{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T17:38:21Z","timestamp":1775065101887,"version":"3.50.1"},"posted":{"date-parts":[[2026,3,30]]},"group-title":"Neuroscience","reference-count":66,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T00:00:00Z","timestamp":1774828800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["DA047413"],"award-info":[{"award-number":["DA047413"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,30]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  The misuse of opioid medications is a significant health issue in the United States. Very few studies have investigated the effect of opioids on perineuronal nets (PNNs), scaffold-like structures that surround neurons and are involved in the regulation of plasticity-dependent mechanisms such as development, learning and memory, and acquisition of addiction-like phenotypes. Regulation of PNNs in the orbitofrontal cortex (OFC) during periods of drug intoxication or withdrawal is widely unknown. In this study, male Wistar rats were injected with fentanyl (0.125 mg\/kg, s.c.) or 0.9% saline twice daily for 7 days and once on day 8 (7continuous days following by 3 days of abstinence) or twice daily for 15 days (5 continuous days followed by 2 days of abstinence for more than 3 weeks) and twice on day 16. Antinociception was evaluated using the tail immersion test immediately before and 30 minutes after injections. Whole-brain coronal slices were collected, and immunohistochemistry was used to identify Wisteria Floribunda Agglutinin (WFA)-positive PNNs and parvalbumin (PV)-expressing cells. Results confirmed that repeated fentanyl injections induced tolerance to the antinociceptive effects, which normalized following acute abstinence periods. WFA intensity decreased following 8 days of injections. Analyses confirmed significant correlations between PV\n                  <jats:sup>+<\/jats:sup>\n                  density and tail withdrawal latency following 8 days of fentanyl injections. These data confirm that repeated fentanyl injections modulate both WFA\n                  <jats:sup>+<\/jats:sup>\n                  and PV\n                  <jats:sup>+<\/jats:sup>\n                  expression in the rodent brain and antinociceptive tolerance in a duration-dependent manner. Overall, these data suggest that perineuronal nets may mediate opioid-induced behavioral effects, such as antinociceptive tolerance, following repeated administration and abstinence in rats.\n                <\/jats:p>","DOI":"10.64898\/2026.03.26.714490","type":"posted-content","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T16:30:12Z","timestamp":1774888212000},"source":"Crossref","is-referenced-by-count":0,"title":["Changes in perineuronal net and parvalbumin expression in the orbitofrontal cortex of male Wistar rats following repeated fentanyl administration"],"prefix":"10.64898","author":[{"given":"Mariana I. H.","family":"Dejeux","sequence":"first","affiliation":[{"name":"Department of Psychology and Neuroscience; Baylor University; Waco, TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah S.","family":"Jewanee","sequence":"additional","affiliation":[{"name":"Department of Psychology and Neuroscience; Baylor University; Waco, TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel","family":"Moutos","sequence":"additional","affiliation":[{"name":"Department of Psychology and Neuroscience; Baylor University; Waco, TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arjun","family":"Trehan","sequence":"additional","affiliation":[{"name":"Department of Psychology and Neuroscience; Baylor University; Waco, TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melody","family":"Golbarani","sequence":"additional","affiliation":[{"name":"Department of Psychology and Neuroscience; Baylor University; Waco, TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joanne","family":"Kwak","sequence":"additional","affiliation":[{"name":"Department of Psychology and Neuroscience; Baylor University; Waco, TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evan","family":"Farach","sequence":"additional","affiliation":[{"name":"Department of Psychology and Neuroscience; Baylor University; Waco, TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nathan","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Psychology and Neuroscience; Baylor University; Waco, TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sri V.","family":"Kasaram","sequence":"additional","affiliation":[{"name":"Department of Psychology and Neuroscience; Baylor University; Waco, TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aliyah","family":"Ogden","sequence":"additional","affiliation":[{"name":"Department of Psychology and Neuroscience; Baylor University; Waco, TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sophia","family":"Wright","sequence":"additional","affiliation":[{"name":"Department of Psychology and Neuroscience; Baylor University; Waco, TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin A.","family":"Schwartz","sequence":"additional","affiliation":[{"name":"Department of Psychology and Neuroscience; Baylor University; Waco, TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0397-0582","authenticated-orcid":false,"given":"Jacques D.","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Psychology and Neuroscience; Baylor University; Waco, TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026040108352497000_2026.03.26.714490v1.1","doi-asserted-by":"crossref","first-page":"100692","DOI":"10.1016\/j.ynstr.2024.100692","article-title":"Modulation of stress-, pain-, and alcohol-related behaviors by perineuronal nets","volume":"33","year":"2024","journal-title":"Neurobiol Stress"},{"key":"2026040108352497000_2026.03.26.714490v1.2","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.neulet.2004.04.017","article-title":"Continuous perfusion with morphine of the orbitofrontal cortex reduces allodynia and hyperalgesia in a rat model for mononeuropathy","volume":"364","year":"2004","journal-title":"Neurosci Lett"},{"key":"2026040108352497000_2026.03.26.714490v1.3","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0854-18.2018"},{"key":"2026040108352497000_2026.03.26.714490v1.4","doi-asserted-by":"crossref","unstructured":"Bosiacki, M. , G\u0105ssowska-Dobrowolska, M. , Kojder, K. , Fabia\u0144ska, M. , Je\u017cewski, D. , Gutowska, I. , Lubkowska, A ., 2019. Perineuronal Nets and Their Role in Synaptic Homeostasis. Int J Mol Sci 20.","DOI":"10.3390\/ijms20174108"},{"key":"2026040108352497000_2026.03.26.714490v1.5","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/s41386-022-01337-x","article-title":"Net gain and loss: influence of natural rewards and drugs of abuse on perineuronal nets","volume":"48","year":"2023","journal-title":"Neuropsychopharmacology"},{"key":"2026040108352497000_2026.03.26.714490v1.6","doi-asserted-by":"crossref","unstructured":"Caccavano, A. P. , Vlachos, A. , McLean, N. , Kimmel, S. , Kim, J. H. , Vargish, G. , Mahadevan, V. , Hewitt, L. , Rossi, A. M. , Spineux, I. , Wu, S. J. , Furlanis, E. , Dai, M. , Leyva Garcia, B. , Wang, Y. , Chittajallu, R. , London, E. , Yuan, X. , Hunt, S. , Abebe, D. , Eldridge, M. A. G. , Cummins, A. C. , Hines, B. E. , Plotnikova, A. , Mohanty, A. , Averbeck, B. B. , Zaghloul, K. A. , Dimidschstein, J. , Fishell, G. , Pelkey, K. A. , McBain, C. J ., 2025. Divergent opioid-mediated suppression of inhibition between hippocampus and neocortex across species and development. Neuron.","DOI":"10.1016\/j.neuron.2025.03.005"},{"key":"2026040108352497000_2026.03.26.714490v1.7","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1705753114"},{"key":"2026040108352497000_2026.03.26.714490v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-2236(98)01298-3"},{"key":"2026040108352497000_2026.03.26.714490v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbb.2013.11.021"},{"key":"2026040108352497000_2026.03.26.714490v1.10","doi-asserted-by":"publisher","DOI":"10.1111\/acer.14810"},{"key":"2026040108352497000_2026.03.26.714490v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbb.2009.02.004"},{"key":"2026040108352497000_2026.03.26.714490v1.12","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1038\/s41398-020-01000-3","article-title":"The type of stress matters: repeated injection and permanent social isolation stress in male mice have a differential effect on anxiety- and depressive-like behaviours, and associated biological alterations","volume":"10","year":"2020","journal-title":"Transl Psychiatry"},{"key":"2026040108352497000_2026.03.26.714490v1.13","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14672"},{"key":"2026040108352497000_2026.03.26.714490v1.14","doi-asserted-by":"publisher","DOI":"10.1016\/J.NEURON.2017.06.028"},{"key":"2026040108352497000_2026.03.26.714490v1.15","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-019-0196-3"},{"key":"2026040108352497000_2026.03.26.714490v1.16","unstructured":"Garber, J. C. , Barbee, R. W. , Bielitzki, J. T. , Clayton, L. A. , Donovan, J. C. , Hendriksen, C. F. M. , Kohn, D. F. , Lipman, N. S. , Locke, P. A. , Melcher, J. , Quimby, F. W. , Turner, P. V. , Wood, G. A. , Wurbel, H. , 2011. Guide for the Care and Use of Laboratory Animals, 8th Edition. National Academies Press, Washington D.C."},{"key":"2026040108352497000_2026.03.26.714490v1.17","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-020-05581-1"},{"key":"2026040108352497000_2026.03.26.714490v1.18","doi-asserted-by":"crossref","first-page":"932391","DOI":"10.3389\/fncel.2022.932391","article-title":"Impact of Perineuronal Net Removal in the Rat Medial Prefrontal Cortex on Parvalbumin Interneurons After Reinstatement of Cocaine Conditioned Place Preference","volume":"16","year":"2022","journal-title":"Front Cell Neurosci"},{"key":"2026040108352497000_2026.03.26.714490v1.19","doi-asserted-by":"crossref","first-page":"109210","DOI":"10.1016\/j.neuropharm.2022.109210","article-title":"Role of Perineuronal nets in the cerebellar cortex in cocaine-induced conditioned preference, extinction, and reinstatement","volume":"218","year":"2022","journal-title":"Neuropharmacology"},{"key":"2026040108352497000_2026.03.26.714490v1.20","unstructured":"Hedegaard, H. , Minino, A. M. , Warner, M ., 2018. Drug Overdose Deaths in the United States, 1999-2017. NCHS Data Brief, 1\u20138."},{"key":"2026040108352497000_2026.03.26.714490v1.21","doi-asserted-by":"crossref","unstructured":"Honeycutt, S. C. , Mukherjee, A. , Paladino, M. S. , Gilles-Thomas, E. A. , Loney, G. C. , 2024. Adolescent nicotine exposure promotes adulthood opioid consumption that persists despite adverse consequences and increases the density of insular perineuronal nets. Addict Neurosci 11.","DOI":"10.1016\/j.addicn.2024.100150"},{"key":"2026040108352497000_2026.03.26.714490v1.22","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3940(01)01497-5"},{"key":"2026040108352497000_2026.03.26.714490v1.23","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0918-22.2023"},{"key":"2026040108352497000_2026.03.26.714490v1.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2022.05.022)"},{"key":"2026040108352497000_2026.03.26.714490v1.25","doi-asserted-by":"crossref","first-page":"e2502558122","DOI":"10.1073\/pnas.2502558122","article-title":"Synergistic deficits in parvalbumin interneurons and dopamine signaling drive ACC dysfunction in chronic pain","volume":"122","year":"2025","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026040108352497000_2026.03.26.714490v1.26","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2049-19.2020"},{"key":"2026040108352497000_2026.03.26.714490v1.27","doi-asserted-by":"crossref","unstructured":"Laubach, M. , Amarante, L. M. , Swanson, K. , White, S. R ., 2018. What, If Anything, Is Rodent Prefrontal Cortex? eNeuro 5.","DOI":"10.31234\/osf.io\/c2a79"},{"key":"2026040108352497000_2026.03.26.714490v1.28","doi-asserted-by":"publisher","DOI":"10.1038\/s41386-020-0643-x"},{"key":"2026040108352497000_2026.03.26.714490v1.29","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.112788"},{"key":"2026040108352497000_2026.03.26.714490v1.30","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1800222"},{"key":"2026040108352497000_2026.03.26.714490v1.31","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.neuroscience.2017.03.010","article-title":"Extracellular matrix alterations in the ketamine model of schizophrenia","volume":"350","year":"2017","journal-title":"Neuroscience"},{"key":"2026040108352497000_2026.03.26.714490v1.32","doi-asserted-by":"crossref","first-page":"2420","DOI":"10.1016\/j.bbagen.2017.06.010","article-title":"Formation and remodeling of the brain extracellular matrix in neural plasticity: Roles of chondroitin sulfate and hyaluronan","volume":"1861","year":"2017","journal-title":"Biochim Biophys Acta Gen Subj"},{"key":"2026040108352497000_2026.03.26.714490v1.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.drugalcdep.2019.107547"},{"key":"2026040108352497000_2026.03.26.714490v1.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.09.034"},{"key":"2026040108352497000_2026.03.26.714490v1.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2019.04.010"},{"key":"2026040108352497000_2026.03.26.714490v1.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbb.2018.07.007"},{"key":"2026040108352497000_2026.03.26.714490v1.37","doi-asserted-by":"crossref","unstructured":"Nguyen, J. D. , Grant, Y. , Taffe, M. A ., 2021. Paradoxical changes in brain reward status during oxycodone self-administration in a novel test of the negative reinforcement hypothesis. Br J Pharmacol.","DOI":"10.1111\/bph.15520"},{"key":"2026040108352497000_2026.03.26.714490v1.38","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2018.06.026"},{"key":"2026040108352497000_2026.03.26.714490v1.39","doi-asserted-by":"crossref","unstructured":"Nguyen, J. D. , Kirson, D. , Steinman, M. Q. , Patel, R. , Khom, S. , Varodayan, F. P. , Hedges, D. M. , Oleata, C. S. , Grant, Y. , Roberto, M. , Taffe, M. A ., 2017. Withdrawal-induced escalated oxycodone self-administration is mediated by kappa opioid receptor function. bioRxiv.","DOI":"10.1101\/177899"},{"key":"2026040108352497000_2026.03.26.714490v1.40","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.alcohol.2024.12.006","article-title":"Enhanced fear extinction through infralimbic perineuronal net digestion: The modulatory role of adolescent alcohol exposure","volume":"123","year":"2025","journal-title":"Alcohol"},{"key":"2026040108352497000_2026.03.26.714490v1.41","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15039"},{"key":"2026040108352497000_2026.03.26.714490v1.42","unstructured":"Paxinos, G. , Watson, C ., 2013. The Rat Brain in Stereotaxic Coordinates. Elsevier Science."},{"key":"2026040108352497000_2026.03.26.714490v1.43","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.09.080"},{"key":"2026040108352497000_2026.03.26.714490v1.44","doi-asserted-by":"publisher","DOI":"10.1126\/science.1072699"},{"key":"2026040108352497000_2026.03.26.714490v1.45","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2403777121"},{"key":"2026040108352497000_2026.03.26.714490v1.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2019.04.003"},{"key":"2026040108352497000_2026.03.26.714490v1.47","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2010.134"},{"key":"2026040108352497000_2026.03.26.714490v1.48","doi-asserted-by":"crossref","first-page":"108290","DOI":"10.1016\/j.neuropharm.2020.108290","article-title":"Comparative analysis of the modulation of perineuronal nets in the prefrontal cortex of rats during protracted withdrawal from cocaine, heroin and sucrose self-administration","volume":"180","year":"2020","journal-title":"Neuropharmacology"},{"key":"2026040108352497000_2026.03.26.714490v1.49","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1122-18.2018"},{"key":"2026040108352497000_2026.03.26.714490v1.50","doi-asserted-by":"publisher","DOI":"10.1111\/bcpt.13994"},{"key":"2026040108352497000_2026.03.26.714490v1.51","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2753"},{"key":"2026040108352497000_2026.03.26.714490v1.52","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbb.2008.06.019"},{"key":"2026040108352497000_2026.03.26.714490v1.53","doi-asserted-by":"publisher","DOI":"10.1016\/j.ibror.2016.10.001"},{"key":"2026040108352497000_2026.03.26.714490v1.54","doi-asserted-by":"crossref","unstructured":"Slaker, M. L. , Jorgensen, E. T. , Hegarty, D. M. , Liu, X. , Kong, Y. , Zhang, F. , Linhardt, R. J. , Brown, T. E. , Aicher, S. A. , Sorg, B. A ., 2018. Cocaine Exposure Modulates Perineuronal Nets and Synaptic Excitability of Fast-Spiking Interneurons in the Medial Prefrontal Cortex. eNeuro 5.","DOI":"10.1523\/ENEURO.0221-18.2018"},{"key":"2026040108352497000_2026.03.26.714490v1.55","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2351-16.2016"},{"key":"2026040108352497000_2026.03.26.714490v1.56","doi-asserted-by":"publisher","DOI":"10.1097\/SLA.0000000000002365"},{"key":"2026040108352497000_2026.03.26.714490v1.57","doi-asserted-by":"crossref","unstructured":"Tsukano, H. , Garcia, M. M. , Dandu, P. R. , Kato, H. K ., 2026. Orbitofrontal cortex drives predictive filtering of sensory responses. Nature Neuroscience.","DOI":"10.1038\/s41593-026-02217-z"},{"key":"2026040108352497000_2026.03.26.714490v1.58","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2010.90"},{"key":"2026040108352497000_2026.03.26.714490v1.59","doi-asserted-by":"publisher","DOI":"10.1111\/adb.12437"},{"key":"2026040108352497000_2026.03.26.714490v1.60","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1038\/s41380-020-0661-4","article-title":"The changing opioid crisis: development, challenges and opportunities","volume":"26","year":"2021","journal-title":"Mol Psychiatry"},{"key":"2026040108352497000_2026.03.26.714490v1.61","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1001\/jamapsychiatry.2018.3126","article-title":"Prevention and Treatment of Opioid Misuse and Addiction: A Review","volume":"76","year":"2019","journal-title":"JAMA Psychiatry"},{"key":"2026040108352497000_2026.03.26.714490v1.62","doi-asserted-by":"crossref","unstructured":"Wingert, J. C. , Ramos, J. D. , Reynolds, S. X. , Gonzalez, A. E. , Rose, R. M. , Hegarty, D. M. , Aicher, S. A. , Bailey, L. G. , Brown, T. E. , Abbas, A. I. , Sorg, B. A ., 2024. Perineuronal Nets in the Rat Medial Prefrontal Cortex Alter Hippocampal-Prefrontal Oscillations and Reshape Cocaine Self-Administration Memories. J Neurosci 44.","DOI":"10.1101\/2024.02.05.577568"},{"key":"2026040108352497000_2026.03.26.714490v1.63","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbb.2008.12.007"},{"key":"2026040108352497000_2026.03.26.714490v1.64","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1706-14.2014"},{"key":"2026040108352497000_2026.03.26.714490v1.65","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2008.10.040"},{"key":"2026040108352497000_2026.03.26.714490v1.66","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1016\/j.neuroscience.2004.04.013","article-title":"Mu but not delta and kappa opioid receptor involvement in ventrolateral orbital cortex opioid-evoked antinociception in formalin test rats","volume":"126","year":"2004","journal-title":"Neuroscience"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.03.26.714490","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T15:35:59Z","timestamp":1775057759000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.03.26.714490"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,30]]},"references-count":66,"URL":"https:\/\/doi.org\/10.64898\/2026.03.26.714490","relation":{},"subject":[],"published":{"date-parts":[[2026,3,30]]},"subtype":"preprint"}}