{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T07:57:08Z","timestamp":1791619028757,"version":"4.3.4"},"reference-count":73,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2022,9,8]],"date-time":"2022-09-08T00:00:00Z","timestamp":1662595200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NICHD","award":["R21HD085496"],"award-info":[{"award-number":["R21HD085496"]}]},{"name":"NICHD","award":["R44DA045414"],"award-info":[{"award-number":["R44DA045414"]}]},{"name":"NICHD","award":["2020-04"],"award-info":[{"award-number":["2020-04"]}]},{"name":"NIDA","award":["R21HD085496"],"award-info":[{"award-number":["R21HD085496"]}]},{"name":"NIDA","award":["R44DA045414"],"award-info":[{"award-number":["R44DA045414"]}]},{"name":"NIDA","award":["2020-04"],"award-info":[{"award-number":["2020-04"]}]},{"name":"Aether CRADA NCATS","award":["R21HD085496"],"award-info":[{"award-number":["R21HD085496"]}]},{"name":"Aether CRADA NCATS","award":["R44DA045414"],"award-info":[{"award-number":["R44DA045414"]}]},{"name":"Aether CRADA NCATS","award":["2020-04"],"award-info":[{"award-number":["2020-04"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Numerous G-protein-coupled receptors (GPCRs) display ligand-free basal signaling with potential physiological functions, a target in drug development. As an example, the \u03bc opioid receptor (MOR) signals in ligand-free form (MOR-\u03bc*), influencing opioid responses. In addition, agonists bind to MOR but can dissociate upon MOR activation, with ligand-free MOR-\u03bc* carrying out signaling. Opioid pain therapy is effective but incurs adverse effects (ADRs) and risk of opioid use disorder (OUD). Sustained opioid agonist exposure increases persistent basal MOR-\u03bc* activity, which could be a driving force for OUD and ADRs. Antagonists competitively prevent resting MOR (MOR-\u03bc) activation to MOR-\u03bc*, while common antagonists, such as naloxone and naltrexone, also bind to and block ligand-free MOR-\u03bc*, acting as potent inverse agonists. A neutral antagonist, 6\u03b2-naltrexol (6BN), binds to but does not block MOR-\u03bc*, preventing MOR-\u03bc activation only competitively with reduced potency. We hypothesize that 6BN gradually accelerates MOR-\u03bc* reversal to resting-state MOR-\u03bc. Thus, 6BN potently prevents opioid dependence in rodents, at doses well below those blocking antinociception or causing withdrawal. Acting as a \u2018retrograde addiction modulator\u2019, 6BN could represent a novel class of therapeutics for OUD. Further studies need to address regulation of MOR-\u03bc* and, more broadly, the physiological and pharmacological significance of ligand-free signaling in GPCRs.<\/jats:p>","DOI":"10.3390\/molecules27185826","type":"journal-article","created":{"date-parts":[[2022,9,8]],"date-time":"2022-09-08T09:51:09Z","timestamp":1662630669000},"page":"5826","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Ligand-Free Signaling of G-Protein-Coupled Receptors: Relevance to \u03bc Opioid Receptors in Analgesia and Addiction"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1894-6374","authenticated-orcid":false,"given":"Wolfgang","family":"Sadee","sequence":"first","affiliation":[{"name":"Cancer Biology and Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA"},{"name":"Pain and Addiction Center Laboratory, Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, CA 94158, USA"},{"name":"Aether Therapeutics Inc., Austin, TX 78756, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John C.","family":"McKew","sequence":"additional","affiliation":[{"name":"Aether Therapeutics Inc., Austin, TX 78756, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1016\/S1043-2760(02)00628-8","article-title":"Lessons from constitutively active mutants of G protein-coupled receptors","volume":"13","author":"Parnot","year":"2002","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/978-1-4939-7219-7_1","article-title":"ErbB Receptors and Cancer","volume":"1652","author":"Wang","year":"2017","journal-title":"Methods Mol. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S1877-1173(10)91001-6","article-title":"Inverse agonism at serotonin and cannabinoid receptors","volume":"91","author":"Aloyo","year":"2010","journal-title":"Prog. Mol. Biol. Transl. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.tips.2011.09.007","article-title":"Domain coupling in GPCRs: The engine for induced conformational changes","volume":"33","author":"Unal","year":"2012","journal-title":"Trends Pharm. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1038\/nrd3320","article-title":"G protein-coupled receptors: Novel targets for drug discovery in cancer","volume":"10","author":"Lappano","year":"2011","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/S0083-6729(06)77005-4","article-title":"Basic aspects of ghrelin action","volume":"77","author":"Pazos","year":"2008","journal-title":"Vitam. Horm."},{"key":"ref_7","first-page":"458","article-title":"The role of ghrelin in weight-regulation disorders: Implications in clinical practice","volume":"13","author":"Solomou","year":"2014","journal-title":"Hormones"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"21","DOI":"10.3928\/02793695-20160523-01","article-title":"An Inverse Agonist Antipsychotic Drug","volume":"54","year":"2016","journal-title":"J. Psychosoc. Nurs. Ment. Health Serv."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"7321","DOI":"10.1073\/pnas.86.19.7321","article-title":"Antagonists with negative intrinsic efficacy at \u03b4 opioid receptors coupled to GTP-binding proteins","volume":"86","author":"Costa","year":"1989","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/0024-3205(94)90022-1","article-title":"Constitutive Receptor Activation as a Regulatory Mechanism Underlying Narcotic Tolerance and Dependence","volume":"54","author":"Wang","year":"1994","journal-title":"Life Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1007\/s13181-015-0521-9","article-title":"Chronic Pain, Chronic Opioid Addiction: A Complex Nexus","volume":"12","author":"Salsitz","year":"2016","journal-title":"J. Med. Toxicol."},{"key":"ref_12","unstructured":"Alter, A., and Yeager, C. (2020, June 01). The Consequences of COVID-19 on the Overdose Epidemic: Overdoses Are Increasing. Washington\/Baltimore High Intensity Drug Trafficking Area. Available online: http:\/\/www.odmap.org\/Content\/docs\/news\/2020\/ODMAP-Report-May2020.pdf."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2307","DOI":"10.1080\/14656566.2016.1244529","article-title":"Update on pharmacotherapy for treatment of opioid use disorder","volume":"17","author":"Ayanga","year":"2016","journal-title":"Expert Opin. Pharm."},{"key":"ref_14","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":"Neuropsychopharm"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e2000017118","DOI":"10.1073\/pnas.2000017118","article-title":"Positive allosteric modulation of the mu-opioid receptor produces analgesia with reduced side effects","volume":"118","author":"Kandasamy","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1016\/j.cell.2017.10.035","article-title":"Bias factor and therapeutic window correlate to predict safer opioid analgesics","volume":"171","author":"Schmid","year":"2017","journal-title":"Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"13873","DOI":"10.1021\/acs.jmedchem.1c01273","article-title":"A Novel Mitragynine Analog with Low-Efficacy Mu Opioid Receptor Agonism Displays Antinociception with Attenuated Adverse Effects","volume":"64","author":"Chakraborty","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1124\/mol.106.028258","article-title":"An opioid agonist that does not induce \u03bc-opioid receptor\u2014Arrestin interactions or receptor internalization","volume":"71","author":"Groer","year":"2007","journal-title":"Mol. Pharm."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.biopsych.2019.06.020","article-title":"Medication Treatment of Opioid Use Disorder","volume":"87","author":"Bell","year":"2020","journal-title":"J. Biol. Psychiatry"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Sadee, W., Oberdick, J., and Wang, Z. (2020). Biased opioid antagonists as modulators of opioid dependence: Opportunities to improve pain therapy and opioid use management. Molecules, 25.","DOI":"10.20944\/preprints202008.0017.v1"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5092","DOI":"10.1523\/JNEUROSCI.1157-07.2007","article-title":"Beta-arrestin2 and c-Src regulate the constitutive activity and recycling of mu opioid receptors in dorsal root ganglion neurons","volume":"27","author":"Walwyn","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/1744-8069-7-24","article-title":"Analgesic tone conferred by constitutively active mu opioid receptors in mice lacking \u03b2-arrestin","volume":"7","author":"Lam","year":"2011","journal-title":"Mol. Pain."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5811","DOI":"10.1523\/JNEUROSCI.2038-21.2022","article-title":"Post-surgical latent pain sensitization is driven by descending serotonergic facilitation and masked by \u00b5-opioid receptor constitutive activity (MORCA) in the rostral ventromedial medulla","volume":"42","author":"Cooper","year":"2022","journal-title":"J. Neurosci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1124\/jpet.116.232835","article-title":"Constitutive Desensitization of Opioid Receptors in Peripheral Sensory Neurons","volume":"359","author":"Sullivan","year":"2016","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1016\/j.pbb.2011.06.025","article-title":"The role of opioid antagonist efficacy and constitutive opioid receptor activity in the opioid withdrawal syndrome in mice","volume":"99","author":"Navani","year":"2011","journal-title":"Pharm. Biochem. Behav."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1038\/sj.npp.1300782","article-title":"Constitutively active opioid receptors mediate the enhanced conditioned aversive effect of naloxone in morphine-dependent mice","volume":"31","author":"Shoblock","year":"2006","journal-title":"Neuropsychopharm"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1124\/mol.60.1.53","article-title":"Chronic exposure to mu-opioid agonists produces constitutive activation of mu-opioid receptors in direct proportion to the efficacy of the agonist used for pretreatment","volume":"60","author":"Liu","year":"2001","journal-title":"Mol. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1016\/j.neuroscience.2007.05.011","article-title":"Enkephalin release promotes homeostatic increases in constitutively active mu opioid receptors during morphine withdrawal","volume":"149","author":"Shoblock","year":"2007","journal-title":"Neuroscience"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1124\/jpet.104.082966","article-title":"In vivo characterization of 6\u03b2-naltrexol, an opioid ligand with less inverse agonist activity compared with naltrexone and naloxone in opioid-dependent mice","volume":"313","author":"Raehal","year":"2005","journal-title":"J Pharmacol. Exp. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1016\/j.lfs.2004.10.024","article-title":"Basal opioid receptor activity, neutral antagonists, and therapeutic opportunities","volume":"76","author":"Sadee","year":"2005","journal-title":"Life Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1124\/jpet.103.054049","article-title":"Basal signaling opioid receptor in mouse brain: Role in narcotic dependence","volume":"308","author":"Wang","year":"2004","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1126\/science.1239403","article-title":"Constitutive \u03bc-opioid receptor activity leads to long-term endogenous analgesia and dependence","volume":"341","author":"Corder","year":"2013","journal-title":"Science"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1001\/jamapsychiatry.2021.3136","article-title":"Expanding Current Approaches to Solve the Opioid Crisis","volume":"79","author":"Blanco","year":"2022","journal-title":"JAMA Psychiatry"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1590","DOI":"10.1046\/j.1471-4159.2001.00362.x","article-title":"Inverse agonists and neutral antagonists at \u03bc opioid receptor (MOR): Possible role of basal receptor signaling in narcotic dependence","volume":"77","author":"Wang","year":"2001","journal-title":"J. Neurochem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1124\/jpet.109.152678","article-title":"The relative potency of inverse opioid agonists and a neutral opioid antagonist in precipitated withdrawal and antagonism of analgesia and toxicity","volume":"330","author":"Sirohi","year":"2009","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/B978-0-12-381298-8.00021-6","article-title":"In vitro and in vivo assessment of m opioid receptor constitutive activity","volume":"484","author":"Bilsky","year":"2010","journal-title":"Methods Enzymol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1002\/syn.20723","article-title":"Identification of a novel \u201calmost neutral\u201d micro-opioid receptor antagonist in CHO cells expressing the cloned human mu-opioid receptor","volume":"64","author":"Sally","year":"2010","journal-title":"Synapse"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1124\/jpet.107.125807","article-title":"[N-allyl-Dmt1]-endomorphins are \u03bc-opioid receptor antagonists lacking inverse agonist properties","volume":"323","author":"Marczak","year":"2007","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1007\/s00210-013-0850-7","article-title":"The in vitro pharmacological profile of TD-1211, a neutral opioid receptor antagonist","volume":"386","author":"Tsuruda","year":"2013","journal-title":"Naunyn. Schmied. Arch. Pharm."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1186\/s13075-018-1661-5","article-title":"A bivalent compound targeting CCR5 and the mu opioid receptor treats inflammatory arthritis pain in mice without inducing pharmacologic tolerance","volume":"20","author":"Dutta","year":"2018","journal-title":"Arthritis. Res. Ther."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2889","DOI":"10.2174\/1568026620666200402115654","article-title":"\u03b4 Opioid Receptor Inverse Agonists and Their In Vivo Pharmacological Effects","volume":"20","author":"Hirayama","year":"2020","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Iwamatsu, C., Hayakawa, D., Kono, T., Honjo, A., Ishizaki, S., Hirayama, S., Gouda, H., and Fujii, H. (2020). Effects of N-Substituents on the Functional Activities of Naltrindole Derivatives for the \u03b4 Opioid Receptor: Synthesis and Evaluation of Sulfonamide Derivatives. Molecules, 25.","DOI":"10.3390\/molecules25173792"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1124\/jpet.102.035964","article-title":"Chronic agonist treatment converts antagonists into inverse agonists at delta-opioid receptors","volume":"302","author":"Liu","year":"2002","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.euroneuro.2020.05.004","article-title":"Pimavanserin exhibits serotonin 5-HT2A receptor inverse agonism for G\u03b1i1- and neutral antagonism for G\u03b1q\/11-proteins in human brain cortex","volume":"36","author":"Horrillo","year":"2020","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1111\/j.1476-5381.1991.tb12271.x","article-title":"Inability of an opioid antagonist lacking negative intrinsic activity to induce opioid receptor up-regulation in vivo","volume":"102","author":"Morris","year":"1991","journal-title":"Br. J. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1124\/mol.104.004549","article-title":"Reciprocal regulation of agonist and inverse agonist signaling efficacy upon short-term treatment of the human delta-opioid receptor with an inverse agonist","volume":"67","author":"Azzi","year":"2005","journal-title":"Mol. Pharmacol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1124\/mol.118.114637","article-title":"Dynamic Opioid Receptor Regulation in the Periphery","volume":"95","author":"Jeske","year":"2019","journal-title":"Mol. Pharmacol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1038\/nm.4262","article-title":"Loss of mu opioid receptor signaling in nociceptors, but not microglia, abrogates morphine tolerance without disrupting analgesia","volume":"23","author":"Corder","year":"2017","journal-title":"Nat. Med."},{"key":"ref_49","first-page":"204","article-title":"Sustained suppression of hyperalgesia during latent sensitization by mu-, delta-, and kappa-opioid receptors and 2A-adrenergic receptors: Role of constitutive activity","volume":"36","author":"Walwyn","year":"2016","journal-title":"Neurobiol. Dis."},{"key":"ref_50","first-page":"272","article-title":"3H-Etorphine Receptor Binding In Vivo: Small Fractional Occupancy Elicits Analgesia","volume":"21","author":"Perry","year":"1982","journal-title":"Mol. Pharmacol."},{"key":"ref_51","first-page":"735","article-title":"In Vivo Receptor Binding of Opioid Drugs at the \u00b5 Site","volume":"233","author":"Rosenbaum","year":"1985","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1176\/appi.neuropsych.19010017","article-title":"An Opioid-Related Amnestic Syndrome with Persistent Effects on Hippocampal Structure and Function","volume":"31","author":"Barash","year":"2019","journal-title":"J. Neuropsychiatry Clin. Neurosci."},{"key":"ref_53","first-page":"379","article-title":"Analgesic responses to morphine and placebo in individuals with postoperative pain","volume":"10","author":"Levine","year":"1981","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1007\/s00213-007-0914-9","article-title":"Comparison of naltrexone, 6\u03b1-naltrexol, and 6\u03b2-naltrexol in morphine-dependent and in non-dependent rhesus monkeys","volume":"195","author":"Li","year":"2007","journal-title":"Psychopharmacology"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1080\/135562102200120442","article-title":"In vivo and in vitro potency studies of 6\u03b2-naltrexol, the major human metabolite of naltrexone","volume":"7","author":"Porter","year":"2002","journal-title":"Addict. Biol."},{"key":"ref_56","first-page":"242","article-title":"Discrimination of three types of opioid binding sites in rat brain in vivo","volume":"25","author":"Rosenbaum","year":"1984","journal-title":"Mol. Pharmacol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1124\/jpet.105.094409","article-title":"Differential in Vivo Potencies of Naltrexone and 6\u03b2-Naltrexol in the Monkey","volume":"316","author":"Ko","year":"2006","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1124\/pr.57.2.2","article-title":"Multiple signaling states of G-protein-coupled receptors","volume":"57","author":"Perez","year":"2005","journal-title":"Pharmacol. Rev."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"11961","DOI":"10.1073\/pnas.1606347113","article-title":"Decay of an active GPCR: Conformational dynamics govern agonist rebinding and persistence of an active, yet empty, receptor state","volume":"113","author":"Schafer","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_60","first-page":"816","article-title":"Short-term inverse agonist treatment induces reciprocal changes in delta-opioid agonist and inverse agonist binding capacity","volume":"67","author":"Azzi","year":"2001","journal-title":"Mol. Pharmacol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"613328","DOI":"10.3389\/fphar.2020.613328","article-title":"Pharmacological prevention of neonatal opioid withdrawal in a pregnant guinea pig model","volume":"11","author":"Safa","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1727","DOI":"10.1111\/j.1526-4637.2011.01279.x","article-title":"6\u03b2-Naltrexol, a peripherally selective opioid antagonist that inhibits morphine-induced slowing of gastrointestinal transit: An exploratory study","volume":"12","author":"Dallaire","year":"2011","journal-title":"Pain Med."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1124\/jpet.106.118810","article-title":"2007 Different effects of opioid antagonists on mu, delta, and kappa opioid receptors with and without agonist pretreatment","volume":"321","author":"Wang","year":"2011","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.ejphar.2008.01.004","article-title":"Comparison of the opioid receptor antagonist properties of naltrexone and 6beta-naltrexol in morphine-na\u00efve and morphine-dependent mice","volume":"583","author":"Divin","year":"2008","journal-title":"Eur. J. Pharmocol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"443","DOI":"10.3181\/00379727-148-38558","article-title":"Narcotic antagonist activity of several metabolites of naloxone and naltrexone tested in morphine dependent mice (38558)","volume":"148","author":"Fujimoto","year":"1975","journal-title":"Proc. Soc. Exp. Biol. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/j.lfs.2009.06.016","article-title":"6\u03b2-Naltrexol preferentially antagonizes opioid effects on gastrointestinal transit compared to antinociception in mice","volume":"85","author":"Raymond","year":"2009","journal-title":"Life Sci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1124\/jpet.115.231902","article-title":"Preferential delivery of an opioid antagonist to the fetal brain in pregnant mice","volume":"358","author":"Oberdick","year":"2016","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/0006-8993(80)90229-2","article-title":"Opiate Antagonist Receptor Binding In Vivo: Evidence for a New Receptor Binding Model","volume":"199","author":"Perry","year":"1980","journal-title":"Brain Res."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Toljan, K., and Vrooman, B. (2018). Low-Dose Naltrexone (LDN)-Review of Therapeutic Utilization. Med. Sci., 6.","DOI":"10.3390\/medsci6040082"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.pbb.2005.08.008","article-title":"Ultra-low-dose naltrexone reduces the rewarding potency of oxycodone and relapse vulnerability in rats","volume":"82","author":"Leri","year":"2018","journal-title":"Pharm. Biochem. Behav."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1111\/j.1369-1600.2008.00119.x","article-title":"Very low dose naltrexone addition in opioid detoxification: A randomized, controlled trial","volume":"14","author":"Mannelli","year":"2009","journal-title":"Addict. Biol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1111\/ajad.13024","article-title":"Transition of Patients with Opioid Use Disorder from Buprenorphine to Extended Release Naltrexone: A Randomized Clinical Trial Assessing Two Transition Regimens","volume":"29","author":"Comer","year":"2020","journal-title":"Am. J. Addict."},{"key":"ref_73","first-page":"A586","article-title":"In vivo studies with 6\u03b2-naltrexamide, a peripherally selective opioid antagonist that has less inverse agonist activity than naltrexone and naloxone","volume":"18","author":"Bartlett","year":"2004","journal-title":"FASEB J."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/18\/5826\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:27:40Z","timestamp":1760142460000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/18\/5826"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,8]]},"references-count":73,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["molecules27185826"],"URL":"https:\/\/doi.org\/10.3390\/molecules27185826","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,8]]}}}