{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,25]],"date-time":"2026-01-25T04:54:47Z","timestamp":1769316887696,"version":"3.49.0"},"reference-count":42,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,2,28]],"date-time":"2023-02-28T00:00:00Z","timestamp":1677542400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Nanjing Fragrant Jasmine Agricultural Technology Co., Ltd.","award":["19H2H22000212"],"award-info":[{"award-number":["19H2H22000212"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The antinociceptive activity of the flower extracts of Styrax japonicus was confirmed in our previous study. However, the key compound for analgesia has not been distinguished, and the corresponding mechanism is obscure. In this study, the active compound was isolated from the flower by multiple chromatographic techniques and structurally illustrated using spectroscopic methods and referring to the related literature. The antinociceptive activity of the compound and the underlying mechanisms were investigated using animal tests. The active compound was determined to be jegosaponin A (JA), which showed significant antinociceptive responses. JA was also shown to possess sedative and anxiolytic activities but no anti-inflammatory effect, implying the association of the antinociceptive effects with the sedative and anxiolytic activities. Further antagonists and calcium ionophore tests showed that the antinociceptive effect of JA was blocked by flumazenil (FM, antagonist for GABA-A receptor) and reversed by WAY100635 (WAY, antagonist for 5-HT1A receptor). Contents of 5-HT and its metabolite (5-HIAA) increased significantly in the hippocampus and striatum tissues after JA administration. The results indicated that the antinociceptive effect of JA was regulated by the neurotransmitter system, especially GABAergic and serotonergic systems.<\/jats:p>","DOI":"10.3390\/molecules28052243","type":"journal-article","created":{"date-parts":[[2023,2,28]],"date-time":"2023-02-28T04:28:41Z","timestamp":1677558521000},"page":"2243","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Involvement of GABAergic and Serotonergic Systems in the Antinociceptive Effect of Jegosaponin A Isolated from Styrax japonicus"],"prefix":"10.3390","volume":"28","author":[{"given":"Lei","family":"He","sequence":"first","affiliation":[{"name":"Department of Resources and Environment, School of Agriculture and Biology, Shanghai Jiao Tong University, 800 Dong Chuan Road, Shanghai 200240, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Landscape Architecture, School of Design, Shanghai Jiao Tong University, 800 Dong Chuan Road, Shanghai 200240, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Landscape Architecture, School of Design, Shanghai Jiao Tong University, 800 Dong Chuan Road, Shanghai 200240, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wencui","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Landscape Architecture, School of Design, Shanghai Jiao Tong University, 800 Dong Chuan Road, Shanghai 200240, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Landscape Architecture, School of Design, Shanghai Jiao Tong University, 800 Dong Chuan Road, Shanghai 200240, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,28]]},"reference":[{"key":"ref_1","first-page":"561","article-title":"Volatile components and antibacterial effects of simultaneous steam distillation and solvent extracts from the leaves of Styrax japonica S. et Z.","volume":"13","author":"Kim","year":"2004","journal-title":"Food Sci. Biotechnol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1007\/s12272-010-0608-4","article-title":"Isolation of virus-cell fusion inhibitory components from the stem bark of Styrax japonica S. et Z","volume":"33","author":"Lee","year":"2010","journal-title":"Arch. Pharm. Res."},{"key":"ref_3","first-page":"931","article-title":"Lignans from the stem of Styrax japonica","volume":"23","author":"Wu","year":"2011","journal-title":"Asian J. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1055\/s-2004-835853","article-title":"Anti-complement activity of norlignans and terpenes from the stem bark of Styrax japonica","volume":"70","author":"Min","year":"2004","journal-title":"Planta Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1248\/bpb.30.139","article-title":"Styraxoside A isolated from the stem bark of Styrax japonica inhibits lipopolysaccharide-induced expression of inducible nitric oxide synthase and cyclooxygenase-2 in RAW 264.7 cells by suppressing nuclear factor-kappa B activation","volume":"30","author":"Yun","year":"2007","journal-title":"Biol. Pharm. Bull."},{"key":"ref_6","unstructured":"Wang, G.Q. (2014). Compilation of National Chinese Herbal Medicine, People Public Health Publishing Company. [3rd ed.]."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"114779","DOI":"10.1016\/j.jep.2021.114779","article-title":"Antinociceptive effects of flower extracts and the active fraction from Styrax japonicus","volume":"284","author":"He","year":"2022","journal-title":"J. Ethnopharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Kaszniak, A. (2001). Emotions, Qualia, and Consciousness, World Scientific.","DOI":"10.1142\/4298"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2421","DOI":"10.1093\/pm\/pnz017","article-title":"Pain pathways and nervous system plasticity: Learning and memory in pain","volume":"20","author":"McCarberg","year":"2019","journal-title":"Pain Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.npep.2016.03.003","article-title":"Oxytocin in hypothalamic supraoptic nucleus is transferred to the caudate nucleus to influence pain modulation","volume":"58","author":"Pan","year":"2016","journal-title":"Neuropeptides"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"805","DOI":"10.2147\/JPR.S250391","article-title":"Antinociceptive effect of the citrus flavonoid eriocitrinon postoperative pain conditions","volume":"13","author":"Alghamdi","year":"2020","journal-title":"J. Pain Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.jep.2014.03.032","article-title":"Antinociceptive effect of ethanol extract of leaves of Lannea coromandelica","volume":"154","author":"Imam","year":"2014","journal-title":"J. Ethnopharmacol."},{"key":"ref_13","first-page":"186","article-title":"Analgesic effect of the aqueous and ethanolic extracts of clove","volume":"3","author":"Nazariborun","year":"2013","journal-title":"Avicenna J. Phytomed."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1007\/s12272-013-0093-7","article-title":"Mechanisms involved in the antinociceptive effects of orally administered oleanolic acid in the mouse","volume":"36","author":"Park","year":"2013","journal-title":"Arch. Pharm. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.1213\/ANE.0000000000004165","article-title":"Systematic review and meta-analysis of virtual reality in pediatrics: Effects on pain and anxiety","volume":"129","author":"Eijlers","year":"2019","journal-title":"Anesth. Analg."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1328","DOI":"10.1248\/bpb.b15-00187","article-title":"Antiinflammatory and analgesic activities of ethanol extract and isolated compounds from Millettia pulchra","volume":"38","author":"Huo","year":"2015","journal-title":"Biol. Pharm. Bull."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1240","DOI":"10.1016\/j.jep.2011.07.052","article-title":"Antinociceptive and hypnotic properties of Celastrus orbiculatus","volume":"137","author":"Park","year":"2011","journal-title":"J. Ethnopharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Nishimura, M., Fuchino, H., Takayanagi, K., Kawakami, H., Nakayama, H., Kawahara, N., and Shimada, Y. (2021). Toxicity of jegosaponins A and B from Styrax japonica Siebold et al. Zuccarini in prostate cancer cells and zebrafish embryos resulting from increased membrane permeability. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22126354"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1248\/cpb.48.1093","article-title":"Antisweet natural products. XV. Structures of jegosaponins A-D from Styrax japonica Sieb. et Zucc","volume":"48","author":"Yoshikawa","year":"2000","journal-title":"Chem. Pharm. Bull."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1152\/physrev.00040.2019","article-title":"Cellular circuits in the brain and their modulation in acute and chronic pain","volume":"101","author":"Kuner","year":"2021","journal-title":"Physiol. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.tins.2008.01.003","article-title":"Cortical excitation and chronic pain","volume":"31","author":"Zhuo","year":"2008","journal-title":"Trends Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1016\/j.jep.2013.12.003","article-title":"Antinociceptive and anti-inflammatory activities of extract and two isolated flavonoids of Carthamus tinctorius L.","volume":"151","author":"Wang","year":"2014","journal-title":"J. Ethnopharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2062","DOI":"10.1021\/np200232s","article-title":"Antinociceptive Properties of Bergenin","volume":"74","author":"Nonato","year":"2011","journal-title":"J. Nat. Prod."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"746","DOI":"10.2174\/1874467213666201204153045","article-title":"Antinociceptive and anti-inflammatory like effects of Berberis baluchistanica","volume":"14","author":"Pervez","year":"2021","journal-title":"Curr. Molec. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/S0304-3959(00)00300-6","article-title":"Antinociceptive properties of neurosteroids II. Experiments with Saffan (R) and its components alphaxalone and alphadolone to reveal separation of anaesthetic and antinociceptive effects and the involvement of spinal cord GABA(A) receptors","volume":"88","author":"Nadeson","year":"2000","journal-title":"Pain"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1002\/ddr.10026","article-title":"Molecular determinants of opioid analgesia: Modulation of presynaptic calcium channels","volume":"54","author":"Beedle","year":"2001","journal-title":"Drug Dev. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/S0014-2999(01)01206-7","article-title":"Participation of the nitric oxide-cyclic GMP-ATP-sensitive K+ channel pathway in the antinociceptive action of ketorolac","volume":"426","year":"2001","journal-title":"Eur. J. Pharmacol."},{"key":"ref_28","first-page":"39","article-title":"Pharmacology of the capsaicin receptor, transient receptor potential vanilloid type-1 ion channel","volume":"Volume 68","author":"AbdelSalam","year":"2014","journal-title":"Capsaicin as a Therapeutic Molecule"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2055102919865160","DOI":"10.1177\/2055102919865161","article-title":"The mechanisms of pain tolerance and pain-related anxiety in acute pain","volume":"6","author":"Cimpean","year":"2019","journal-title":"Health Psychol. Open"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/1756-6606-5-10","article-title":"M-4 muscarinic receptor knockout mice display abnormal social behavior and decreased prepulse inhibition","volume":"5","author":"Koshimizu","year":"2012","journal-title":"Mol. Brain"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Hossain, M.F., Talukder, B., Rana, M.N., Refat, T., Sharmin Nipun, T., Naim Uddin, S.M., and Moazzem Hossen, S.M. (2016). In vivo sedative activity of methanolic extract of Stericulia villosa Roxb. leaves. BMC Complement. Altern. Med., 16.","DOI":"10.1186\/s12906-016-1374-8"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1002\/ptr.3106","article-title":"Behavioural characterization of four endemic Stachys taxa","volume":"24","author":"Savic","year":"2010","journal-title":"Phytother. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.jep.2013.06.033","article-title":"Correlation among cytotoxicity, hemolytic activity and the composition of steroidal saponins from Paris L.","volume":"149","author":"Liu","year":"2013","journal-title":"J. Ethnopharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1076\/phbi.40.4.253.8470","article-title":"Structure-activity relationships of haemolytic saponins","volume":"40","author":"Voutquenne","year":"2002","journal-title":"Pharm. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.trac.2012.02.007","article-title":"Quantitative H-1 NMR spectroscopy","volume":"35","author":"Bharti","year":"2012","journal-title":"Trac-Trends Anal. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1579","DOI":"10.1021\/np9001898","article-title":"Monoterpenes from Paeonia albiflora and their inhibitory activity on nitric oxide production by lipopolysaccharide-activated microglia","volume":"72","author":"Duan","year":"2009","journal-title":"J. Nat. Prod."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1007\/s11095-019-2745-x","article-title":"Intraperitoneal route of drug administration: Should it be used in experimental animal studies?","volume":"37","author":"Archie","year":"2020","journal-title":"Pharm. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.jphs.2019.11.004","article-title":"Involvement of the dopamine D-1 receptor system in the anxiolytic effect of cedrol in the elevated plus maze and light-dark box tests","volume":"142","author":"Zhang","year":"2020","journal-title":"J. Pharmacol. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"418","DOI":"10.3389\/fnmol.2018.00418","article-title":"Glutamate, glutamine and GABA levels in rat brain measured using MRS, HPLC and NMR methods in study of two models of autism","volume":"11","author":"Zieminska","year":"2018","journal-title":"Front. Molec. Neurosci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2357","DOI":"10.1016\/j.febslet.2011.06.004","article-title":"Central PGE(2) exhibits anxiolytic-like activity via EP1 and EP4 receptors in a manner dependent on serotonin 5-HT1A, dopamine D-1 and GABA(A) receptors","volume":"585","author":"Suzuki","year":"2011","journal-title":"FEBS Lett."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1002\/mnfr.201300237","article-title":"Identification of novel beta-lactoglobulin-derived peptides, wheylin-1 and -2, having anxiolytic-like activity in mice","volume":"58","author":"Yamada","year":"2014","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.physbeh.2018.01.004","article-title":"The anxiolytic effect of Juniperus virginiana L. essential oil and determination of its active constituents","volume":"189","author":"Zhang","year":"2018","journal-title":"Physiol. Behav."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/5\/2243\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:43:59Z","timestamp":1760121839000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/5\/2243"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,28]]},"references-count":42,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["molecules28052243"],"URL":"https:\/\/doi.org\/10.3390\/molecules28052243","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,28]]}}}