{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T13:23:47Z","timestamp":1787232227743,"version":"build-2736575974"},"reference-count":52,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"}],"content-domain":{"domain":["clinicalkey.com","clinicalkey.com.au","clinicalkey.es","clinicalkey.fr","clinicalkey.jp","ibroneuroscience.org","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Neuroscience"],"published-print":{"date-parts":[[2026,10]]},"DOI":"10.1016\/j.neuroscience.2026.08.005","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T06:45:07Z","timestamp":1785825907000},"page":"90-103","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":0,"special_numbering":"C","title":["In vivo evaluation of the dual MOP\/NOP agonist AT121: a potent analgesic that delays opioid tolerance and offers a superior withdrawal suppression profile to methadone"],"prefix":"10.1016","volume":"613","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-8802-597X","authenticated-orcid":false,"given":"Baraa E.","family":"Elawy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1132-9659","authenticated-orcid":false,"given":"Loai","family":"Aljerf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaza A.","family":"Allaham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georges M.","family":"Deeb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.neuroscience.2026.08.005_b0005","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1097\/ALN.0b013e318238bba6","article-title":"Molecular mechanisms of opioid receptor-dependent signaling and behavior","volume":"115","author":"Al-Hasani","year":"2011","journal-title":"Anesthesiology"},{"key":"10.1016\/j.neuroscience.2026.08.005_b0010","doi-asserted-by":"crossref","DOI":"10.3389\/fphar.2014.00280","article-title":"Opioid receptor desensitization: mechanisms and its link to tolerance","volume":"5","author":"Allouche","year":"2014","journal-title":"Front. Pharmacol."},{"key":"10.1016\/j.neuroscience.2026.08.005_b0015","doi-asserted-by":"crossref","DOI":"10.1002\/brb3.2975","article-title":"Effect of risperidone on morphine induced conditioned place preference and dopamine receptor D2 gene expression in male rat hippocampus","volume":"13","author":"Arani","year":"2023","journal-title":"Brain and Behavior"},{"key":"10.1016\/j.neuroscience.2026.08.005_b0020","doi-asserted-by":"crossref","first-page":"e136","DOI":"10.1016\/j.bja.2019.03.006","article-title":"Hot topics in opioid pharmacology: mixed and biased opioids","volume":"122","author":"Azzam","year":"2019","journal-title":"Br. J. Anaesth."},{"key":"10.1016\/j.neuroscience.2026.08.005_b0025","doi-asserted-by":"crossref","first-page":"3874","DOI":"10.3390\/ijms23073874","article-title":"A novel morphine drinking model of opioid dependence in rats","volume":"23","author":"Berr\u00edos-C\u00e1rcamo","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"10.1016\/j.neuroscience.2026.08.005_b0030","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1631\/jzus.2006.B0892","article-title":"Chronic morphine drinking establishes morphine tolerance, but not addiction in Wistar rats","volume":"7","author":"Binsack","year":"2006","journal-title":"J. Zhejiang Univ. Sci. B"},{"key":"10.1016\/j.neuroscience.2026.08.005_b0035","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0260880","article-title":"MOP and NOP receptor interaction: studies with a dual expression system and bivalent peptide ligands","volume":"17","author":"Bird","year":"2022","journal-title":"PLoS One"},{"key":"10.1016\/j.neuroscience.2026.08.005_b0040","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1016\/j.coph.2006.06.007","article-title":"Opioid receptor signaling: relevance for gastrointestinal therapy","volume":"6","author":"Bohn","year":"2006","journal-title":"Curr. Opin. Pharmacol."},{"key":"10.1016\/j.neuroscience.2026.08.005_b0045","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-017-10360-8","article-title":"Morphine activation of mu opioid receptors causes disinhibition of neurons in the ventral tegmental area mediated by \u03b2-arrestin2 and c-Src","volume":"7","author":"Bull","year":"2017","journal-title":"Sci. Rep."},{"key":"10.1016\/j.neuroscience.2026.08.005_b0050","doi-asserted-by":"crossref","first-page":"1764","DOI":"10.1152\/japplphysiol.00462.2002","article-title":"Effect of morphine on sympathetic nerve activity in humans","volume":"93","author":"Carter","year":"2002","journal-title":"Journal of Applied Physiology (Bethesda, Md: 1985)"},{"key":"10.1016\/j.neuroscience.2026.08.005_b0055","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1111\/jnc.14863","article-title":"Phosphorylation of unique C-terminal sites of the mu-opioid receptor variants 1B2 and 1C1 influences their Gs association following chronic morphine","volume":"152","author":"Chakrabarti","year":"2020","journal-title":"J. Neurochem."},{"key":"10.1016\/j.neuroscience.2026.08.005_b0060","doi-asserted-by":"crossref","first-page":"1478","DOI":"10.1002\/jnr.21272","article-title":"Activation of the nociceptin opioid system in rat sensory neurons produces antinociceptive effects in inflammatory pain: Involvement of inflammatory mediators","volume":"85","author":"Chen","year":"2007","journal-title":"J. Neurosci. Res."},{"key":"10.1016\/j.neuroscience.2026.08.005_b0065","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1038\/sj.npp.1301559","article-title":"Synaptic plasticity: multiple forms, functions, and mechanisms","volume":"33","author":"Citri","year":"2007","journal-title":"Neuropsychopharmacology"},{"key":"10.1016\/j.neuroscience.2026.08.005_b0070","unstructured":"Colgan G, Patel K, Lewis S, Colgan P, Lewis. AT-121 as a Potential Opioid Replacement. 2020. https:\/\/vtechworks.lib.vt.edu\/server\/api\/core\/bitstreams\/283eeb03-2130-4ce6-8a7d-d9ae774f9c0e\/content."},{"key":"10.1016\/j.neuroscience.2026.08.005_b0075","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1007\/s40263-022-00924-2","article-title":"Current and future therapeutic optionsin pain management: multi-mechanistic opioids involving both MOR and NOP receptor activation","volume":"36","author":"Coluzzi","year":"2022","journal-title":"CNS Drugs"},{"key":"10.1016\/j.neuroscience.2026.08.005_b0080","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1124\/mol.119.115956","article-title":"A biased view of \u03bc-opioid receptors?","volume":"96","author":"Conibear","year":"2019","journal-title":"Mol. Pharmacol."},{"key":"10.1016\/j.neuroscience.2026.08.005_b0085","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-022-11189-6","article-title":"Attenuated G protein signaling and minimal receptor phosphorylation as a biochemical signature of low side-effect opioid analgesics","volume":"12","author":"Dasgupta","year":"2022","journal-title":"Sci. Rep."},{"key":"10.1016\/j.neuroscience.2026.08.005_b0090","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.ejphar.2015.08.012","article-title":"Nociceptin\/orphanin FQ receptor and pain: Feasibility of the fourth opioid family member","volume":"766","author":"Di","year":"2015","journal-title":"Eur. J. Pharmacol."},{"key":"10.1016\/j.neuroscience.2026.08.005_b0095","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.aar3483","article-title":"A bifunctional nociceptin and mu opioid receptor agonist is analgesic without opioid side effects in nonhuman primates","volume":"10","author":"Ding","year":"2018","journal-title":"Sci. Transl. Med."},{"key":"10.1016\/j.neuroscience.2026.08.005_b0100","doi-asserted-by":"crossref","unstructured":"Donica CL, Awwad HO, Thakker DR, Standifer KM. Cellular Mechanisms of Nociceptin\/Orphanin FQ (N\/OFQ) Peptide (NOP) Receptor Regulation and Heterologous Regulation by N\/OFQ 2013;83:907\u201318. doi: 10.1124\/mol.112.084632.","DOI":"10.1124\/mol.112.084632"},{"key":"10.1016\/j.neuroscience.2026.08.005_b0115","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1038\/s41467-020-14884-y","article-title":"Haloperidol bound D2 dopamine receptor structure inspired the discovery of subtype selective ligands","volume":"11","author":"Fan","year":"2020","journal-title":"Nat. Commun."},{"key":"10.1016\/j.neuroscience.2026.08.005_b0120","doi-asserted-by":"crossref","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":"10.1016\/j.neuroscience.2026.08.005_b0125","article-title":"Mitragynine attenuates morphine withdrawal effects in rats\u2014a comparison with methadone and buprenorphine","volume":"11","author":"Hassan","year":"2020","journal-title":"Front. Psych."},{"key":"10.1016\/j.neuroscience.2026.08.005_b0130","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.jad.2019.03.078","article-title":"Mental health and cognitive function responses to quetiapine in patients with methamphetamine abuse under methadone maintenance treatment","volume":"251","author":"Javdan","year":"2019","journal-title":"J. Affect. Disord."},{"key":"10.1016\/j.neuroscience.2026.08.005_b0135","doi-asserted-by":"crossref","first-page":"8460","DOI":"10.1038\/s41598-023-35673-9","article-title":"Sex differences in VTA GABA transmission and plasticity during opioid withdrawal","volume":"13","author":"Kalamarides","year":"2023","journal-title":"Sci. Rep."},{"key":"10.1016\/j.neuroscience.2026.08.005_b0140","doi-asserted-by":"crossref","first-page":"3328","DOI":"10.3390\/ijms20133328","article-title":"The NLRP3 inflammasome: an overview of mechanisms of activation and regulation","volume":"20","author":"Kelley","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"10.1016\/j.neuroscience.2026.08.005_b0145","doi-asserted-by":"crossref","DOI":"10.1177\/17448069241227922","article-title":"Sensitization of human and rat nociceptors by low dose morphine is TLR4-dependent","volume":"20","author":"Khomula","year":"2024","journal-title":"Mol. Pain"},{"key":"10.1016\/j.neuroscience.2026.08.005_b0150","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1002\/jnr.24624","article-title":"Therapeutic potentials of NOP and MOP receptor coactivation for the treatment of pain and opioid abuse","volume":"100","author":"Kiguchi","year":"2020","journal-title":"J. Neurosci. Res."},{"key":"10.1016\/j.neuroscience.2026.08.005_b0155","doi-asserted-by":"crossref","first-page":"645","DOI":"10.14348\/molcells.2016.0137","article-title":"Brain reward circuits in morphine addiction","volume":"39","author":"Kim","year":"2016","journal-title":"Mol. Cells"},{"key":"10.1016\/j.neuroscience.2026.08.005_b0160","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/S0304-3959(03)00205-7","article-title":"QTc interval prolongation associated with intravenous methadone","volume":"105","author":"Kornick","year":"2003","journal-title":"Pain"},{"key":"10.1016\/j.neuroscience.2026.08.005_b0165","doi-asserted-by":"crossref","first-page":"3677","DOI":"10.1007\/s00018-015-1948-5","article-title":"Structure of potassium channels","volume":"72","author":"Kuang","year":"2015","journal-title":"Cell. Mol. Life Sci."},{"key":"10.1016\/j.neuroscience.2026.08.005_b0170","doi-asserted-by":"crossref","first-page":"607","DOI":"10.32598\/bcn.12.5.886.3","article-title":"Environmental enrichment ameliorates psychological dependence symptoms and voluntary morphine consumption in morphine withdrawn rats under methadone maintenance treatment","volume":"12","author":"Lari","year":"2021","journal-title":"Basic and Clinical Neuroscience Journal"},{"key":"10.1016\/j.neuroscience.2026.08.005_b0175","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2024.1353865","article-title":"Complete Freund\u2019s adjuvant as a confounding factor in multiple sclerosis research","volume":"15","author":"Lazarevi\u0107","year":"2024","journal-title":"Front. Immunol."},{"key":"10.1016\/j.neuroscience.2026.08.005_b0180","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1152\/physrev.00005.2009","article-title":"Reward processing by the opioid system in the brain","volume":"89","author":"Le Merrer","year":"2009","journal-title":"Physiol. Rev."},{"key":"10.1016\/j.neuroscience.2026.08.005_b0185","doi-asserted-by":"crossref","unstructured":"Marti M, Mela F, Fantin M, Zucchini S, Brown JR, Witta J, et al. Blockade of Nociceptin\/Orphanin FQ Transmission Attenuates Symptoms and Neurodegeneration Associated with Parkinson\u2019s Disease 2005;25:9591\u2013601. doi: 10.1523\/jneurosci.2546-05.2005.","DOI":"10.1523\/JNEUROSCI.2546-05.2005"},{"key":"10.1016\/j.neuroscience.2026.08.005_b0190","doi-asserted-by":"crossref","first-page":"79","DOI":"10.2165\/00139709-200625020-00002","article-title":"Does high-dose buprenorphine cause respiratory depression?","volume":"25","author":"M\u00e9garbane","year":"2006","journal-title":"Toxicol. Rev."},{"key":"10.1016\/j.neuroscience.2026.08.005_b0195","doi-asserted-by":"crossref","DOI":"10.1186\/1423-0127-20-77","article-title":"Gap junction blockers: a potential approach to attenuate morphine withdrawal symptoms","volume":"20","author":"Moradi","year":"2013","journal-title":"J. Biomed. Sci."},{"issue":"7","key":"10.1016\/j.neuroscience.2026.08.005_b0200","article-title":"The ARRIVE guidelines 2.0: updated guidelines for reporting animal research","volume":"18","author":"Percie du Sert","year":"2020","journal-title":"PLoS Biol."},{"key":"10.1016\/j.neuroscience.2026.08.005_b0205","doi-asserted-by":"crossref","DOI":"10.3389\/fnmol.2018.00464","article-title":"Emerging trends in pain modulation by metabotropic glutamate receptors","volume":"11","author":"Pereira","year":"2019","journal-title":"Front. Mol. Neurosci."},{"key":"10.1016\/j.neuroscience.2026.08.005_b0210","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1124\/jpet.105.087254","article-title":"Morphine side effects in \u03b2-arrestin 2 knockout mice","volume":"314","author":"Raehal","year":"2005","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"10.1016\/j.neuroscience.2026.08.005_b0215","doi-asserted-by":"crossref","DOI":"10.3389\/fnmol.2022.919773","article-title":"Opioid receptor-mediated regulation of neurotransmission in the brain","volume":"15","author":"Reeves","year":"2022","journal-title":"Front. Mol. Neurosci."},{"key":"10.1016\/j.neuroscience.2026.08.005_b0220","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1002\/hup.698","article-title":"Buprenorphine mortality, seizures and prescription data in the UK, 1980-2002","volume":"20","author":"Schifano","year":"2005","journal-title":"Hum. Psychopharmacol. Clin. Exp."},{"key":"10.1016\/j.neuroscience.2026.08.005_b0225","first-page":"303","article-title":"Impacts of morphine addiction on spermatogenesis in rats","volume":"14","author":"Takzare","year":"2016","journal-title":"International Journal of Reproductive BioMedicine"},{"key":"10.1016\/j.neuroscience.2026.08.005_b0230","doi-asserted-by":"crossref","unstructured":"Tan C, Wong JF, Yee CM, Hum A. Methadone rotation for cancer pain: an observational study. BMJ Supportive & Palliative Care 2020:bmjspcare-2019-002175. doi: 10.1136\/bmjspcare-2019-002175.","DOI":"10.1136\/bmjspcare-2019-002175"},{"key":"10.1016\/j.neuroscience.2026.08.005_b0235","doi-asserted-by":"crossref","first-page":"2514","DOI":"10.1038\/s41386-018-0225-3","article-title":"Untangling the complexity of opioid receptor function","volume":"43","author":"Valentino","year":"2018","journal-title":"Neuropsychopharmacology"},{"key":"10.1016\/j.neuroscience.2026.08.005_b0240","doi-asserted-by":"crossref","first-page":"5092","DOI":"10.1523\/JNEUROSCI.1157-07.2007","article-title":"Arrestin2 and c-Src regulate the constitutive activity and recycling of opioid receptors in dorsal root ganglion neurons","volume":"27","author":"Walwyn","year":"2007","journal-title":"J. Neurosci."},{"key":"10.1016\/j.neuroscience.2026.08.005_b0245","doi-asserted-by":"crossref","DOI":"10.3389\/fnmol.2018.00120","article-title":"The neuroprotection of low-dose morphine in cellular and animal models of parkinson\u2019s disease through ameliorating endoplasmic reticulum (ER) stress and activating autophagy","volume":"11","author":"Wang","year":"2018","journal-title":"Front. Mol. Neurosci."},{"key":"10.1016\/j.neuroscience.2026.08.005_b0255","doi-asserted-by":"crossref","first-page":"3777","DOI":"10.1111\/bph.12744","article-title":"Functional plasticity of the N\/OFQ-NOP receptor system determines analgesic properties of NOP receptor agonists","volume":"171","author":"Schr\u00f6der","year":"2014","journal-title":"Br. J. Pharmacol."},{"key":"10.1016\/j.neuroscience.2026.08.005_b0260","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejphar.2024.176333","article-title":"The \u03bc-opioid receptor-mediated Gi\/o protein and \u03b2-arrestin2 signaling pathways both contribute to morphine-induced side effects","volume":"966","author":"Xia","year":"2024","journal-title":"Eur. J. Pharmacol."},{"key":"10.1016\/j.neuroscience.2026.08.005_b0265","doi-asserted-by":"crossref","first-page":"7011","DOI":"10.1021\/acs.jmedchem.5b01499","article-title":"Nociceptin opioid receptor (NOP) as a therapeutic target: progress in translation from preclinical research to clinical utility","volume":"59","author":"Zaveri","year":"2016","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.neuroscience.2026.08.005_b0270","article-title":"The nociceptin receptor (NOP) agonist AT-312 blocks acquisition of morphine- and cocaine-induced conditioned place preference in mice","volume":"9","author":"Zaveri","year":"2018","journal-title":"Front. Psych."},{"key":"10.1016\/j.neuroscience.2026.08.005_b0275","article-title":"Dynamic recognition of naloxone, morphine and endomorphin1 in the same pocket of \u00b5-opioid receptors","volume":"9","author":"Zhang","year":"2022","journal-title":"Front. Mol. Biosci."}],"container-title":["Neuroscience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0306452226005348?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0306452226005348?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T12:25:56Z","timestamp":1787228756000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0306452226005348"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10]]},"references-count":52,"alternative-id":["S0306452226005348"],"URL":"https:\/\/doi.org\/10.1016\/j.neuroscience.2026.08.005","relation":{},"ISSN":["0306-4522"],"issn-type":[{"value":"0306-4522","type":"print"}],"subject":[],"published":{"date-parts":[[2026,10]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"In vivo evaluation of the dual MOP\/NOP agonist AT121: a potent analgesic that delays opioid tolerance and offers a superior withdrawal suppression profile to methadone","name":"articletitle","label":"Article Title"},{"value":"Neuroscience","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.neuroscience.2026.08.005","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2026 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.","name":"copyright","label":"Copyright"}]}}