{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T17:53:38Z","timestamp":1790013218630,"version":"4.0.1"},"reference-count":23,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,5,23]],"date-time":"2023-05-23T00:00:00Z","timestamp":1684800000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000026","name":"National Institute on Drug Abuse","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003768","name":"Universit\u00e9 de Strasbourg","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003768","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Psychiatry"],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Tianeptine is approved in some countries to treat depression and anxiety. In addition to its activity on serotonin and glutamate neurotransmission, tianeptine has been proven to be a mu-opioid receptor (MOR) agonist, but only a few preclinical studies have characterized the opioid-like behavioral effects of tianeptine.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this study, we tested tianeptine activity on G protein activation using the [S35] GTP\u03b3S binding assay in brain tissue from MOR+\/+ and MOR\u2212\/\u2212 mice. Then, to determine whether tianeptine behavioral responses are MOR-dependent, we characterized the analgesic, locomotor, and rewarding responses of tianeptine in MOR+\/+ and MOR\u2212\/\u2212 mice using tail immersion, hot plate, locomotor, and conditioned place preference tests.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Using the [S35] GTP\u03b3S binding assay, we found that tianeptine signaling is mediated by MOR in the brain with properties similar to those of DAMGO (a classic MOR agonist). Furthermore, we found that the MOR is necessary for tianeptine's analgesic (tail immersion and hot plate), locomotor, and rewarding (conditioned place preference) effects. Indeed, these behavioral effects could only be measured in MOR+\/+ mice but not in MOR\u2212\/\u2212 mice. Additionally, chronic administration of tianeptine induced tolerance to its analgesic and hyperlocomotor effects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>These findings suggest that tianeptine's opioid-like effects require MOR and that chronic use could lead to tolerance.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fpsyt.2023.1186397","type":"journal-article","created":{"date-parts":[[2023,5,23]],"date-time":"2023-05-23T04:34:13Z","timestamp":1684816453000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Chronic tianeptine induces tolerance in analgesia and hyperlocomotion via mu-opioid receptor activation in mice"],"prefix":"10.3389","volume":"14","author":[{"given":"Florence","family":"Allain","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aliza T.","family":"Ehrlich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"McNicholas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florence","family":"Gross","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiya","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigitte L.","family":"Kieffer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel","family":"Darcq","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,5,23]]},"reference":[{"key":"B1","first-page":"S21","article-title":"Structure-activity relationships of tricyclic antidepressants, with special reference to tianeptine","volume":"11","author":"Labrid","year":"1988","journal-title":"Clin Neuropharmacol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"231","DOI":"10.2165\/00023210-200115030-00006","article-title":"Tianeptine: a review of its use in depressive disorders","volume":"15","author":"Wagstaff","year":"2001","journal-title":"CNS Drugs."},{"key":"B3","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1038\/sj.mp.4001648","article-title":"Neurobiology of mood, anxiety, and emotions as revealed by studies of a unique antidepressant: tianeptine","volume":"10","author":"Mcewen","year":"2005","journal-title":"Mol Psychiatry."},{"key":"B4","doi-asserted-by":"publisher","first-page":"478","DOI":"10.1007\/BF00169302","article-title":"Tianeptine, a selective enhancer of serotonin uptake in rat brain","volume":"336","author":"Mennini","year":"1987","journal-title":"Naunyn Schmiedebergs Arch Pharmacol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"3509","DOI":"10.1111\/j.1460-9568.2007.05952.x","article-title":"Involvement of AMPA receptor phosphorylation in antidepressant actions with special reference to tianeptine","volume":"26","author":"Svenningsson","year":"2007","journal-title":"Eur J Neurosci."},{"key":"B6","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1038\/mp.2009.80","article-title":"The neurobiological properties of tianeptine (Stablon): from monoamine hypothesis to glutamatergic modulation","volume":"15","author":"Mcewen","year":"2010","journal-title":"Mol Psychiatry."},{"key":"B7","doi-asserted-by":"publisher","first-page":"e411","DOI":"10.1038\/tp.2014.30","article-title":"The atypical antidepressant and neurorestorative agent tianeptine is a mu-opioid receptor agonist","volume":"4","author":"Gassaway","year":"2014","journal-title":"Transl Psychiatry."},{"key":"B8","doi-asserted-by":"publisher","first-page":"2052","DOI":"10.1038\/npp.2017.60","article-title":"The behavioral effects of the antidepressant tianeptine require the mu-opioid receptor","volume":"42","author":"Samuels","year":"2017","journal-title":"Neuropsychopharmacology."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1387","DOI":"10.1038\/s41386-021-01192-2","article-title":"Mu opioid receptors on hippocampal GABAergic interneurons are critical for the antidepressant effects of tianeptine","volume":"47","author":"Han","year":"2022","journal-title":"Neuropsychopharmacology."},{"key":"B10","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1097\/FBP.0b013e32833db7d4","article-title":"Tianeptine reduces morphine antinociceptive tolerance and physical dependence","volume":"21","author":"Chu","year":"2010","journal-title":"Behav Pharmacol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1038\/383819a0","article-title":"Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the mu-opioid-receptor gene","volume":"383","author":"Matthes","year":"1996","journal-title":"Nature."},{"key":"B12","doi-asserted-by":"publisher","first-page":"917","DOI":"10.1016\/j.biopsych.2015.05.020","article-title":"Mice lacking GPR88 show motor deficit, improved spatial learning, and low anxiety reversed by delta opioid antagonist","volume":"79","author":"Meirsman","year":"2016","journal-title":"Biol Psychiatry."},{"key":"B13","doi-asserted-by":"publisher","first-page":"ENEURO","DOI":"10.1523\/ENEURO.0202-16.2016","article-title":"GPR88 in A2AR neurons enhances anxiety-like behaviors","volume":"3","author":"Meirsman","year":"2016","journal-title":"eNeuro."},{"key":"B14","doi-asserted-by":"publisher","first-page":"aaz3140","DOI":"10.1126\/scisignal.aaz3140","article-title":"Low intrinsic efficacy for G protein activation can explain the improved side effect profiles of new opioid agonists","volume":"13","author":"Gillis","year":"2020","journal-title":"Sci Signal."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1288","DOI":"10.1038\/npp.2011.316","article-title":"RSK2 signaling in medial habenula contributes to acute morphine analgesia","volume":"37","author":"Darcq","year":"2012","journal-title":"Neuropsychopharmacology."},{"key":"B16","doi-asserted-by":"publisher","first-page":"574","DOI":"10.1101\/lm.2221011","article-title":"RSK2 signaling in brain habenula contributes to place aversion learning","volume":"18","author":"Darcq","year":"2011","journal-title":"Learn Mem."},{"key":"B17","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1016\/0163-7258(87)90108-2","article-title":"The role of reward pathways in the development of drug dependence","volume":"35","author":"Wise","year":"1987","journal-title":"Pharmacol Ther."},{"key":"B18","doi-asserted-by":"publisher","first-page":"700","DOI":"10.1016\/j.biopsych.2010.10.021","article-title":"Deletion of the \u03b4 opioid receptor gene impairs place conditioning but preserves morphine reinforcement","volume":"69","author":"Le Merrer","year":"2011","journal-title":"Biol Psychiatr."},{"key":"B19","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1097\/FBP.0b013e32834a1f2c","article-title":"Delta opioid receptor analgesia: recent contributions from pharmacology and molecular approaches","volume":"22","author":"Gaveriaux-Ruff","year":"2011","journal-title":"Behav Pharmacol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1016\/0165-0173(93)90013-P","article-title":"The neural basis of drug craving: an incentive-sensitization theory of addiction","volume":"18","author":"Robinson","year":"1993","journal-title":"Brain Res Brain Res Rev."},{"key":"B21","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1007\/s002130050273","article-title":"Morphine-induced long-term sensitization to the locomotor effects of morphine and amphetamine depends on the temporal pattern of the pretreatment regimen","volume":"131","author":"Vanderschuren","year":"1997","journal-title":"Psychopharmacology."},{"key":"B22","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1016\/j.psym.2018.07.006","article-title":"Tianeptine abuse and dependence: case report and literature review","volume":"59","author":"Lauhan","year":"2018","journal-title":"Psychosomatics."},{"key":"B23","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1097\/JCP.0b013e3182217a50","article-title":"Absence of psychostimulant effects of a supratherapeutic dose of tianeptine: a placebo-controlled study versus methylphenidate in young healthy volunteers","volume":"31","author":"Bernard","year":"2011","journal-title":"J Clin Psychopharmacol."}],"container-title":["Frontiers in Psychiatry"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpsyt.2023.1186397\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,23]],"date-time":"2023-05-23T04:34:17Z","timestamp":1684816457000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpsyt.2023.1186397\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,23]]},"references-count":23,"alternative-id":["10.3389\/fpsyt.2023.1186397"],"URL":"https:\/\/doi.org\/10.3389\/fpsyt.2023.1186397","relation":{},"ISSN":["1664-0640"],"issn-type":[{"value":"1664-0640","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,23]]},"article-number":"1186397"}}