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Like other opioid drugs, tramadol abuse has adverse effects on central nervous system components. Chronic administration of tramadol induces maladaptive plasticity in brain structures responsible for cognitive function, such as the hippocampus. However, the mechanisms by which tramadol induces these alternations are not entirely understood. Here, we examine the effect of tramadol on apoptosis and synaptogenesis of hippocampal neuronal in vitro. First, the primary culture of hippocampal neurons from neonatal rats was established, and the purity of the neuronal cells was verified by immunofluorescent staining. To evaluate the effect of tramadol on neuronal cell viability MTT assay was carried out. The western blot analysis technique was performed for the assessment of apoptosis and synaptogenesis markers. Results show that chronic exposure to tramadol reduces cell viability of neuronal cells and naloxone reverses this effect. Also, the level of caspase\u20103 significantly increased in tramadol\u2010exposed hippocampal neurons. Moreover, tramadol downregulates protein levels of synaptophysin and stathmin as synaptogenesis markers. Interestingly, the effects of tramadol were abrogated by naloxone treatment. These findings suggest that tramadol can induce neurotoxicity in hippocampal neuronal cells, and this effect was partly mediated through opioid receptors.<\/jats:p>","DOI":"10.1002\/ddr.21973","type":"journal-article","created":{"date-parts":[[2022,7,9]],"date-time":"2022-07-09T03:43:23Z","timestamp":1657338203000},"page":"1425-1433","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Effect of tramadol on apoptosis and synaptogenesis in hippocampal neurons: The possible role of \u00b5\u2010opioid receptor"],"prefix":"10.1002","volume":"83","author":[{"given":"Saereh","family":"Hosseindoost","sequence":"first","affiliation":[{"name":"Pain Research Center, Neuroscience Institute Tehran University of Medical Science Tehran Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ardeshir","family":"Akbarabadi","sequence":"additional","affiliation":[{"name":"Iranian National Center for Addiction Studies Tehran University of Medical Sciences Tehran Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitra\u2010Sadat","family":"Sadat\u2010Shirazi","sequence":"additional","affiliation":[{"name":"Iranian National Center for Addiction Studies Tehran University of Medical Sciences Tehran Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seyed Mojtaba","family":"Mousavi","sequence":"additional","affiliation":[{"name":"Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine Tehran University of Medical Sciences Tehran Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Solmaz","family":"Khalifeh","sequence":"additional","affiliation":[{"name":"Cognitive and Neuroscience Research Center (CNRC), Tehran Medical Sciences, Amir\u2010Almomenin Hospital Islamic Azad University Tehran Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Azarakhsh","family":"Mokri","sequence":"additional","affiliation":[{"name":"Iranian National Center for Addiction Studies Tehran University of Medical Sciences Tehran Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmoudreza","family":"Hadjighassem","sequence":"additional","affiliation":[{"name":"Brain and Spinal Cord Injury Research Center, Neuroscience Institute Tehran University of Medical Sciences Tehran Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0688-5378","authenticated-orcid":false,"given":"Mohammad\u2010Reza","family":"Zarrindast","sequence":"additional","affiliation":[{"name":"Iranian National Center for Addiction Studies Tehran University of Medical Sciences Tehran Iran"},{"name":"Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine Tehran University of Medical Sciences Tehran Iran"},{"name":"Department of Pharmacology, School of Medicine Tehran University of Medical Sciences Tehran Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,7,9]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12640-020-00214-z"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1248\/bpb.26.1403"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1080\/00207450490461314"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2016.04.024"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11011-018-0194-6"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2017.00254"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02284844"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00406-007-0730-6"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2014.09.002"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2014.2411"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tox.2010.06.009"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2014.04.003"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyt.2019.00704"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12640-021-00354-w"},{"issue":"11","key":"e_1_2_8_16_1","first-page":"7323","article-title":"Effect of chronic usage of tramadol on motor cerebral cortex and testicular tissues of adult male albino rats and the effect of its withdrawal: Histological, immunohistochemical and biochemical study","volume":"7","author":"Ghoneim F. 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