{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T08:55:59Z","timestamp":1774342559590,"version":"3.50.1"},"reference-count":52,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T00:00:00Z","timestamp":1774051200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: Postoperative pain pharmacology is complex. We investigated the sensitivity of analgesic-like effects induced by morphine, ibuprofen, and their combination to peripheral opioid antagonism in a mouse laparotomy model. Methods: Mechanical hypersensitivity was assessed using von Frey filaments, and ongoing pain (abdominal licking and facial expressions) was evaluated using artificial intelligence algorithms. We tested the sensitivity of the analgesic treatments to the opioid antagonist naloxone or its peripherally restricted analog, naloxone methiodide. We also tested the effects of neutrophil depletion using an anti-Ly6G antibody. Gastrointestinal transit and pupillary diameter were measured to assess non-analgesic opioid effects. Results: Morphine reversed all pain-related behaviors; its effect on mechanical hypersensitivity was reversed by peripheral opioid antagonism, whereas its effects on ongoing pain were not. Ibuprofen reduced mechanical hypersensitivity and facial expressions but failed to alter licking. Interestingly, the ibuprofen effect on mechanical hypersensitivity depended on peripheral opioid receptors and neutrophils at the injury site. The morphine\u2013ibuprofen combination produced synergistic analgesia across all endpoints without enhancing opioid-induced gastrointestinal inhibition or mydriasis. Peripheral opioid antagonism reversed the effect of the combination on mechanical hypersensitivity and facial expressions but not on licking. Conclusions: Our results replicate the key clinical phenomena relevant to the postoperative pain context, including the potentiation of morphine analgesia by ibuprofen without the exacerbation of adverse effects. Our results suggest that drug effects on different postoperative pain measures rely on distinct neurobiological mechanisms and are not interchangeable. Therefore, the use of a battery of complementary pain endpoints in preclinical pharmacology studies is advisable.<\/jats:p>","DOI":"10.3390\/pharmaceutics18030392","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T13:07:06Z","timestamp":1774271226000},"page":"392","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pain Outcome Determines the Sensitivity to Peripheral Opioid Antagonism of Morphine, Ibuprofen, and Their Combination in Laparotomized Mice"],"prefix":"10.3390","volume":"18","author":[{"given":"Makeya A.","family":"Hasoun","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, University of Granada, 18016 Granada, Spain"},{"name":"Institute of Neuroscience, Biomedical Research Center, University of Granada, 18016 Granada, Spain"},{"name":"Biosanitary Research Institute ibs.GRANADA, 18012 Granada, Spain"},{"name":"Biotechnology College, Al-Qadisiyah University, Diwaniya 58006, Iraq"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5713-4136","authenticated-orcid":false,"given":"Miriam","family":"Santos-Caballero","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, University of Granada, 18016 Granada, Spain"},{"name":"Institute of Neuroscience, Biomedical Research Center, University of Granada, 18016 Granada, Spain"},{"name":"Biosanitary Research Institute ibs.GRANADA, 18012 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2842-0085","authenticated-orcid":false,"given":"Miguel \u00c1.","family":"Huerta","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, University of Granada, 18016 Granada, Spain"},{"name":"Institute of Neuroscience, Biomedical Research Center, University of Granada, 18016 Granada, Spain"},{"name":"Biosanitary Research Institute ibs.GRANADA, 18012 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1275-5185","authenticated-orcid":false,"given":"Mar\u00eda","family":"Robles-Funes","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, University of Granada, 18016 Granada, Spain"},{"name":"Institute of Neuroscience, Biomedical Research Center, University of Granada, 18016 Granada, Spain"},{"name":"Biosanitary Research Institute ibs.GRANADA, 18012 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1826-4442","authenticated-orcid":false,"given":"Amada","family":"Puerto-Moya","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, University of Granada, 18016 Granada, Spain"},{"name":"Institute of Neuroscience, Biomedical Research Center, University of Granada, 18016 Granada, Spain"},{"name":"Biosanitary Research Institute ibs.GRANADA, 18012 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6968-0946","authenticated-orcid":false,"given":"M. Carmen","family":"Ruiz-Cantero","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology and Therapeutic Chemistry, University of Barcelona, 08028 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1308-6264","authenticated-orcid":false,"given":"Enrique J.","family":"Cobos","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, University of Granada, 18016 Granada, Spain"},{"name":"Institute of Neuroscience, Biomedical Research Center, University of Granada, 18016 Granada, Spain"},{"name":"Biosanitary Research Institute ibs.GRANADA, 18012 Granada, Spain"},{"name":"Te\u00f3filo Hernando Institute for Drug Discovery, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9657-4521","authenticated-orcid":false,"given":"Rafael","family":"Gonz\u00e1lez-Cano","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, University of Granada, 18016 Granada, Spain"},{"name":"Institute of Neuroscience, Biomedical Research Center, University of Granada, 18016 Granada, Spain"},{"name":"Biosanitary Research Institute ibs.GRANADA, 18012 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/j.amjsurg.2017.01.001","article-title":"Trends in Open Abdominal Surgery in the United States-Observations from 9,950,759 Discharges Using the 2009\u20132013 National Inpatient Sample (NIS) Datasets","volume":"214","author":"Carney","year":"2017","journal-title":"Am. J. Surg."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"117459","DOI":"10.1016\/j.biopha.2024.117459","article-title":"Pharmacological Differences in Postoperative Cutaneous Sensitivity, Pain at Rest, and Movement-Induced Pain in Laparotomized Mice","volume":"180","author":"Hasoun","year":"2024","journal-title":"Biomed. Pharmacother."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"118298","DOI":"10.1016\/j.biopha.2025.118298","article-title":"Sigma-1 Receptor Antagonism as a Promising Strategy for Postoperative Pain Treatment: A Study in Laparotomized Mice","volume":"189","author":"Mayr","year":"2025","journal-title":"Biomed. Pharmacother."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2550","DOI":"10.1097\/j.pain.0000000000003720","article-title":"Evaluating the Efficacy of Neurokinin-1 (Substance P) Receptor Antagonist CP-99994 on Facial Grimacing and Allodynia in Mice Postsurgery: A Comparative Study with Known Analgesics","volume":"166","author":"McCoy","year":"2025","journal-title":"Pain"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Deuis, J.R., Dvorakova, L.S., and Vetter, I. (2017). Methods Used to Evaluate Pain Behaviors in Rodents. Front. Mol. Neurosci., 10.","DOI":"10.3389\/fnmol.2017.00284"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1038\/nmeth.1455","article-title":"Coding of Facial Expressions of Pain in the Laboratory Mouse","volume":"7","author":"Langford","year":"2010","journal-title":"Nat. Methods"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.neubiorev.2020.03.004","article-title":"The Search for Translational Pain Outcomes to Refine Analgesic Development: Where Did We Come from and Where Are We Going?","volume":"113","author":"Tejada","year":"2020","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1038\/nrn2606","article-title":"Animal Models of Pain: Progress and Challenges","volume":"10","author":"Mogil","year":"2009","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1111\/bph.16003","article-title":"The Sigma-1 Receptor Curtails Endogenous Opioid Analgesia during Sensitization of TRPV1 Nociceptors","volume":"180","author":"Jain","year":"2023","journal-title":"Br. J. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"8396","DOI":"10.1073\/pnas.1620068114","article-title":"Sigma-1 Receptors Control Immune-Driven Peripheral Opioid Analgesia during Inflammation in Mice","volume":"114","author":"Tejada","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.jpainsymman.2007.01.017","article-title":"Opioid-Induced Bowel Dysfunction","volume":"35","author":"Thomas","year":"2008","journal-title":"J. Pain. Symptom Manag."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1016\/j.jpainsymman.2017.08.022","article-title":"Drugs for Treating Opioid-Induced Constipation: A Mixed Treatment Comparison Network Meta-Analysis of Randomized Controlled Clinical Trials","volume":"55","author":"Sridharan","year":"2018","journal-title":"J. Pain. Symptom Manag."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"eado6593","DOI":"10.1126\/science.ado6593","article-title":"Morphine-Responsive Neurons That Regulate Mechanical Antinociception","volume":"385","author":"Fatt","year":"2024","journal-title":"Science"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1093\/brain\/awg115","article-title":"Peripheral Opioid Analgesia in Experimental Human Pain Models","volume":"126","author":"Tegeder","year":"2003","journal-title":"Brain"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/S0028-3908(01)00173-3","article-title":"Comparison of the Peripheral and Central Effects of the Opioid Agonists Loperamide and Morphine in the Formalin Test in Rats","volume":"42","author":"Shannon","year":"2002","journal-title":"Neuropharmacology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1124\/jpet.104.075176","article-title":"Peripheral versus Central Antinociceptive Actions of 6-Amino Acid-Substituted Derivatives of 14-O-Methyloxymorphone in Acute and Inflammatory Pain in the Rat","volume":"312","author":"Riba","year":"2005","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1124\/jpet.116.233551","article-title":"New Morphine Analogs Produce Peripheral Antinociception within a Certain Dose Range of Their Systemic Administration","volume":"359","author":"Riba","year":"2016","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1007\/s11064-018-2542-7","article-title":"The Peripheral Versus Central Antinociception of a Novel Opioid Agonist: Acute Inflammatory Pain in Rats","volume":"43","author":"Balogh","year":"2018","journal-title":"Neurochem. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1111\/j.1476-5381.1996.tb15494.x","article-title":"Reversal by Naloxone of the Spinal Antinociceptive Actions of a Systemically-Administered NSAID","volume":"118","author":"Herrero","year":"1996","journal-title":"Br. J. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.2147\/JPR.S138360","article-title":"Antinociceptive Tolerance to NSAIDs in the Agranular Insular Cortex Is Mediated by Opioid Mechanism","volume":"10","author":"Pirkulashvili","year":"2017","journal-title":"J. Pain Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.brainresrev.2008.04.002","article-title":"Alarm or Curse? The Pain of Neuroinflammation","volume":"58","author":"Saab","year":"2008","journal-title":"Brain Res. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1126\/science.aaf8924","article-title":"Pain Regulation by Non-Neuronal Cells and Inflammation","volume":"354","author":"Ji","year":"2016","journal-title":"Science"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1097\/00000542-200407000-00030","article-title":"Effects of Laparotomy on Spontaneous Exploratory Activity and Conditioned Operant Responding in the Rat: A Model for Postoperative Pain","volume":"101","author":"Martin","year":"2004","journal-title":"Anesthesiology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1097\/00000542-200506000-00027","article-title":"Effects of Nonsteroidal Antiinflammatory Drugs on Patient-Controlled Analgesia Morphine Side Effects: Meta-Analysis of Randomized Controlled Trials","volume":"102","author":"Marret","year":"2005","journal-title":"Anesthesiology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1001\/jama.283.3.367","article-title":"Methylnaltrexone for Reversal of Constipation Due to Chronic Methadone Use: A Randomized Controlled Trial","volume":"283","author":"Yuan","year":"2000","journal-title":"JAMA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"401","DOI":"10.2147\/TCRM.S80749","article-title":"Methylnaltrexone for Opioid-Induced Constipation: Review and Meta-Analyses for Objective plus Subjective Efficacy and Safety Outcomes","volume":"12","author":"Siemens","year":"2016","journal-title":"Ther. Clin. Risk Manag."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1016\/0024-3205(83)90123-6","article-title":"The Pupillary Effects of Opioids","volume":"33","author":"Murray","year":"1983","journal-title":"Life Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1007\/s12630-020-01905-z","article-title":"Pupillometry in Perioperative Medicine: A Narrative Review","volume":"68","author":"Packiasabapathy","year":"2021","journal-title":"Can. J. Anaesth."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1093\/bja\/65.3.415","article-title":"Pupillary Effects of Alfentanil and Morphine","volume":"65","author":"Miller","year":"1990","journal-title":"Br. J. Anaesth."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1016\/j.neuropharm.2013.03.002","article-title":"Potentiation of Morphine-Induced Mechanical Antinociception by \u03a31 Receptor Inhibition: Role of Peripheral \u03c31 Receptors","volume":"70","author":"Nieto","year":"2013","journal-title":"Neuropharmacology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1002\/ejp.712","article-title":"Meloxicam Prevents COX-2-Mediated Post-Surgical Inflammation but Not Pain Following Laparotomy in Mice","volume":"20","author":"Roughan","year":"2016","journal-title":"Eur. J. Pain."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Gonzalez-Cano, R., Boivin, B., Bullock, D., Cornelissen, L., Andrews, N., and Costigan, M. (2018). Up-Down Reader: An Open Source Program for Efficiently Processing 50% von Frey Thresholds. Front. Pharmacol., 9.","DOI":"10.3389\/fphar.2018.00433"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/j.jpain.2022.09.016","article-title":"Minocycline Prevents the Development of Key Features of Inflammation and Pain in DSS-Induced Colitis in Mice","volume":"24","author":"Vezza","year":"2023","journal-title":"J. Pain."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e63377","DOI":"10.7554\/eLife.63377","article-title":"DeepEthogram, a Machine Learning Pipeline for Supervised Behavior Classification from Raw Pixels","volume":"10","author":"Bohnslav","year":"2021","journal-title":"eLife"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1038\/s41593-018-0209-y","article-title":"DeepLabCut: Markerless Pose Estimation of User-Defined Body Parts with Deep Learning","volume":"21","author":"Mathis","year":"2018","journal-title":"Nat. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.ejphar.2013.04.018","article-title":"Sigma-1 Receptor Antagonism as Opioid Adjuvant Strategy: Enhancement of Opioid Antinociception without Increasing Adverse Effects","volume":"711","author":"Rocasalbas","year":"2013","journal-title":"Eur. J. Pharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"140381","DOI":"10.1098\/rsos.140381","article-title":"Receiving of Emotional Signal of Pain from Conspecifics in Laboratory Rats","volume":"2","author":"Nakashima","year":"2015","journal-title":"R. Soc. Open Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2737","DOI":"10.1111\/bph.13812","article-title":"Opioid System and Human Emotions","volume":"175","author":"Nummenmaa","year":"2018","journal-title":"Br. J. Pharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.brainres.2017.01.011","article-title":"Dissociation of Morphine Analgesic Effects in the Sensory and Affective Components of Formalin-Induced Spontaneous Pain in Male and Female Rats","volume":"1658","author":"Harton","year":"2017","journal-title":"Brain Res."},{"key":"ref_40","first-page":"93","article-title":"WHO Guidelines for the Use of Analgesics in Cancer Pain","volume":"7","author":"Ventafridda","year":"1985","journal-title":"Int. J. Tissue React."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1038\/s41583-021-00536-7","article-title":"Innovations and Advances in Modelling and Measuring Pain in Animals","volume":"23","author":"Sadler","year":"2022","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"104468","DOI":"10.1016\/j.jpain.2024.01.333","article-title":"Normative Preclinical Algesiometry Data on the von Frey and Radiant Heat Paw-Withdrawal Tests: An Analysis of Data from More Than 8,000 Mice Over 20 Years","volume":"25","author":"Zumbusch","year":"2024","journal-title":"J. Pain."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.1097\/j.pain.0000000000003450","article-title":"The Role of Neutrophils in Pain: Systematic Review and Meta-Analysis of Animal Studies","volume":"166","author":"Huerta","year":"2025","journal-title":"Pain"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Tsiklauri, N., Pirkulashvili, N., Nozadze, I., Nebieridze, M., Gurtskaia, G., Abzianidze, E., and Tsagareli, M.G. (2018). Antinociceptive Tolerance to NSAIDs in the Anterior Cingulate Cortex Is Mediated via Endogenous Opioid Mechanism. BMC Pharmacol. Toxicol., 19.","DOI":"10.1186\/s40360-017-0193-y"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2717","DOI":"10.1111\/bph.13750","article-title":"Opioids and the Immune System\u2014Friend or Foe","volume":"175","author":"Plein","year":"2018","journal-title":"Br. J. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.imlet.2020.08.005","article-title":"Immune Cell-Mediated Opioid Analgesia","volume":"227","author":"Machelska","year":"2020","journal-title":"Immunol. Lett."},{"key":"ref_47","first-page":"1048","article-title":"The Value of \u201cMultimodal\u201d or \u201cBalanced Analgesia\u201d in Postoperative Pain Treatment","volume":"77","author":"Kehlet","year":"1993","journal-title":"Anesth. Analg."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.jpain.2015.12.008","article-title":"Management of Postoperative Pain: A Clinical Practice Guideline From the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists\u2019 Committee on Regional Anesthesia, Executive Committee, and Administrative Council","volume":"17","author":"Chou","year":"2016","journal-title":"J. Pain."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1097\/AAP.0000000000000671","article-title":"The Efficacy of Peripheral Opioid Antagonists in Opioid-Induced Constipation and Postoperative Ileus: A Systematic Review of the Literature","volume":"42","author":"Schwenk","year":"2017","journal-title":"Reg. Anesth. Pain. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1038\/sj.clpt.6100164","article-title":"Reversal of Opioid-Induced Bladder Dysfunction by Intravenous Naloxone and Methylnaltrexone","volume":"82","author":"Rosow","year":"2007","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1097\/ALN.0000000000004567","article-title":"Morphine and Hydromorphone Effects, Side Effects, and Variability: A Crossover Study in Human Volunteers","volume":"139","author":"Meissner","year":"2023","journal-title":"Anesthesiology"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/B978-0-7020-4086-3.00038-2","article-title":"Nonsteroidal Anti-Inflammatory Drugs Exposure and the Central Nervous System","volume":"119","author":"Auriel","year":"2014","journal-title":"Handb. Clin. Neurol."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/3\/392\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T05:23:48Z","timestamp":1774329828000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/3\/392"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,21]]},"references-count":52,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["pharmaceutics18030392"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics18030392","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,21]]}}}