015.03.005","volume":"4","author":"TD Muller","year":"2015","unstructured":"Muller, T. D. et al. Ghrelin. Mol Metab. 4(6), 437\u201360 (2015).","journal-title":"Mol Metab."},{"issue":"1","key":"51140_CR13","doi-asserted-by":"publisher","first-page":"37","DOI":"10.2174\/157015909787602779","volume":"7","author":"F Ferrini","year":"2009","unstructured":"Ferrini, F., Salio, C., Lossi, L. & Merighi, A. Ghrelin in central neurons. Curr Neuropharmacol. 7(1), 37\u201349 (2009).","journal-title":"Curr Neuropharmacol."},{"key":"51140_CR14","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.peptides.2016.07.006","volume":"83","author":"FY Liu","year":"2016","unstructured":"Liu, F. Y. et al. Study on the molecular mechanism of antinociception induced by ghrelin in acute pain in mice. Peptides. 83, 1\u20137 (2016).","journal-title":"Peptides."},{"issue":"2","key":"51140_CR15","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1159\/000480478","volume":"43","author":"YQ Mao","year":"2017","unstructured":"Mao, Y. Q. et al. Antinociceptive Effect of Ghrelin in a Rat Model of Irritable Bowel Syndrome Involves TRPV1\/Opioid Systems. Cell Physiol Biochem. 43(2), 518\u2013530 (2017).","journal-title":"Cell Physiol Biochem."},{"issue":"2","key":"51140_CR16","doi-asserted-by":"publisher","first-page":"114","DOI":"10.18869\/acadpub.ibj.21.2.114","volume":"21","author":"F Azizzadeh","year":"2017","unstructured":"Azizzadeh, F., Mahmoodi, J., Sadigh-Eteghad, S., Farajdokht, F. & Mohaddes, G. Ghrelin Exerts Analgesic Effects through Modulation of IL-10 and TGF-beta Levels in a Rat Model of Inflammatory Pain. Iran Biomed J. 21(2), 114\u20139 (2017).","journal-title":"Iran Biomed J."},{"key":"51140_CR17","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.peptides.2013.03.004","volume":"43","author":"J Wei","year":"2013","unstructured":"Wei, J. et al. In vivo characterization of the effects of ghrelin on the modulation of acute pain at the supraspinal level in mice. Peptides. 43, 76\u201382 (2013).","journal-title":"Peptides."},{"issue":"2","key":"51140_CR18","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1097\/AAP.0000000000000050","volume":"39","author":"C-H Zhou","year":"2014","unstructured":"Zhou, C.-H. et al. Ghrelin Alleviates Neuropathic Pain Through GHSR-1amodulation of acute pain the p38 MAPK\/NF-\u03baB Pathway in a Rat Chronic Constriction Injury Model. Regional Anesthesia and Pain Medicine. 39(2), 137\u2013148 (2014).","journal-title":"Regional Anesthesia and Pain Medicine."},{"key":"51140_CR19","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/j.ejphar.2017.11.024","volume":"819","author":"N Ishii","year":"2018","unstructured":"Ishii, N. et al. Ghrelin alleviates paclitaxel-induced peripheral neuropathy by reducing oxidative stress and enhancing mitochondrial anti-oxidant functions in mice. Eur J Pharmacol. 819, 35\u201342 (2018).","journal-title":"Eur J Pharmacol."},{"issue":"5","key":"51140_CR20","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1507\/endocrj.K10E-396","volume":"58","author":"H Chung","year":"2011","unstructured":"Chung, H., Chung, H. Y., Bae, C. W., Kim, C. J. & Park, S. Ghrelin suppresses tunicamycin- or thapsigargin-triggered endoplasmic reticulum stress-mediated apoptosis in primary cultured rat cortical neuronal cells. Endocr J. 58(5), 409\u201320 (2011).","journal-title":"Endocr J."},{"issue":"1","key":"51140_CR21","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1016\/j.expneurol.2011.04.003","volume":"230","author":"E Lim","year":"2011","unstructured":"Lim, E., Lee, S., Li, E., Kim, Y. & Park, S. Ghrelin protects spinal cord motoneurons against chronic glutamate-induced excitotoxicity via ERK1\/2 and phosphatidylinositol-3-kinase\/Akt\/glycogen synthase kinase-3beta pathways. Exp Neurol. 230(1), 114\u201322 (2011).","journal-title":"Exp Neurol."},{"issue":"1","key":"51140_CR22","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1530\/JME-10-0143","volume":"47","author":"YP Xu","year":"2011","unstructured":"Xu, Y. P. et al. Ghrelin ameliorates hypoxia-induced pulmonary hypertension via phospho-GSK3 beta\/beta-catenin signaling in neonatal rats. J Mol Endocrino. 47(1), 33\u201343 (2011).","journal-title":"J Mol Endocrino."},{"issue":"3","key":"51140_CR23","doi-asserted-by":"publisher","first-page":"395","DOI":"10.3727\/096368916X694364","volume":"26","author":"Y Zhao","year":"2017","unstructured":"Zhao, Y. et al. GSK-3beta Inhibition Induced Neuroprotection, Regeneration, and Functional Recovery After Intracerebral Hemorrhagic Stroke. Cell Transplant. 26(3), 395\u2013407 (2017).","journal-title":"Cell Transplant."},{"issue":"2","key":"51140_CR24","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1016\/j.mehy.2006.12.042","volume":"69","author":"E Guneli","year":"2007","unstructured":"Guneli, E., Kazikdas, K. C. & Kolatan, E. Ghrelin may attenuate proinflammatory cytokine-mediated neuropathic pain. Med Hypotheses. 69(2), 356\u2013360 (2007).","journal-title":"Med Hypotheses."},{"issue":"3","key":"51140_CR25","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1016\/j.neulet.2010.05.066","volume":"479","author":"E Guneli","year":"2010","unstructured":"Guneli, E. et al. Gumustekin, M., Effects of repeated administered ghrelin on chronic constriction injury of the sciatic nerve in rats. Neurosci Lett. 479(3), 226\u201330 (2010).","journal-title":"Neurosci Lett."},{"issue":"31","key":"51140_CR26","doi-asserted-by":"crossref","first-page":"31901","DOI":"10.18632\/oncotarget.5043","volume":"6","author":"P Zhao","year":"2015","unstructured":"Zhao, P. et al. GSK-3beta regulates tumor growth and angiogenesis in human glioma cells. Oncotarget. 6(31), 31901\u201315 (2015).","journal-title":"Oncotarget."},{"issue":"1","key":"51140_CR27","doi-asserted-by":"publisher","first-page":"a007898","DOI":"10.1101\/cshperspect.a007898","volume":"5","author":"JL Stamos","year":"2013","unstructured":"Stamos, J. L. & Weis, W. I. The beta-catenin destruction complex. Cold Spring Harb Perspect Biol. 5(1), a007898 (2013).","journal-title":"Cold Spring Harb Perspect Biol."},{"key":"51140_CR28","doi-asserted-by":"crossref","unstructured":"Xu, F. et al. Misaligned Feeding May Aggravate Pain by Disruption of Sleeplioma cellss. Anesthesia & Analgesia. (1), 255\u2013261 (2017)","DOI":"10.1213\/ANE.0000000000002727"},{"issue":"2","key":"51140_CR29","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1007\/s12576-016-0517-5","volume":"68","author":"M So","year":"2018","unstructured":"So, M. et al. Inhibition of ghrelin-induced feeding in rats by pretreatment with a novel dual orexin receptor antagonist. J Physiol Sci. 68(2), 129\u2013136 (2018).","journal-title":"J Physiol Sci."},{"key":"51140_CR30","doi-asserted-by":"publisher","first-page":"1638","DOI":"10.1210\/en.2006-0993","volume":"148","author":"H Hashimoto","year":"2007","unstructured":"Hashimoto, H. et al. Centrally and peripherally administered ghrelin potently inhibits water intake in rats. Endocinology 148, 1638\u20131647 (2007).","journal-title":"Endocinology"},{"issue":"4","key":"51140_CR31","doi-asserted-by":"publisher","first-page":"746","DOI":"10.1097\/00000542-199310000-00017","volume":"79","author":"K Omote","year":"1993","unstructured":"Omote, K., Sonoda, H., Kawamata, M., Iwasaki, H. & Namiki, A. Potentiation of Antinociceptive Effects of Morphine by Calcium-Channel Blockers at the Level of the Spinal-Cord. Anesthesiology. 79(4), 746\u2013752 (1993).","journal-title":"Anesthesiology."},{"issue":"1","key":"51140_CR32","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1016\/0304-3959(88)90209-6","volume":"33","author":"GJ Bennett","year":"1988","unstructured":"Bennett, G. J. & Xie, Y. K. A Peripheral Mononeuropathy in Rat That Produces Disorders of Pain Sensation Like Those Seen in Man. Pain. 33(1), 87\u2013107 (1988).","journal-title":"Pain."},{"issue":"39","key":"51140_CR33","doi-asserted-by":"publisher","first-page":"10128","DOI":"10.1523\/JNEUROSCI.0800-16.2016","volume":"36","author":"N Xu","year":"2016","unstructured":"Xu, N. et al. Inhibition of YAP\/TAZ Activity in Spinal Cord Suppresses Neuropathic Pain. J Neurosci. 36(39), 10128\u201340 (2016).","journal-title":"J Neurosci."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-51140-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-51140-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-51140-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T14:28:04Z","timestamp":1671287284000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-51140-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,10]]},"references-count":33,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["51140"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-51140-w","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,10]]},"assertion":[{"value":"6 June 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 September 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 October 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"14664"}}