{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T00:31:55Z","timestamp":1793665915580,"version":"4.5.1"},"reference-count":167,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T00:00:00Z","timestamp":1764892800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0"},{"start":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T00:00:00Z","timestamp":1764892800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0"}],"funder":[{"name":"Tris Pharma"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Pain Ther"],"published-print":{"date-parts":[[2026,2]]},"DOI":"10.1007\/s40122-025-00794-8","type":"journal-article","created":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T06:47:43Z","timestamp":1764917263000},"page":"71-95","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["The Therapeutic Potential of Dual NMR (NOP\/MOP) Agonism in Pain Management"],"prefix":"10.1007","volume":"15","author":[{"given":"Roberto","family":"Ciccocioppo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Gudin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles E.","family":"Argoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuela","family":"Offidani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Hackworth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David S.","family":"Fam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jim","family":"Potenziano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,5]]},"reference":[{"key":"794_CR1","doi-asserted-by":"publisher","first-page":"770","DOI":"10.1186\/1471-2458-11-770","volume":"11","author":"DS Goldberg","year":"2011","unstructured":"Goldberg DS, McGee SJ. Pain as a global public health priority. BMC Public Health. 2011;11:770. https:\/\/doi.org\/10.1186\/1471-2458-11-770.","journal-title":"BMC Public Health"},{"issue":"12","key":"794_CR2","doi-asserted-by":"publisher","first-page":"1859","DOI":"10.1111\/j.1526-4637.2010.00983.x","volume":"11","author":"R Sinatra","year":"2010","unstructured":"Sinatra R. Causes and consequences of inadequate management of acute pain. Pain Med. 2010;11(12):1859\u201371. https:\/\/doi.org\/10.1111\/j.1526-4637.2010.00983.x.","journal-title":"Pain Med"},{"issue":"1","key":"794_CR3","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.33757","volume":"15","author":"F Felix","year":"2023","unstructured":"Felix F, Oliveira E, Silva SC, Agualusa L. The overuse of the emergency department at a multidisciplinary pain clinic by patients with chronic pain: a cross-sectional study. Cureus. 2023;15(1):e33757. https:\/\/doi.org\/10.7759\/cureus.33757.","journal-title":"Cureus"},{"key":"794_CR4","doi-asserted-by":"publisher","first-page":"2287","DOI":"10.2147\/JPR.S144066","volume":"10","author":"TJ Gan","year":"2017","unstructured":"Gan TJ. Poorly controlled postoperative pain: prevalence, consequences, and prevention. J Pain Res. 2017;10:2287\u201398. https:\/\/doi.org\/10.2147\/JPR.S144066.","journal-title":"J Pain Res"},{"issue":"6","key":"794_CR5","doi-asserted-by":"publisher","DOI":"10.1097\/PR9.0000000000000627","volume":"2","author":"SA Schug","year":"2017","unstructured":"Schug SA, Bruce J. Risk stratification for the development of chronic postsurgical pain. Pain Rep. 2017;2(6):e627. https:\/\/doi.org\/10.1097\/PR9.0000000000000627.","journal-title":"Pain Rep"},{"issue":"15","key":"794_CR6","doi-asserted-by":"publisher","first-page":"379","DOI":"10.15585\/mmwr.mm7215a1","volume":"72","author":"SM Rikard","year":"2023","unstructured":"Rikard SM, Strahan AE, Schmit KM, Guy GP Jr. Chronic pain among adults - United States, 2019\u20132021. MMWR Morb Mortal Wkly Rep. 2023;72(15):379\u201385. https:\/\/doi.org\/10.15585\/mmwr.mm7215a1.","journal-title":"MMWR Morb Mortal Wkly Rep"},{"issue":"5","key":"794_CR7","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1016\/j.bjae.2021.11.008","volume":"22","author":"DC Rosenberger","year":"2022","unstructured":"Rosenberger DC, Pogatzki-Zahn EM. Chronic post-surgical pain\u2014update on incidence, risk factors and preventive treatment options. BJA Educ. 2022;22(5):190\u20136. https:\/\/doi.org\/10.1016\/j.bjae.2021.11.008.","journal-title":"BJA Educ"},{"key":"794_CR8","doi-asserted-by":"publisher","first-page":"457","DOI":"10.2147\/JPR.S105892","volume":"9","author":"M Due\u00f1as","year":"2016","unstructured":"Due\u00f1as M, Ojeda B, Salazar A, Mico JA, Failde I. A review of chronic pain impact on patients, their social environment and the health care system. J Pain Res. 2016;9:457\u201367. https:\/\/doi.org\/10.2147\/JPR.S105892.","journal-title":"J Pain Res"},{"issue":"3","key":"794_CR9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.15585\/mmwr.rr7103a1","volume":"71","author":"D Dowell","year":"2022","unstructured":"Dowell D, Ragan KR, Jones CM, Baldwin GT, Chou R. CDC clinical practice guideline for prescribing opioids for pain\u2014United States, 2022. MMWR Recomm Rep. 2022;71(3):1\u201395. https:\/\/doi.org\/10.15585\/mmwr.rr7103a1.","journal-title":"MMWR Recomm Rep"},{"key":"794_CR10","unstructured":"Herman TF, Cascella M, Muzio MR. Mu Receptors. StatPearls [Internet]. Treasure Island: StatPearls Publishing; 2024. https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK551554\/."},{"issue":"13","key":"794_CR11","doi-asserted-by":"publisher","first-page":"1253","DOI":"10.1056\/NEJMra1507771","volume":"374","author":"ND Volkow","year":"2016","unstructured":"Volkow ND, McLellan AT. Opioid abuse in chronic pain\u2013misconceptions and mitigation strategies. N Engl J Med. 2016;374(13):1253\u201363. https:\/\/doi.org\/10.1056\/NEJMra1507771.","journal-title":"N Engl J Med"},{"key":"794_CR12","unstructured":"Dydyk AM, Jain NK, Gupta M. Opioid use disorder: evaluation and management. StatPearls [Internet]. Treasure Island: StatPearls Publishing. 2025. https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK553166\/."},{"issue":"2","key":"794_CR13","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1016\/j.annemergmed.2015.11.033","volume":"68","author":"MM Butler","year":"2016","unstructured":"Butler MM, Ancona RM, Beauchamp GA, et al. Emergency department prescription opioids as an initial exposure preceding addiction. Ann Emerg Med. 2016;68(2):202\u20138. https:\/\/doi.org\/10.1016\/j.annemergmed.2015.11.033.","journal-title":"Ann Emerg Med"},{"key":"794_CR14","unstructured":"Substance Abuse and Mental Health Services Administration. Key substance use and mental health indicators in the United States: Results from the 2023 National Survey on Drug Use and Health (HHS Publication No. PEP24-07-021, NSDUH Series H-59) [Internet]. 2024. Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration. https:\/\/www.samhsa.gov\/data\/sites\/default\/files\/reports\/rpt47095\/National%20Report\/National%20Report\/2023-nsduh-annual-national.pdf. Accessed 24 June 2025."},{"key":"794_CR15","unstructured":"US Department of Health and Human Services. Pain management best practices inter-agency task force report: updates, gaps, inconsistencies, and recommendations [Internet]; 2019. https:\/\/www.hhs.gov\/sites\/default\/files\/pmtf-final-report-2019-05-23.pdf. Accessed 27 May 2023."},{"issue":"7","key":"794_CR16","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1111\/bph.15580","volume":"180","author":"JT Bateman","year":"2023","unstructured":"Bateman JT, Saunders SE, Levitt ES. Understanding and countering opioid-induced respiratory depression. Br J Pharmacol. 2023;180(7):813\u201328. https:\/\/doi.org\/10.1111\/bph.15580.","journal-title":"Br J Pharmacol"},{"issue":"2","key":"794_CR17","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1016\/j.jpainsymman.2007.03.015","volume":"35","author":"M Noble","year":"2008","unstructured":"Noble M, Tregear SJ, Treadwell JR, Schoelles K. Long-term opioid therapy for chronic noncancer pain: a systematic review and meta-analysis of efficacy and safety. J Pain Symptom Manag. 2008;35(2):214\u201328. https:\/\/doi.org\/10.1016\/j.jpainsymman.2007.03.015.","journal-title":"J Pain Symptom Manag"},{"issue":"1","key":"794_CR18","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/s0014-2999(97)01411-8","volume":"340","author":"JC Meunier","year":"1997","unstructured":"Meunier JC. Nociceptin\/orphanin FQ and the opioid receptor-like ORL1 receptor. Eur J Pharmacol. 1997;340(1):1\u201315. https:\/\/doi.org\/10.1016\/s0014-2999(97)01411-8.","journal-title":"Eur J Pharmacol"},{"issue":"5237","key":"794_CR19","doi-asserted-by":"publisher","first-page":"792","DOI":"10.1126\/science.270.5237.792","volume":"270","author":"RK Reinscheid","year":"1995","unstructured":"Reinscheid RK, Nothacker HP, Bourson A, et al. Orphanin FQ: a neuropeptide that activates an opioidlike G protein-coupled receptor. Science. 1995;270(5237):792\u20134. https:\/\/doi.org\/10.1126\/science.270.5237.792.","journal-title":"Science"},{"issue":"1","key":"794_CR20","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/0014-5793(94)80235-1","volume":"341","author":"C Mollereau","year":"1994","unstructured":"Mollereau C, Parmentier M, Mailleux P, et al. ORL1, a novel member of the opioid receptor family: cloning, functional expression and localization. FEBS Lett. 1994;341(1):33\u20138. https:\/\/doi.org\/10.1016\/0014-5793(94)80235-1.","journal-title":"FEBS Lett"},{"issue":"2\u20133","key":"794_CR21","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1016\/0014-5793(94)00561-3","volume":"347","author":"JR Bunzow","year":"1994","unstructured":"Bunzow JR, Saez C, Mortrud M, et al. Molecular cloning and tissue distribution of a putative member of the rat opioid receptor gene family that is not a \u03bc, \u03b4 or \u03ba opioid receptor type. FEBS Lett. 1994;347(2\u20133):284\u20138. https:\/\/doi.org\/10.1016\/0014-5793(94)00561-3.","journal-title":"FEBS Lett"},{"issue":"2","key":"794_CR22","doi-asserted-by":"publisher","first-page":"1353","DOI":"10.1006\/bbrc.1994.2814","volume":"205","author":"M Nishi","year":"1994","unstructured":"Nishi M, Takeshima H, Mori M, Nakagawara KI, Takeuchi T. Structure and chromosomal mapping of genes for the mouse \u03ba-opioid receptor and an opioid receptor homologue (MOR-C). Biochem Biophys Res Commun. 1994;205(2):1353\u20137. https:\/\/doi.org\/10.1006\/bbrc.1994.2814.","journal-title":"Biochem Biophys Res Commun"},{"issue":"15","key":"794_CR23","doi-asserted-by":"publisher","first-page":"7011","DOI":"10.1021\/acs.jmedchem.5b01499","volume":"59","author":"NT Zaveri","year":"2016","unstructured":"Zaveri NT. Nociceptin opioid receptor (NOP) as a therapeutic target: progress in translation from preclinical research to clinical utility. J Med Chem. 2016;59(15):7011\u201328. https:\/\/doi.org\/10.1021\/acs.jmedchem.5b01499.","journal-title":"J Med Chem"},{"issue":"2","key":"794_CR24","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1124\/pr.114.009209","volume":"68","author":"L Toll","year":"2016","unstructured":"Toll L, Bruchas MR, Calo G, Cox BM, Zaveri NT. Nociceptin\/orphanin FQ receptor structure, signaling, ligands, functions, and interactions with opioid systems. Pharmacol Rev. 2016;68(2):419\u201357. https:\/\/doi.org\/10.1124\/pr.114.009209.","journal-title":"Pharmacol Rev"},{"issue":"9","key":"794_CR25","doi-asserted-by":"publisher","first-page":"2088","DOI":"10.1038\/npp.2009.33","volume":"34","author":"MC Ko","year":"2009","unstructured":"Ko MC, Woods JH, Fantegrossi WE, Galuska CM, Wichmann J, Prinssen EP. Behavioral effects of a synthetic agonist selective for nociceptin\/orphanin FQ peptide receptors in monkeys. Neuropsychopharmacology. 2009;34(9):2088\u201396. https:\/\/doi.org\/10.1038\/npp.2009.33.","journal-title":"Neuropsychopharmacology"},{"issue":"9","key":"794_CR26","doi-asserted-by":"publisher","first-page":"1976","DOI":"10.1097\/j.pain.0000000000001939","volume":"161","author":"SN Raja","year":"2020","unstructured":"Raja SN, Carr DB, Cohen M, et al. The revised International Association for the Study of Pain definition of pain: concepts, challenges, and compromises. Pain. 2020;161(9):1976\u201382. https:\/\/doi.org\/10.1097\/j.pain.0000000000001939.","journal-title":"Pain"},{"key":"794_CR27","doi-asserted-by":"publisher","DOI":"10.2174\/1573405620666230519144112","author":"DC Gonzalez-Hermosillo","year":"2023","unstructured":"Gonzalez-Hermosillo DC, Gonzalez-Hermosillo LM, Villase\u00f1or-Almaraz M, et al. Current concepts of pain pathways: a brief review of anatomy, physiology, and medical imaging. Curr Med Imaging Rev. 2023. https:\/\/doi.org\/10.2174\/1573405620666230519144112.","journal-title":"Curr Med Imaging Rev"},{"issue":"8","key":"794_CR28","doi-asserted-by":"publisher","first-page":"2164","DOI":"10.3390\/ijms19082164","volume":"19","author":"MF Yam","year":"2018","unstructured":"Yam MF, Loh YC, Tan CS, Khadijah Adam S, Abdul Manan N, Basir R. General pathways of pain sensation and the major neurotransmitters involved in pain regulation. Int J Mol Sci. 2018;19(8):2164. https:\/\/doi.org\/10.3390\/ijms19082164.","journal-title":"Int J Mol Sci"},{"issue":"1","key":"794_CR29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/s0301-0082(98)00048-3","volume":"57","author":"MJ Millan","year":"1999","unstructured":"Millan MJ. The induction of pain: an integrative review. Prog Neurobiol. 1999;57(1):1\u2013164. https:\/\/doi.org\/10.1016\/s0301-0082(98)00048-3.","journal-title":"Prog Neurobiol"},{"issue":"8","key":"794_CR30","doi-asserted-by":"publisher","first-page":"694","DOI":"10.1038\/nrd2572","volume":"7","author":"DG Lambert","year":"2008","unstructured":"Lambert DG. The nociceptin\/orphanin FQ receptor: a target with broad therapeutic potential. Nat Rev Drug Discov. 2008;7(8):694\u2013710. https:\/\/doi.org\/10.1038\/nrd2572.","journal-title":"Nat Rev Drug Discov"},{"issue":"6312","key":"794_CR31","doi-asserted-by":"publisher","first-page":"578","DOI":"10.1126\/science.aaf8933","volume":"354","author":"C Peirs","year":"2016","unstructured":"Peirs C, Seal RP. Neural circuits for pain: recent advances and current views. Science. 2016;354(6312):578\u201384. https:\/\/doi.org\/10.1126\/science.aaf8933.","journal-title":"Science"},{"issue":"1","key":"794_CR32","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1152\/physrev.00040.2019","volume":"101","author":"R Kuner","year":"2021","unstructured":"Kuner R, Kuner T. Cellular circuits in the brain and their modulation in acute and chronic pain. Physiol Rev. 2021;101(1):213\u201358. https:\/\/doi.org\/10.1152\/physrev.00040.2019.","journal-title":"Physiol Rev"},{"issue":"8","key":"794_CR33","doi-asserted-by":"publisher","first-page":"458","DOI":"10.1038\/s41583-021-00468-2","volume":"22","author":"LL Tan","year":"2021","unstructured":"Tan LL, Kuner R. Neocortical circuits in pain and pain relief. Nat Rev Neurosci. 2021;22(8):458\u201371. https:\/\/doi.org\/10.1038\/s41583-021-00468-2.","journal-title":"Nat Rev Neurosci"},{"issue":"6","key":"794_CR34","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1016\/s0301-0082(02)00009-6","volume":"66","author":"MJ Millan","year":"2002","unstructured":"Millan MJ. Descending control of pain. Prog Neurobiol. 2002;66(6):355\u2013474. https:\/\/doi.org\/10.1016\/s0301-0082(02)00009-6.","journal-title":"Prog Neurobiol"},{"issue":"3","key":"794_CR35","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1016\/j.brainresrev.2004.07.004","volume":"46","author":"H Vanegas","year":"2004","unstructured":"Vanegas H, Schaible HG. Descending control of persistent pain: inhibitory or facilitatory? Brain Res Rev. 2004;46(3):295\u2013309. https:\/\/doi.org\/10.1016\/j.brainresrev.2004.07.004.","journal-title":"Brain Res Rev"},{"issue":"6","key":"794_CR36","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1016\/j.tins.2024.04.006","volume":"47","author":"CC De Preter","year":"2024","unstructured":"De Preter CC, Heinricher MM. The \u201cin\u2019s and out\u2019s\u201d of descending pain modulation from the rostral ventromedial medulla. Trends Neurosci. 2024;47(6):447\u201360. https:\/\/doi.org\/10.1016\/j.tins.2024.04.006.","journal-title":"Trends Neurosci"},{"issue":"3","key":"794_CR37","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1097\/00044067-200507000-00003","volume":"16","author":"JE Holden","year":"2005","unstructured":"Holden JE, Jeong Y, Forrest JM. The endogenous opioid system and clinical pain management. AACN Clin Issues. 2005;16(3):291\u2013301.","journal-title":"AACN Clin Issues"},{"key":"794_CR38","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1146\/annurev-neuro-080317-061522","volume":"41","author":"G Corder","year":"2018","unstructured":"Corder G, Castro DC, Bruchas MR, Scherrer G. Endogenous and exogenous opioids in pain. Annu Rev Neurosci. 2018;41:453\u201373. https:\/\/doi.org\/10.1146\/annurev-neuro-080317-061522.","journal-title":"Annu Rev Neurosci"},{"issue":"13","key":"794_CR39","doi-asserted-by":"publisher","first-page":"2514","DOI":"10.1038\/s41386-018-0225-3","volume":"43","author":"RJ Valentino","year":"2018","unstructured":"Valentino RJ, Volkow ND. Untangling the complexity of opioid receptor function. Neuropsychopharmacology. 2018;43(13):2514\u201320. https:\/\/doi.org\/10.1038\/s41386-018-0225-3.","journal-title":"Neuropsychopharmacology"},{"key":"794_CR40","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2022.105011","volume":"145","author":"J Cuitavi","year":"2023","unstructured":"Cuitavi J, Torres-P\u00e9rez JV, Lorente JD, et al. Crosstalk between mu-opioid receptors and neuroinflammation: consequences for drug addiction and pain. Neurosci Biobehav Rev. 2023;145:105011. https:\/\/doi.org\/10.1016\/j.neubiorev.2022.105011.","journal-title":"Neurosci Biobehav Rev"},{"key":"794_CR41","doi-asserted-by":"publisher","DOI":"10.1016\/j.bjao.2023.100141","volume":"6","author":"DG Lambert","year":"2023","unstructured":"Lambert DG. Opioids and opioid receptors; understanding pharmacological mechanisms as a key to therapeutic advances and mitigation of the misuse crisis. BJA Open. 2023;6:100141. https:\/\/doi.org\/10.1016\/j.bjao.2023.100141.","journal-title":"BJA Open"},{"key":"794_CR42","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/j.neuropharm.2019.03.006","volume":"151","author":"CW Cunningham","year":"2019","unstructured":"Cunningham CW, Elballa WM, Vold SU. Bifunctional opioid receptor ligands as novel analgesics. Neuropharmacology. 2019;151:195\u2013207. https:\/\/doi.org\/10.1016\/j.neuropharm.2019.03.006.","journal-title":"Neuropharmacology"},{"issue":"2","key":"794_CR43","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1124\/mol.120.119388","volume":"98","author":"LD Fricker","year":"2020","unstructured":"Fricker LD, Margolis EB, Gomes I, Devi LA. Five decades of research on opioid peptides: current knowledge and unanswered questions. Mol Pharmacol. 2020;98(2):96\u2013108. https:\/\/doi.org\/10.1124\/mol.120.119388.","journal-title":"Mol Pharmacol"},{"issue":"1","key":"794_CR44","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1186\/s44158-024-00201-2","volume":"4","author":"L Rullo","year":"2024","unstructured":"Rullo L, Morosini C, Lacorte A, et al. Opioid system and related ligands: from the past to future perspectives. J Anesth Analg Crit Care. 2024;4(1):70. https:\/\/doi.org\/10.1186\/s44158-024-00201-2.","journal-title":"J Anesth Analg Crit Care"},{"issue":"5","key":"794_CR45","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2024.103950","volume":"29","author":"A Eliasof","year":"2024","unstructured":"Eliasof A, Liu-Chen LY, Li Y. Peptide-derived ligands for the discovery of safer opioid analgesics. Drug Discov Today. 2024;29(5):103950. https:\/\/doi.org\/10.1016\/j.drudis.2024.103950.","journal-title":"Drug Discov Today"},{"issue":"7","key":"794_CR46","doi-asserted-by":"publisher","first-page":"975","DOI":"10.1111\/bph.15760","volume":"180","author":"BR Varga","year":"2023","unstructured":"Varga BR, Streicher JM, Majumdar S. Strategies towards safer opioid analgesics\u2013a review of old and upcoming targets. Br J Pharmacol. 2023;180(7):975\u201393. https:\/\/doi.org\/10.1111\/bph.15760.","journal-title":"Br J Pharmacol"},{"issue":"3","key":"794_CR47","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1124\/jpet.114.213694","volume":"349","author":"K Linz","year":"2014","unstructured":"Linz K, Christoph T, Tzschentke TM, et al. Cebranopadol: a novel potent analgesic nociceptin\/orphanin FQ peptide and opioid receptor agonist. J Pharmacol Exp Ther. 2014;349(3):535\u201348. https:\/\/doi.org\/10.1124\/jpet.114.213694.","journal-title":"J Pharmacol Exp Ther"},{"issue":"9","key":"794_CR48","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1007\/s40265-023-01878-5","volume":"83","author":"H Ding","year":"2023","unstructured":"Ding H, Kiguchi N, Dobbins M, Romero-Sandoval EA, Kishioka S, Ko MC. Nociceptin receptor-related agonists as safe and non-addictive analgesics. Drugs. 2023;83(9):771\u201393. https:\/\/doi.org\/10.1007\/s40265-023-01878-5.","journal-title":"Drugs"},{"issue":"1","key":"794_CR49","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1002\/jnr.24624","volume":"100","author":"N Kiguchi","year":"2022","unstructured":"Kiguchi N, Ding H, Ko MC. Therapeutic potentials of NOP and MOP receptor coactivation for the treatment of pain and opioid abuse. J Neurosci Res. 2022;100(1):191\u2013202. https:\/\/doi.org\/10.1002\/jnr.24624.","journal-title":"J Neurosci Res"},{"issue":"4","key":"794_CR50","doi-asserted-by":"publisher","first-page":"860","DOI":"10.1124\/pr.110.003145","volume":"63","author":"C Stein","year":"2011","unstructured":"Stein C, Machelska H. Modulation of peripheral sensory neurons by the immune system: implications for pain therapy. Pharmacol Rev. 2011;63(4):860\u201381. https:\/\/doi.org\/10.1124\/pr.110.003145.","journal-title":"Pharmacol Rev"},{"issue":"2","key":"794_CR51","doi-asserted-by":"publisher","first-page":"476","DOI":"10.1124\/jpet.103.064808","volume":"309","author":"TF Finnegan","year":"2004","unstructured":"Finnegan TF, Li DP, Chen SR, Pan HL. Activation of mu-opioid receptors inhibits synaptic inputs to spinally projecting rostral ventromedial medulla neurons. J Pharmacol Exp Ther. 2004;309(2):476\u201383. https:\/\/doi.org\/10.1124\/jpet.103.064808.","journal-title":"J Pharmacol Exp Ther"},{"key":"794_CR52","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2019.146623","volume":"1729","author":"J Sun","year":"2020","unstructured":"Sun J, Chen SR, Pan HL. \u039c-opioid receptors in primary sensory neurons are involved in supraspinal opioid analgesia. Brain Res. 2020;1729:146623. https:\/\/doi.org\/10.1016\/j.brainres.2019.146623.","journal-title":"Brain Res"},{"issue":"7","key":"794_CR53","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1038\/nrn1431","volume":"5","author":"H Fields","year":"2004","unstructured":"Fields H. State-dependent opioid control of pain. Nat Rev Neurosci. 2004;5(7):565\u201375. https:\/\/doi.org\/10.1038\/nrn1431.","journal-title":"Nat Rev Neurosci"},{"issue":"5528","key":"794_CR54","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1126\/science.1060952","volume":"293","author":"JK Zubieta","year":"2001","unstructured":"Zubieta JK, Smith YR, Bueller JA, et al. Regional mu opioid receptor regulation of sensory and affective dimensions of pain. Science. 2001;293(5528):311\u20135. https:\/\/doi.org\/10.1126\/science.1060952.","journal-title":"Science"},{"issue":"1","key":"794_CR55","doi-asserted-by":"publisher","first-page":"17837","DOI":"10.1038\/s41598-019-54128-8","volume":"9","author":"L Goedecke","year":"2019","unstructured":"Goedecke L, Bengoetxea X, Blaesse P, Pape HC, J\u00fcngling K. \u00b5-opioid receptor-mediated downregulation of midline thalamic pathways to basal and central amygdala. Sci Rep. 2019;9(1):17837. https:\/\/doi.org\/10.1038\/s41598-019-54128-8.","journal-title":"Sci Rep"},{"key":"794_CR56","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1016\/j.brainres.2009.09.036","volume":"1314","author":"EJ Van Bockstaele","year":"2010","unstructured":"Van Bockstaele EJ, Reyes BA, Valentino RJ. The locus coeruleus: a key nucleus where stress and opioids intersect to mediate vulnerability to opiate abuse. Brain Res. 2010;1314:162\u201374.","journal-title":"Brain Res"},{"key":"794_CR57","doi-asserted-by":"publisher","unstructured":"Bodnar RJ. Endogenous opiates and behavior: 2024.\u00a0Peptides. 2025. https:\/\/doi.org\/10.1016\/j.peptides.2025.171422.","DOI":"10.1016\/j.peptides.2025.171422"},{"issue":"4","key":"794_CR58","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1080\/08897077.2021.1878084","volume":"42","author":"NE Spencer","year":"2021","unstructured":"Spencer NE, Taubenberger SP, Roberto R, Krishnamurti LS, Chang JC, Hacker K. Stories of starting\": understanding the complex contexts of opioid misuse initiation. Subst Abus. 2021;42(4):865\u201372. https:\/\/doi.org\/10.1080\/08897077.2021.1878084.","journal-title":"Subst Abus"},{"issue":"4","key":"794_CR59","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1177\/0022042615604345","volume":"45","author":"A Harocopos","year":"2015","unstructured":"Harocopos A, Allen B. Routes into opioid analgesic misuse: emergent typologies of initiation. J Drug Issues. 2015;45(4):385\u201395. https:\/\/doi.org\/10.1177\/0022042615604345.","journal-title":"J Drug Issues"},{"issue":"1","key":"794_CR60","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1038\/s41380-020-0661-4","volume":"26","author":"ND Volkow","year":"2021","unstructured":"Volkow ND, Blanco C. The changing opioid crisis: development, challenges and opportunities. Mol Psychiatry. 2021;26(1):218\u201333. https:\/\/doi.org\/10.1038\/s41380-020-0661-4.","journal-title":"Mol Psychiatry"},{"key":"794_CR61","unstructured":"US Food and Drug Administration. FDA identifies harm reported from sudden discontinuation of opioid pain medicines and requires label changes to guide prescribers on gradual, individualized tapering [Internet]. 2019. https:\/\/www.fda.gov\/drugs\/drug-safety-and-availability\/fda-identifies-harm-reported-sudden-discontinuation-opioid-pain-medicines-and-requires-label-changes. Accessed 27 May 2023."},{"issue":"2","key":"794_CR62","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1016\/j.jsat.2014.03.004","volume":"47","author":"RD Weiss","year":"2014","unstructured":"Weiss RD, Potter JS, Griffin ML, et al. Reasons for opioid use among patients with dependence on prescription opioids: the role of chronic pain. J Subst Abuse Treat. 2014;47(2):140\u20135. https:\/\/doi.org\/10.1016\/j.jsat.2014.03.004.","journal-title":"J Subst Abuse Treat"},{"issue":"2","key":"794_CR63","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1111\/ajad.12862","volume":"28","author":"TR Kosten","year":"2019","unstructured":"Kosten TR, Baxter LE. Review article: Effective management of opioid withdrawal symptoms: a gateway to opioid dependence treatment. Am J Addict. 2019;28(2):55\u201362. https:\/\/doi.org\/10.1111\/ajad.12862.","journal-title":"Am J Addict"},{"issue":"1","key":"794_CR64","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1097\/ALN.0b013e3181c38c25","volume":"112","author":"A Dahan","year":"2010","unstructured":"Dahan A, Aarts L, Smith TW. Incidence, reversal, and prevention of opioid-induced respiratory depression. Anesthesiology. 2010;112(1):226\u201338. https:\/\/doi.org\/10.1097\/ALN.0b013e3181c38c25.","journal-title":"Anesthesiology"},{"issue":"3","key":"794_CR65","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1177\/0310057X0503300306","volume":"33","author":"EJ Murphy","year":"2005","unstructured":"Murphy EJ. Acute pain management pharmacology for the patient with concurrent renal or hepatic disease. Anaesth Intensive Care. 2005;33(3):311\u201322. https:\/\/doi.org\/10.1177\/0310057X0503300306.","journal-title":"Anaesth Intensive Care"},{"issue":"4","key":"794_CR66","doi-asserted-by":"publisher","DOI":"10.5812\/hepatmon.32636","volume":"16","author":"H Soleimanpour","year":"2016","unstructured":"Soleimanpour H, Safari S, Shahsavari Nia K, Sanaie S, Alavian SM. Opioid drugs in patients with liver disease: a systematic review. Hepat Mon. 2016;16(4):e32636. https:\/\/doi.org\/10.5812\/hepatmon.32636.","journal-title":"Hepat Mon"},{"issue":"11","key":"794_CR67","doi-asserted-by":"publisher","first-page":"1911","DOI":"10.1111\/pme.12480","volume":"15","author":"B Zedler","year":"2014","unstructured":"Zedler B, Xie L, Wang L, et al. Risk factors for serious prescription opioid-related toxicity or overdose among Veterans Health Administration patients. Pain Med. 2014;15(11):1911\u201329. https:\/\/doi.org\/10.1111\/pme.12480.","journal-title":"Pain Med"},{"issue":"10","key":"794_CR68","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1002396","volume":"14","author":"T Gomes","year":"2017","unstructured":"Gomes T, Juurlink DN, Antoniou T, Mamdani MM, Paterson JM, van den Brink W. Gabapentin, opioids, and the risk of opioid-related death: a population-based nested case-control study. PLoS Med. 2017;14(10):e1002396. https:\/\/doi.org\/10.1371\/journal.pmed.1002396.","journal-title":"PLoS Med"},{"issue":"3","key":"794_CR69","doi-asserted-by":"publisher","DOI":"10.3390\/pharmacy8030154","volume":"8","author":"A Matos","year":"2020","unstructured":"Matos A, Bankes DL, Bain KT, Ballinghoff T, Turgeon J. Opioids, polypharmacy, and drug interactions: a technological paradigm shift is needed to ameliorate the ongoing opioid epidemic. Pharmacy (Basel). 2020;8(3):154. https:\/\/doi.org\/10.3390\/pharmacy8030154.","journal-title":"Pharmacy (Basel)"},{"issue":"16","key":"794_CR70","doi-asserted-by":"publisher","first-page":"3777","DOI":"10.1111\/bph.12744","volume":"171","author":"W Schr\u00f6der","year":"2014","unstructured":"Schr\u00f6der W, Lambert DG, Ko MC, Koch T. Functional plasticity of the N\/OFQ-NOP receptor system determines analgesic properties of NOP receptor agonists. Br J Pharmacol. 2014;171(16):3777\u2013800. https:\/\/doi.org\/10.1111\/bph.12744.","journal-title":"Br J Pharmacol"},{"issue":"9","key":"794_CR71","doi-asserted-by":"publisher","first-page":"1111","DOI":"10.1002\/jcph.1276","volume":"58","author":"AN Nafziger","year":"2018","unstructured":"Nafziger AN, Barkin RL. Opioid therapy in acute and chronic pain. J Clin Pharmacol. 2018;58(9):1111\u201322. https:\/\/doi.org\/10.1002\/jcph.1276.","journal-title":"J Clin Pharmacol"},{"issue":"6","key":"794_CR72","doi-asserted-by":"publisher","first-page":"375","DOI":"10.5055\/jom.2014.0234","volume":"10","author":"RN Jamison","year":"2014","unstructured":"Jamison RN, Sheehan KA, Scanlan E, Matthews M, Ross EL. Beliefs and attitudes about opioid prescribing and chronic pain management: survey of primary care providers. J Opioid Manag. 2014;10(6):375\u201382. https:\/\/doi.org\/10.5055\/jom.2014.0234.","journal-title":"J Opioid Manag"},{"issue":"7","key":"794_CR73","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2019.6928","volume":"2","author":"PA Lagisetty","year":"2019","unstructured":"Lagisetty PA, Healy N, Garpestad C, Jannausch M, Tipirneni R, Bohnert ASB. Access to primary care clinics for patients with chronic pain receiving opioids. JAMA Netw Open. 2019;2(7):e196928. https:\/\/doi.org\/10.1001\/jamanetworkopen.2019.6928.","journal-title":"JAMA Netw Open"},{"issue":"6","key":"794_CR74","doi-asserted-by":"publisher","first-page":"1840","DOI":"10.1097\/j.pain.0000000000002173","volume":"162","author":"K Kwekkeboom","year":"2021","unstructured":"Kwekkeboom K, Serlin RC, Ward SE, LeBlanc TW, Ogunseitan A, Cleary J. Revisiting patient-related barriers to cancer pain management in the context of the US opioid crisis. Pain. 2021;162(6):1840\u20137. https:\/\/doi.org\/10.1097\/j.pain.0000000000002173.","journal-title":"Pain"},{"issue":"6","key":"794_CR75","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1007\/s40263-022-00924-2","volume":"36","author":"F Coluzzi","year":"2022","unstructured":"Coluzzi F, Rullo L, Scerpa MS, et al. Current and future therapeutic options in pain management: multi-mechanistic opioids involving both MOR and NOP receptor activation. CNS Drugs. 2022;36(6):617\u201332. https:\/\/doi.org\/10.1007\/s40263-022-00924-2.","journal-title":"CNS Drugs"},{"issue":"8","key":"794_CR76","doi-asserted-by":"publisher","first-page":"1614","DOI":"10.1111\/j.1476-5381.1996.tb16080.x","volume":"119","author":"M Connor","year":"1996","unstructured":"Connor M, Vaughan CW, Chieng B, Christie MJ. Nociceptin receptor coupling to a potassium conductance in rat locus coeruleus neurones in vitro. Br J Pharmacol. 1996;119(8):1614\u20138.","journal-title":"Br J Pharmacol"},{"issue":"3","key":"794_CR77","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1016\/S0031-6997(24)01502-3","volume":"53","author":"JS Mogil","year":"2001","unstructured":"Mogil JS, Pasternak GW. The molecular and behavioral pharmacology of the orphanin FQ\/nociceptin peptide and receptor family. Pharmacol Rev. 2001;53(3):381\u2013415.","journal-title":"Pharmacol Rev"},{"issue":"3","key":"794_CR78","doi-asserted-by":"publisher","first-page":"595","DOI":"10.3390\/molecules27030595","volume":"27","author":"A El Daibani","year":"2022","unstructured":"El Daibani A, Che T. Spotlight on nociceptin\/orphanin FQ receptor in the treatment of pain. Molecules. 2022;27(3):595. https:\/\/doi.org\/10.3390\/molecules27030595.","journal-title":"Molecules"},{"issue":"7","key":"794_CR79","doi-asserted-by":"publisher","first-page":"1567","DOI":"10.1111\/j.1476-5381.1996.tb15576.x","volume":"118","author":"S Giuliani","year":"1996","unstructured":"Giuliani S, Maggi CA. Inhibition of tachykinin release from peripheral endings of sensory nerves by nociceptin, a novel opioid peptide. Br J Pharmacol. 1996;118(7):1567\u20139. https:\/\/doi.org\/10.1111\/j.1476-5381.1996.tb15576.x.","journal-title":"Br J Pharmacol"},{"issue":"4","key":"794_CR80","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1038\/sj.bjp.0701209","volume":"121","author":"Z Helyes","year":"1997","unstructured":"Helyes Z, N\u00e9meth J, Pint\u00e9r E, Szolcs\u00e1nyi J. Inhibition by nociceptin of neurogenic inflammation and the release of SP and CGRP from sensory nerve terminals. Br J Pharmacol. 1997;121(4):613\u20135.","journal-title":"Br J Pharmacol"},{"issue":"1","key":"794_CR81","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1136\/jnnp.37.1.47","volume":"37","author":"L Grimby","year":"1974","unstructured":"Grimby L, Hannerz J. Disturbances in the voluntary recruitment order of anterior tibial motor units in bradykinesia of Parkinsonism. J Neurol Neurosurg Psychiatry. 1974;37(1):47\u201354. https:\/\/doi.org\/10.1136\/jnnp.37.1.47.","journal-title":"J Neurol Neurosurg Psychiatry"},{"issue":"3","key":"794_CR82","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1016\/s0304-3940(99)00579-0","volume":"272","author":"A Di Giannuario","year":"1999","unstructured":"Di Giannuario A, Pieretti S, Catalani A, Loizzo A. Orphanin FQ reduces morphine-induced dopamine release in the nucleus accumbens: a microdialysis study in rats. Neurosci Lett. 1999;272(3):183\u20136. https:\/\/doi.org\/10.1016\/s0304-3940(99)00579-0.","journal-title":"Neurosci Lett"},{"issue":"1\u20132","key":"794_CR83","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1016\/s0006-8993(99)01425-0","volume":"832","author":"NP Murphy","year":"1999","unstructured":"Murphy NP, Lee Y, Maidment NT. Orphanin FQ\/nociceptin blocks acquisition of morphine place preference. Brain Res. 1999;832(1\u20132):168\u201370. https:\/\/doi.org\/10.1016\/s0006-8993(99)01425-0.","journal-title":"Brain Res"},{"issue":"1\u20132","key":"794_CR84","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1016\/s0014-2999(00)00590-2","volume":"404","author":"R Ciccocioppo","year":"2000","unstructured":"Ciccocioppo R, Angeletti S, Sanna PP, Weiss F, Massi M. Effect of nociceptin\/orphanin FQ on the rewarding properties of morphine. Eur J Pharmacol. 2000;404(1\u20132):153\u20139. https:\/\/doi.org\/10.1016\/s0014-2999(00)00590-2.","journal-title":"Eur J Pharmacol"},{"key":"794_CR85","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2022.109408","volume":"226","author":"B Coutens","year":"2023","unstructured":"Coutens B, Ingram SL. Key differences in regulation of opioid receptors localized to presynaptic terminals compared to somas: relevance for novel therapeutics. Neuropharmacology. 2023;226:109408. https:\/\/doi.org\/10.1016\/j.neuropharm.2022.109408.","journal-title":"Neuropharmacology"},{"issue":"23","key":"794_CR86","doi-asserted-by":"publisher","DOI":"10.3390\/ijms222312956","volume":"22","author":"M Ubaldi","year":"2021","unstructured":"Ubaldi M, Cannella N, Borruto AM, et al. Role of nociceptin\/orphanin FQ-NOP receptor system in the regulation of stress-related disorders. Int J Mol Sci. 2021;22(23):12956. https:\/\/doi.org\/10.3390\/ijms222312956.","journal-title":"Int J Mol Sci"},{"issue":"4","key":"794_CR87","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1002\/(SICI)1096-9861(19991004)412:4<563::AID-CNE2>3.0.CO;2-Z","volume":"412","author":"CR Neal Jr","year":"1999","unstructured":"Neal CR Jr, Mansour A, Reinscheid R, et al. Opioid receptor-like (ORL1) receptor distribution in the rat central nervous system: comparison of ORL1 receptor mRNA expression with 125I-[14Tyr]-orphanin FQ binding. J Comp Neurol. 1999;412(4):563\u2013605.","journal-title":"J Comp Neurol"},{"issue":"1\u20132","key":"794_CR88","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/s0006-8993(00)02669-x","volume":"880","author":"S Florin","year":"2000","unstructured":"Florin S, Meunier JC, Costentin J. Autoradiographic localization of [3H] nociceptin binding sites in the rat brain. Brain Res. 2000;880(1\u20132):11\u20136. https:\/\/doi.org\/10.1016\/s0006-8993(00)02669-x.","journal-title":"Brain Res"},{"issue":"33","key":"794_CR89","doi-asserted-by":"publisher","first-page":"11682","DOI":"10.1523\/JNEUROSCI.5122-14.2015","volume":"35","author":"A Ozawa","year":"2015","unstructured":"Ozawa A, Brunori G, Mercatelli D, et al. Knock-in mice with NOP-eGFP receptors identify receptor cellular and regional localization. J Neurosci. 2015;35(33):11682\u201393.","journal-title":"J Neurosci"},{"key":"794_CR90","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1016\/bs.apha.2015.10.001","volume":"75","author":"N Kiguchi","year":"2016","unstructured":"Kiguchi N, Ding H, Ko MC. Central N\/OFQ-NOP receptor system in pain modulation. Adv Pharmacol. 2016;75:217\u201343. https:\/\/doi.org\/10.1016\/bs.apha.2015.10.001.","journal-title":"Adv Pharmacol."},{"issue":"31","key":"794_CR91","doi-asserted-by":"publisher","first-page":"2878","DOI":"10.2174\/1568026620666200508082615","volume":"20","author":"N Kiguchi","year":"2020","unstructured":"Kiguchi N, Ding H, Kishioka S, Ko MC. Nociceptin\/orphanin FQ peptide receptor-related ligands as novel analgesics. Curr Top Med Chem. 2020;20(31):2878\u201388. https:\/\/doi.org\/10.2174\/1568026620666200508082615.","journal-title":"Curr Top Med Chem"},{"issue":"3","key":"794_CR92","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1016\/S0304-3959(98)00071-2","volume":"76","author":"JX Hao","year":"1998","unstructured":"Hao JX, Xu IS, Wiesenfeld-Hallin Z, Xu XJ. Anti-hyperalgesic and anti-allodynic effects of intrathecal nociceptin\/orphanin FQ in rats after spinal cord injury, peripheral nerve injury and inflammation. Pain. 1998;76(3):385\u201393. https:\/\/doi.org\/10.1016\/S0304-3959(98)00071-2.","journal-title":"Pain"},{"issue":"2","key":"794_CR93","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1124\/jpet.111.184663","volume":"339","author":"TV Khroyan","year":"2011","unstructured":"Khroyan TV, Polgar WE, Orduna J, et al. Differential effects of nociceptin\/orphanin FQ (NOP) receptor agonists in acute versus chronic pain: studies with bifunctional NOP\/\u03bc receptor agonists in the sciatic nerve ligation chronic pain model in mice. J Pharmacol Exp Ther. 2011;339(2):687\u201393. https:\/\/doi.org\/10.1124\/jpet.111.184663.","journal-title":"J Pharmacol Exp Ther"},{"key":"794_CR94","doi-asserted-by":"crossref","unstructured":"Khroyan TV, Polgar WE, Cami-Kobeci G, Husbands SM, Zaveri NT, Toll L. The first universal opioid ligand, (2S)-2-[(5R,6R,7R,14S)-N-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6-meth oxymorphinan-7-yl]-3,3-dimethylpentan-2-ol (BU08028): characterization of the in vitro profile and in vivo behavioral effects in mouse models of acute pain and cocaine-induced reward. J Pharmacol Exp Ther. 2011;336(3):952\u201361. 10.124\/jpet.110.175620.","DOI":"10.1124\/jpet.110.175620"},{"issue":"1","key":"794_CR95","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1124\/jpet.113.203984","volume":"346","author":"DD Sukhtankar","year":"2013","unstructured":"Sukhtankar DD, Zaveri NT, Husbands SM, Ko MC. Effects of spinally administered bifunctional nociceptin\/orphanin FQ peptide receptor\/mu-opioid receptor ligands in mouse models of neuropathic and inflammatory pain. J Pharmacol Exp Ther. 2013;346(1):11\u201322. https:\/\/doi.org\/10.1124\/jpet.113.203984.","journal-title":"J Pharmacol Exp Ther"},{"issue":"3","key":"794_CR96","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1124\/jpet.113.209825","volume":"348","author":"M Sobczak","year":"2014","unstructured":"Sobczak M, Mokrowiecka A, Cygankiewicz AI, et al. Anti-inflammatory and antinociceptive action of an orally available Nociceptin receptor agonist SCH 221510 in a mouse model of inflammatory bowel diseases. J Pharmacol Exp Ther. 2014;348(3):401\u20139. https:\/\/doi.org\/10.1124\/jpet.113.209825.","journal-title":"J Pharmacol Exp Ther"},{"issue":"5","key":"794_CR97","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1016\/j.jpain.2008.11.006","volume":"10","author":"MC Ko","year":"2009","unstructured":"Ko MC, Naughton NN. Antinociceptive effects of nociceptin\/orphanin FQ administered intrathecally in monkeys. J Pain. 2009;10(5):509\u201316. https:\/\/doi.org\/10.1016\/j.jpain.2008.11.006.","journal-title":"J Pain"},{"issue":"1","key":"794_CR98","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/j.pain.2009.10.026","volume":"148","author":"E Hu","year":"2010","unstructured":"Hu E, Cal\u00f2 G, Guerrini R, Ko MC. Long-lasting antinociceptive spinal effects in primates of the novel nociceptin\/orphanin FQ receptor agonist UFP-112. Pain. 2010;148(1):107\u201313. https:\/\/doi.org\/10.1016\/j.pain.2009.10.026.","journal-title":"Pain"},{"issue":"1\u20132","key":"794_CR99","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1016\/0006-8993(96)00476-3","volume":"727","author":"DP Devine","year":"1996","unstructured":"Devine DP, Reinscheid RK, Monsma FJ Jr, Civelli O, Akil H. The novel neuropeptide orphanin FQ fails to produce conditioned place preference or aversion. Brain Res. 1996;727(1\u20132):225\u20139. https:\/\/doi.org\/10.1016\/0006-8993(96)00476-3.","journal-title":"Brain Res"},{"key":"794_CR100","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1007\/164_2019_209.PMID:30968214;PMCID:PMC6641545","volume":"254","author":"R Ciccocioppo","year":"2019","unstructured":"Ciccocioppo R, Borruto AM, Domi A, Teshima K, Cannella N, Weiss F. NOP-related mechanisms in substance use disorders. Handb Exp Pharmacol. 2019;254:187\u2013212. https:\/\/doi.org\/10.1007\/164_2019_209.PMID:30968214;PMCID:PMC6641545.","journal-title":"Handb Exp Pharmacol"},{"key":"794_CR101","doi-asserted-by":"publisher","unstructured":"Witkin JM, Statnick MA, Rorick-Kehn LM, et al. The biology of nociceptin\/orphanin FQ (N\/OFQ) related to obesity, stress, anxiety, mood, and drug dependence. Pharmacol Ther. 2014;143(3):351. Corrected and republished from: Pharmacol Ther. 2014;141(3):283\u201399. https:\/\/doi.org\/10.1016\/j.pharmthera.2013.10.011.","DOI":"10.1016\/j.pharmthera.2013.10.011"},{"key":"794_CR102","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1016\/j.ejphar.2014.10.029","volume":"745","author":"DD Sukhtankar","year":"2014","unstructured":"Sukhtankar DD, Lagorio CH, Ko MC. Effects of the NOP agonist SCH221510 on producing and attenuating reinforcing effects as measured by drug self-administration in rats. Eur J Pharmacol. 2014;745:182\u20139. https:\/\/doi.org\/10.1016\/j.ejphar.2014.10.029.","journal-title":"Eur J Pharmacol"},{"issue":"1","key":"794_CR103","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1007\/s00213-010-2012-7","volume":"213","author":"CA Podlesnik","year":"2011","unstructured":"Podlesnik CA, Ko MC, Winger G, Wichmann J, Prinssen EP, Woods JH. The effects of nociceptin\/orphanin FQ receptor agonist Ro 64\u20136198 and diazepam on antinociception and remifentanil self-administration in rhesus monkeys. Psychopharmacology. 2011;213(1):53\u201360. https:\/\/doi.org\/10.1007\/s00213-010-2012-7.","journal-title":"Psychopharmacology"},{"issue":"7","key":"794_CR104","doi-asserted-by":"publisher","first-page":"1125","DOI":"10.1016\/s0196-9781(00)00250-3","volume":"21","author":"A Di Giannuario","year":"2000","unstructured":"Di Giannuario A, Pieretti S. Nociceptin differentially affects morphine-induced dopamine release from the nucleus accumbens and nucleus caudate in rats. Peptides. 2000;21(7):1125\u201330. https:\/\/doi.org\/10.1016\/s0196-9781(00)00250-3.","journal-title":"Peptides"},{"issue":"456","key":"794_CR105","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aar3483","volume":"10","author":"H Ding","year":"2018","unstructured":"Ding H, Kiguchi N, Yasuda D, et al. A bifunctional nociceptin and mu opioid receptor agonist is analgesic without opioid side effects in nonhuman primates. Sci Transl Med. 2018;10(456):eaar3483. https:\/\/doi.org\/10.1126\/scitranslmed.aar3483.","journal-title":"Sci Transl Med"},{"issue":"4","key":"794_CR106","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1111\/adb.12157","volume":"20","author":"G de Guglielmo","year":"2015","unstructured":"de Guglielmo G, Martin-Fardon R, Teshima K, Ciccocioppo R, Weiss F. MT\u20107716, a potent NOP receptor agonist, preferentially reduces ethanol seeking and reinforcement in post\u2010dependent rats. Addict Biol. 2015;20(4):643\u201351. https:\/\/doi.org\/10.1111\/adb.12157.","journal-title":"Addict Biol"},{"issue":"11","key":"794_CR107","doi-asserted-by":"publisher","first-page":"2601","DOI":"10.1038\/npp.2014.113","volume":"39","author":"R Ciccocioppo","year":"2014","unstructured":"Ciccocioppo R, Stopponi S, Economidou D, et al. Chronic treatment with novel brain-penetrating selective NOP receptor agonist MT-7716 reduces alcohol drinking and seeking in the rat. Neuropsychopharmacology. 2014;39(11):2601\u201310. https:\/\/doi.org\/10.1038\/npp.2014.113.","journal-title":"Neuropsychopharmacology"},{"issue":"2","key":"794_CR108","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1007\/s00213-003-1645-1","volume":"172","author":"R Ciccocioppo","year":"2004","unstructured":"Ciccocioppo R, Economidou D, Fedeli A, et al. Attenuation of ethanol self-administration and of conditioned reinstatement of alcohol-seeking behaviour by the antiopioid peptide nociceptin\/orphanin FQ in alcohol-preferring rats. Psychopharmacology. 2004;172(2):170\u20138. https:\/\/doi.org\/10.1007\/s00213-003-1645-1.","journal-title":"Psychopharmacology"},{"issue":"3","key":"794_CR109","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1038\/sj.bjp.0704279","volume":"134","author":"K Lutfy","year":"2001","unstructured":"Lutfy K, Hossain SM, Khaliq I, Maidment NT. Orphanin FQ\/nociceptin attenuates the development of morphine tolerance in rats. Br J Pharmacol. 2001;134(3):529\u201334. https:\/\/doi.org\/10.1038\/sj.bjp.0704279.","journal-title":"Br J Pharmacol"},{"issue":"4","key":"794_CR110","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1016\/j.peptides.2009.12.028","volume":"31","author":"GM Scoto","year":"2010","unstructured":"Scoto GM, Aric\u00f2 G, Iemolo A, Ronsisvalle G, Parenti C. Selective inhibition of the NOP receptor in the ventrolateral periaqueductal gray attenuates the development and the expression of tolerance to morphine-induced antinociception in rats. Peptides. 2010;31(4):696\u2013700. https:\/\/doi.org\/10.1016\/j.peptides.2009.12.028.","journal-title":"Peptides"},{"issue":"5","key":"794_CR111","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1016\/s0166-2236(97)01204-6","volume":"21","author":"T Darland","year":"1998","unstructured":"Darland T, Heinricher MM, Grandy DK. Orphanin FQ\/nociceptin: a role in pain and analgesia, but so much more. Trends Neurosci. 1998;21(5):215\u201321.\u00a0https:\/\/doi.org\/10.1016\/s0166-2236(97)01204-6","journal-title":"Trends Neurosci"},{"issue":"6","key":"794_CR112","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1016\/j.npep.2007.09.002","volume":"41","author":"MK Green","year":"2007","unstructured":"Green MK, Barbieri EV, Brown BD, Chen KW, Devine DP. Roles of the bed nucleus of stria terminalis and of the amygdala in N\/OFQ-mediated anxiety and HPA axis activation. Neuropeptides. 2007;41(6):399\u2013410. https:\/\/doi.org\/10.1016\/j.npep.2007.09.002.","journal-title":"Neuropeptides"},{"issue":"4","key":"794_CR113","doi-asserted-by":"publisher","first-page":"2051","DOI":"10.1016\/j.neuroscience.2006.05.036","volume":"141","author":"JD Leggett","year":"2006","unstructured":"Leggett JD, Harbuz MS, Jessop DS, Fulford AJ. The nociceptin receptor antagonist [Nphe1,Arg14,Lys15]nociceptin\/orphanin FQ-NH2 blocks the stimulatory effects of nociceptin\/orphanin FQ on the HPA axis in rats. Neuroscience. 2006;141(4):2051\u20137. https:\/\/doi.org\/10.1016\/j.neuroscience.2006.05.036.","journal-title":"Neuroscience"},{"issue":"2","key":"794_CR114","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1523\/JNEUROSCI.2400-13.2014","volume":"34","author":"R Ciccocioppo","year":"2014","unstructured":"Ciccocioppo R, de Guglielmo G, Hansson AC, et al. Restraint stress alters nociceptin\/orphanin FQ and CRF systems in the rat central amygdala: significance for anxiety-like behaviors. J Neurosci. 2014;34(2):363\u201372. https:\/\/doi.org\/10.1523\/JNEUROSCI.2400-13.2014.","journal-title":"J Neurosci"},{"issue":"5","key":"794_CR115","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1007\/s00210-006-0035-8","volume":"372","author":"EC Gavioli","year":"2006","unstructured":"Gavioli EC, Calo G. Antidepressant- and anxiolytic-like effects of nociceptin\/orphanin FQ receptor ligands. Naunyn Schmiedebergs Arch Pharmacol. 2006;372(5):319\u201330. https:\/\/doi.org\/10.1007\/s00210-006-0035-8.","journal-title":"Naunyn Schmiedebergs Arch Pharmacol"},{"key":"794_CR116","doi-asserted-by":"publisher","unstructured":"Varty GB, Lu SX, Morgan CA, et al. The anxiolytic-like effects of the novel, orally active nociceptin opioid receptor agonist 8-[bis(2-methylphenyl)methyl]-3-phenyl-8-azabicyclo[3.2.1]octan-3-ol (SCH 221510). J Pharmacol Exp Ther. 2008;326(2):672\u201382. https:\/\/doi.org\/10.1124\/jpet.108.136937.","DOI":"10.1124\/jpet.108.136937"},{"issue":"9","key":"794_CR117","doi-asserted-by":"publisher","first-page":"4938","DOI":"10.1073\/pnas.090514397","volume":"97","author":"F Jenck","year":"2000","unstructured":"Jenck F, Wichmann J, Dautzenberg FM, et al. A synthetic agonist at the orphanin FQ\/nociceptin receptor ORL1: anxiolytic profile in the rat. Proc Natl Acad Sci USA. 2000;97(9):4938\u201343. https:\/\/doi.org\/10.1073\/pnas.090514397.","journal-title":"Proc Natl Acad Sci USA"},{"issue":"2","key":"794_CR118","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1007\/s00213-012-2636-x","volume":"222","author":"C Goeldner","year":"2012","unstructured":"Goeldner C, Spooren W, Wichmann J, Prinssen EP. Further characterization of the prototypical nociceptin\/orphanin FQ peptide receptor agonist Ro 64\u20136198 in rodent models of conflict anxiety and despair. Psychopharmacology. 2012;222(2):203\u201314. https:\/\/doi.org\/10.1007\/s00213-012-2636-x.","journal-title":"Psychopharmacology"},{"issue":"4","key":"794_CR119","doi-asserted-by":"publisher","first-page":"747","DOI":"10.1111\/j.1530-0277.2010.01392.x","volume":"35","author":"D Economidou","year":"2011","unstructured":"Economidou D, Cippitelli A, Stopponi S, et al. Activation of brain NOP receptors attenuates acute and protracted alcohol withdrawal symptoms in the rat. Alcohol Clin Exp Res. 2011;35(4):747\u201355.\u00a0https:\/\/doi.org\/10.1111\/j.1530-0277.2010.01392.x.","journal-title":"Alcohol Clin Exp Res"},{"key":"794_CR120","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/j.brainres.2009.12.027","volume":"1314","author":"R Martin-Fardon","year":"2010","unstructured":"Martin-Fardon R, Zorrilla EP, Ciccocioppo R, Weiss F. Role of innate and drug-induced dysregulation of brain stress and arousal systems in addiction: focus on corticotropin-releasing factor, nociceptin\/orphanin FQ, and orexin\/hypocretin. Brain Res. 2010;1314:145\u201361. https:\/\/doi.org\/10.1016\/j.brainres.2009.12.027.","journal-title":"Brain Res"},{"issue":"2","key":"794_CR121","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1007\/s00213-002-1020-7","volume":"161","author":"R Ciccocioppo","year":"2002","unstructured":"Ciccocioppo R, Biondini M, Antonelli L, Wichmann J, Jenck F, Massi M. Reversal of stress- and CRF-induced anorexia in rats by the synthetic nociceptin\/orphanin FQ receptor agonist, Ro 64\u20136198. Psychopharmacology. 2002;161(2):113\u20139. https:\/\/doi.org\/10.1007\/s00213-002-1020-7.","journal-title":"Psychopharmacology"},{"issue":"28","key":"794_CR122","doi-asserted-by":"publisher","first-page":"9445","DOI":"10.1523\/JNEUROSCI.23-28-09445.2003","volume":"23","author":"R Ciccocioppo","year":"2003","unstructured":"Ciccocioppo R, Fedeli A, Economidou D, Policani F, Weiss F, Massi M. The bed nucleus is a neuroanatomical substrate for the anorectic effect of corticotropin-releasing factor and for its reversal by nociceptin\/orphanin FQ. J Neurosci. 2003;23(28):9445\u201351. https:\/\/doi.org\/10.1523\/JNEUROSCI.23-28-09445.2003.","journal-title":"J Neurosci"},{"issue":"4","key":"794_CR123","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1007\/s00213-007-0985-7","volume":"196","author":"D Rodi","year":"2008","unstructured":"Rodi D, Zucchini S, Simonato M, Cifani C, Massi M, Polidori C. Functional antagonism between nociceptin\/orphanin FQ (N\/OFQ) and corticotropin-releasing factor (CRF) in the rat brain: evidence for involvement of the bed nucleus of the stria terminalis. Psychopharmacology. 2008;196(4):523\u201331. https:\/\/doi.org\/10.1007\/s00213-007-0985-7.","journal-title":"Psychopharmacology"},{"key":"794_CR124","doi-asserted-by":"publisher","unstructured":"Cruz MT, Herman MA, Kallupi M, Roberto M. Nociceptin\/orphanin FQ blockade of corticotropin-releasing factor-induced gamma-aminobutyric acid release in central amygdala is enhanced after chronic ethanol exposure. Biol Psychiatry. 2012;71(8):666\u201376. https:\/\/doi.org\/10.1016\/j.biopsych.2011.10.032.","DOI":"10.1016\/j.biopsych.2011.10.032"},{"issue":"13","key":"794_CR125","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2214171120","volume":"120","author":"SR Morairty","year":"2023","unstructured":"Morairty SR, Sun Y, Toll L, Bruchas MR, Kilduff TS. Activation of the nociceptin\/orphanin-FQ receptor promotes NREM sleep and EEG slow wave activity. Proc Natl Acad Sci USA. 2023;120(13):e2214171120. https:\/\/doi.org\/10.1073\/pnas.2214171120.","journal-title":"Proc Natl Acad Sci USA"},{"issue":"1","key":"794_CR126","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1213\/01.ane.0000250403.88649.51","volume":"104","author":"AJ Byford","year":"2007","unstructured":"Byford AJ, Anderson A, Jones PS, Palin R, Houghton AK. The hypnotic, electroencephalographic, and antinociceptive properties of nonpeptide ORL1 receptor agonists after intravenous injection in rodents. Anesth Analg. 2007;104(1):174\u20139. https:\/\/doi.org\/10.1213\/01.ane.0000250403.88649.51.","journal-title":"Anesth Analg"},{"issue":"4","key":"794_CR127","doi-asserted-by":"publisher","first-page":"708","DOI":"10.1097\/ALN.0000000000001530","volume":"126","author":"K Linz","year":"2017","unstructured":"Linz K, Schr\u00f6der W, Frosch S, Christoph T. Opioid-type respiratory depressant side effects of cebranopadol in rats are limited by its nociceptin\/orphanin FQ peptide receptor agonist activity. Anesthesiology. 2017;126(4):708\u201315. https:\/\/doi.org\/10.1097\/ALN.0000000000001530.","journal-title":"Anesthesiology"},{"issue":"8","key":"794_CR128","doi-asserted-by":"publisher","first-page":"1031","DOI":"10.1111\/papr.12558","volume":"17","author":"TM Tzschentke","year":"2017","unstructured":"Tzschentke TM, Linz K, Frosch L, Christoph T. Antihyperalgesic, antiallodynic, and antinociceptive effects of cebranopadol, a novel potent nociception\/orphanin FQ and opioid receptor agonist, after peripheral and central administration in rodent models of neuropathic pain. Pain Pract. 2017;17(8):1031\u201341.\u00a0https:\/\/doi.org\/10.1111\/papr.12558.","journal-title":"Pain Pract"},{"issue":"5","key":"794_CR129","doi-asserted-by":"publisher","first-page":"1010","DOI":"10.1111\/adb.12550","volume":"23","author":"TM Tzschentke","year":"2018","unstructured":"Tzschentke TM, K\u00f6gel BY, Frosch S, Linz K. Limited potential of cebranopadol to produce opioid-type physical dependence in rodents. Addict Biol. 2018;23(5):1010\u20139.\u00a0https:\/\/doi.org\/10.1111\/adb.12550.","journal-title":"Addict Biol"},{"issue":"3","key":"794_CR130","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1097\/ALN.0000000000003848","volume":"135","author":"H Ding","year":"2021","unstructured":"Ding H, Trapella C, Kiguchi N, Hsu FC, Cal\u00f3 G, Ko MC. Functional profile of systemic and intrathecal cebranopadol in nonhuman primates. Anesthesiology. 2021;135(3):482\u201393. https:\/\/doi.org\/10.1097\/ALN.0000000000003848.","journal-title":"Anesthesiology"},{"key":"794_CR131","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2024.110048","volume":"257","author":"N Cannella","year":"2024","unstructured":"Cannella N, Lunerti V, Shen Q, et al. Cebranopadol, a novel long-acting opioid agonist with low abuse liability, to treat opioid use disorder: preclinical evidence of efficacy. Neuropharmacology. 2024;257:110048. https:\/\/doi.org\/10.1016\/j.neuropharm.2024.110048.","journal-title":"Neuropharmacology"},{"issue":"37","key":"794_CR132","doi-asserted-by":"publisher","first-page":"E5511","DOI":"10.1073\/pnas.1605295113","volume":"113","author":"H Ding","year":"2016","unstructured":"Ding H, Czoty PW, Kiguchi N, et al. A novel orvinol analog, BU08028, as a safe opioid analgesic without abuse liability in primates. Proc Natl Acad Sci USA. 2016;113(37):E5511\u20138. https:\/\/doi.org\/10.1073\/pnas.1605295113.","journal-title":"Proc Natl Acad Sci USA"},{"key":"794_CR133","doi-asserted-by":"publisher","first-page":"e146","DOI":"10.1016\/j.bja.2018.10.065","volume":"122","author":"N Kiguchi","year":"2019","unstructured":"Kiguchi N, Ding H, Cami-Kobeci G, Sukhtankar DD, Czoty PW, DeLoid HB, et al. BU10038 as a safe opioid analgesic with fewer side-effects after systemic and intrathecal administration in primates. Br J Anaesth. 2019;122:e146\u201356.\u00a0https:\/\/doi.org\/10.1016\/j.bja.2018.10.065","journal-title":"Br J Anaesth"},{"issue":"6","key":"794_CR134","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1097\/FBP.0000000000000684","volume":"33","author":"LR Gerak","year":"2022","unstructured":"Gerak LR, Maguire DR, Cami-Kobeci G, et al. Orex-1038: a potential new treatment for pain with low abuse liability and limited adverse effects. Behav Pharmacol. 2022;33(6):377\u201394. https:\/\/doi.org\/10.1097\/FBP.0000000000000684.","journal-title":"Behav Pharmacol"},{"key":"794_CR135","doi-asserted-by":"publisher","DOI":"10.1111\/bph.70151","author":"A Cippitelli","year":"2025","unstructured":"Cippitelli A, Zhang Y, Kealoha K, et al. The opioid partial agonist PPL-138 reduces alcohol self-administration in rats susceptible to post-traumatic stress disorder. Br J Pharmacol. 2025. https:\/\/doi.org\/10.1111\/bph.70151.","journal-title":"Br J Pharmacol"},{"key":"794_CR136","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2019.107678","volume":"166","author":"PK Chao","year":"2020","unstructured":"Chao PK, Chang HF, Chang WT, et al. BPR1M97, a dual mu opioid receptor\/nociceptin-orphanin FQ peptide receptor agonist, produces potent antinociceptive effects with safer properties than morphine. Neuropharmacology. 2020;166:107678. https:\/\/doi.org\/10.1016\/j.neuropharm.2019.107678.","journal-title":"Neuropharmacology"},{"issue":"3","key":"794_CR137","doi-asserted-by":"publisher","first-page":"954","DOI":"10.1124\/jpet.109.157446","volume":"331","author":"L Toll","year":"2009","unstructured":"Toll L, Khroyan TV, Polgar WE, Jiang F, Olsen C, Zaveri NT. Comparison of the antinociceptive and antirewarding profiles of novel bifunctional nociceptin receptor\/mu-opioid receptor ligands: implications for therapeutic applications. J Pharmacol Exp Ther. 2009;331(3):954\u201364. https:\/\/doi.org\/10.1124\/jpet.109.157446.","journal-title":"J Pharmacol Exp Ther"},{"key":"794_CR138","doi-asserted-by":"publisher","unstructured":"Khroyan TV, Zaveri NT, Polgar WE, et al. SR 16435 [1-(1-(bicyclo[3.3.1]nonan-9-yl)piperidin-4-yl)indolin-2-one], a novel mixed nociceptin\/orphanin FQ\/mu-opioid receptor partial agonist: analgesic and rewarding properties in mice. J Pharmacol Exp Ther. 2007;320(2):934\u201343. https:\/\/doi.org\/10.1124\/jpet.106.111997.","DOI":"10.1124\/jpet.106.111997"},{"key":"794_CR139","unstructured":"Kumar R, Viswanath O, Saadabadi A. Buprenorphine. [Updated 2024 Jun 8]. StatPearls [Internet]. Treasure Island: StatPearls Publishing; 2025. https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK459126\/."},{"issue":"7","key":"794_CR140","doi-asserted-by":"publisher","first-page":"1141","DOI":"10.1016\/s0196-9781(00)00252-7","volume":"21","author":"P Bloms-Funke","year":"2000","unstructured":"Bloms-Funke P, Gillen C, Schuettler AJ, Wnendt S. Agonistic effects of the opioid buprenorphine on the nociceptin\/OFQ receptor. Peptides. 2000;21(7):1141\u20136. https:\/\/doi.org\/10.1016\/s0196-9781(00)00252-7.","journal-title":"Peptides"},{"issue":"5","key":"794_CR141","doi-asserted-by":"publisher","first-page":"831","DOI":"10.1111\/j.1476-5381.2009.00209.x","volume":"157","author":"Z Ding","year":"2009","unstructured":"Ding Z, Raffa RB. Identification of an additional supraspinal component to the analgesic mechanism of action of buprenorphine. Br J Pharmacol. 2009;157(5):831\u201343. https:\/\/doi.org\/10.1111\/j.1476-5381.2009.00209.x.","journal-title":"Br J Pharmacol"},{"issue":"32","key":"794_CR142","doi-asserted-by":"publisher","first-page":"10331","DOI":"10.1523\/JNEUROSCI.23-32-10331.2003","volume":"23","author":"K Lutfy","year":"2003","unstructured":"Lutfy K, Eitan S, Bryant CD, et al. Buprenorphine-induced antinociception is mediated by mu-opioid receptors and compromised by concomitant activation of opioid receptor-like receptors. J Neurosci. 2003;23(32):10331\u20137. https:\/\/doi.org\/10.1523\/JNEUROSCI.23-32-10331.2003.","journal-title":"J Neurosci"},{"issue":"3","key":"794_CR143","doi-asserted-by":"publisher","first-page":"946","DOI":"10.1124\/jpet.109.156711","volume":"331","author":"TV Khroyan","year":"2009","unstructured":"Khroyan TV, Polgar WE, Jiang F, Zaveri NT, Toll L. Nociceptin\/orphanin FQ receptor activation attenuates antinociception induced by mixed nociceptin\/orphanin FQ\/mu-opioid receptor agonists. J Pharmacol Exp Ther. 2009;331(3):946\u201353. https:\/\/doi.org\/10.1124\/jpet.109.156711.","journal-title":"J Pharmacol Exp Ther"},{"issue":"19","key":"794_CR144","doi-asserted-by":"publisher","first-page":"6531","DOI":"10.1021\/jm2003238","volume":"54","author":"G Cami-Kobeci","year":"2011","unstructured":"Cami-Kobeci G, Polgar WE, Khroyan TV, Toll L, Husbands SM. Structural determinants of opioid and NOP receptor activity in derivatives of buprenorphine. J Med Chem. 2011;54(19):6531\u20137. https:\/\/doi.org\/10.1021\/jm2003238.","journal-title":"J Med Chem"},{"issue":"1","key":"794_CR145","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1124\/jpet.112.194308","volume":"343","author":"CM Cremeans","year":"2012","unstructured":"Cremeans CM, Gruley E, Kyle DJ, Ko MC. Roles of \u03bc-opioid receptors and nociceptin\/orphanin FQ peptide receptors in buprenorphine-induced physiological responses in primates. J Pharmacol Exp Ther. 2012;343(1):72\u201381. https:\/\/doi.org\/10.1124\/jpet.112.194308.","journal-title":"J Pharmacol Exp Ther"},{"key":"794_CR146","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1016\/j.ejphar.2018.05.005","volume":"832","author":"K Schiene","year":"2018","unstructured":"Schiene K, Schr\u00f6der W, Linz K, et al. Nociceptin\/orphanin FQ opioid peptide (NOP) receptor and \u00b5-opioid peptide (MOP) receptors both contribute to the anti-hypersensitive effect of cebranopadol in a rat model of arthritic pain. Eur J Pharmacol. 2018;832:90\u20135. https:\/\/doi.org\/10.1016\/j.ejphar.2018.05.005.","journal-title":"Eur J Pharmacol"},{"key":"794_CR147","doi-asserted-by":"publisher","first-page":"234","DOI":"10.3389\/fpsyt.2017.00234","volume":"8","author":"Q Shen","year":"2017","unstructured":"Shen Q, Deng Y, Ciccocioppo R, Cannella N. Cebranopadol, a mixed opioid agonist, reduces cocaine self-administration through nociceptin opioid and mu opioid receptors. Front Psychiatry. 2017;8:234. https:\/\/doi.org\/10.3389\/fpsyt.2017.00234.","journal-title":"Front Psychiatry"},{"issue":"3","key":"794_CR148","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1124\/jpet.117.241042","volume":"362","author":"G de Guglielmo","year":"2017","unstructured":"de Guglielmo G, Matzeu A, Kononoff J, Mattioni J, Martin-Fardon R, George O. Cebranopadol blocks the escalation of cocaine intake and conditioned reinstatement of cocaine seeking in rats. J Pharmacol Exp Ther. 2017;362(3):378\u201384. https:\/\/doi.org\/10.1124\/jpet.117.241042.","journal-title":"J Pharmacol Exp Ther"},{"key":"794_CR149","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1016\/j.neuropharm.2017.11.026","volume":"129","author":"TM Tzschentke","year":"2018","unstructured":"Tzschentke TM, Rutten K. Mu-opioid peptide (MOP) and nociceptin\/orphanin FQ peptide (NOP) receptor activation both contribute to the discriminative stimulus properties of cebranopadol in the rat. Neuropharmacology. 2018;129:100\u20138. https:\/\/doi.org\/10.1016\/j.neuropharm.2017.11.026.","journal-title":"Neuropharmacology"},{"key":"794_CR150","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/j.peptides.2018.12.001","volume":"112","author":"C Ruzza","year":"2019","unstructured":"Ruzza C, Holanda VA, Gavioli EC, Trapella C, Calo G. NOP agonist action of cebranopadol counteracts its liability to promote physical dependence. Peptides. 2019;112:101\u20135. https:\/\/doi.org\/10.1016\/j.peptides.2018.12.001.","journal-title":"Peptides"},{"issue":"4","key":"794_CR151","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1097\/01.j.pain.0000460357.01998.f1","volume":"156","author":"KE Vowles","year":"2015","unstructured":"Vowles KE, McEntee ML, Julnes PS, Frohe T, Ney JP, van der Goes DN. Rates of opioid misuse, abuse, and addiction in chronic pain: a systematic review and data synthesis. Pain. 2015;156(4):569\u201376. https:\/\/doi.org\/10.1097\/01.j.pain.0000460357.01998.f1.","journal-title":"Pain"},{"issue":"Suppl.","key":"794_CR152","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.29.1_supplement.616.2","volume":"29","author":"H Ding","year":"2015","unstructured":"Ding H, Czoty P, Cami-Kobeci G, et al. BU08028 displays a promising therapeutic profile as an analgesic in monkeys. FASEB J. 2015;29(Suppl.):616.2. https:\/\/doi.org\/10.1096\/fasebj.29.1_supplement.616.2.","journal-title":"FASEB J"},{"key":"794_CR153","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/j.ejphar.2016.11.026","volume":"794","author":"MC Cerlesi","year":"2017","unstructured":"Cerlesi MC, Ding H, Bird MF, et al. Pharmacological studies on the NOP and opioid receptor agonist PWT2-[Dmt1]N\/OFQ(1\u201313). Eur J Pharmacol. 2017;794:115\u201326. https:\/\/doi.org\/10.1016\/j.ejphar.2016.11.026.","journal-title":"Eur J Pharmacol"},{"issue":"13","key":"794_CR154","doi-asserted-by":"publisher","first-page":"3302","DOI":"10.1111\/bph.13124","volume":"172","author":"H Ding","year":"2015","unstructured":"Ding H, Hayashida K, Suto T, et al. Supraspinal actions of nociceptin\/orphanin FQ, morphine and substance P in regulating pain and itch in non-human primates. Br J Pharmacol. 2015;172(13):3302\u201312. https:\/\/doi.org\/10.1111\/bph.13124.","journal-title":"Br J Pharmacol"},{"key":"794_CR155","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/j.ejphar.2015.02.020","volume":"754","author":"L Micheli","year":"2015","unstructured":"Micheli L, Di Cesare Mannelli L, Guerrini R, et al. Acute and subchronic antinociceptive effects of nociceptin\/orphanin FQ receptor agonists infused by intrathecal route in rats. Eur J Pharmacol. 2015;754:73\u201381. https:\/\/doi.org\/10.1016\/j.ejphar.2015.02.020.","journal-title":"Eur J Pharmacol"},{"key":"794_CR156","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2024.109866","volume":"248","author":"M Petrella","year":"2024","unstructured":"Petrella M, Borruto AM, Curti L, et al. Pharmacological blockage of NOP receptors decreases ventral tegmental area dopamine neuronal activity through GABAB receptor-mediated mechanism. Neuropharmacology. 2024;248:109866. https:\/\/doi.org\/10.1016\/j.neuropharm.2024.109866.","journal-title":"Neuropharmacology"},{"issue":"5","key":"794_CR157","doi-asserted-by":"publisher","DOI":"10.1523\/ENEURO.0376-19.2020","volume":"7","author":"JR Driscoll","year":"2020","unstructured":"Driscoll JR, Wallace TL, Mansourian KA, Martin WJ, Margolis EB. Differential modulation of ventral tegmental area circuits by the nociceptin\/orphanin FQ system. eNeuro. 2020;7(5):ENEURO.0376-19.2020. https:\/\/doi.org\/10.1523\/ENEURO.0376-19.2020.","journal-title":"eNeuro"},{"issue":"7","key":"794_CR158","doi-asserted-by":"publisher","first-page":"1065","DOI":"10.1038\/sj.bjp.0704806","volume":"136","author":"F Zheng","year":"2002","unstructured":"Zheng F, Grandy DK, Johnson SW. Actions of orphanin FQ\/nociceptin on rat ventral tegmental area neurons in vitro. Br J Pharmacol. 2002;136(7):1065\u201371. https:\/\/doi.org\/10.1038\/sj.bjp.0704806.","journal-title":"Br J Pharmacol"},{"key":"794_CR159","doi-asserted-by":"publisher","unstructured":"Kotli\u0144ska J, Suder P, Legowska A, Rolka K, Silberring J. Orphanin FQ\/nociceptin inhibits morphine withdrawal.\u00a0Life Sci. 2000;66(8):PL119\u201323. https:\/\/doi.org\/10.1016\/s0024-3205(99)00648-7.","DOI":"10.1016\/s0024-3205(99)00648-7"},{"issue":"4","key":"794_CR160","doi-asserted-by":"publisher","first-page":"2140","DOI":"10.1073\/pnas.1915143117","volume":"117","author":"M Kallupi","year":"2020","unstructured":"Kallupi M, Carrette LLG, Kononoff J, et al. Nociceptin attenuates the escalation of oxycodone self-administration by normalizing CeA-GABA transmission in highly addicted rats. Proc Natl Acad Sci USA. 2020;117(4):2140\u20138. https:\/\/doi.org\/10.1073\/pnas.1915143117.","journal-title":"Proc Natl Acad Sci USA"},{"issue":"1","key":"794_CR161","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1097\/JCP.0000000000000995","volume":"39","author":"K G\u00f6hler","year":"2019","unstructured":"G\u00f6hler K, Sokolowska M, Schoedel KA, et al. Assessment of the abuse potential of cebranopadol in nondependent recreational opioid users: a phase 1 randomized controlled study. J Clin Psychopharmacol. 2019;39(1):46\u201356. https:\/\/doi.org\/10.1097\/JCP.0000000000000995.","journal-title":"J Clin Psychopharmacol"},{"issue":"4","key":"794_CR162","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1097\/ALN.0000000000001529","volume":"126","author":"A Dahan","year":"2017","unstructured":"Dahan A, Boom M, Sarton E, et al. Respiratory effects of the nociceptin\/orphanin FQ peptide and opioid receptor agonist, cebranopadol, in healthy human volunteers. Anesthesiology. 2017;126(4):697\u2013707. https:\/\/doi.org\/10.1097\/ALN.0000000000001529.","journal-title":"Anesthesiology"},{"issue":"3","key":"794_CR163","doi-asserted-by":"publisher","first-page":"390","DOI":"10.1016\/j.jpainsymman.2019.05.012","volume":"58","author":"ED Koch","year":"2019","unstructured":"Koch ED, Kapanadze S, Eerdekens MH, et al. Cebranopadol, a novel first-in-class analgesic drug candidate: first experience with cancer-related pain for up to 26 weeks. J Pain Symptom Manag. 2019;58(3):390\u20139. https:\/\/doi.org\/10.1016\/j.jpainsymman.2019.05.012.","journal-title":"J Pain Symptom Manag"},{"issue":"3","key":"794_CR164","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1002\/ejp.1331","volume":"23","author":"MH Eerdekens","year":"2019","unstructured":"Eerdekens MH, Kapanadze S, Koch ED, et al. Cancer-related chronic pain: investigation of the novel analgesic drug candidate cebranopadol in a randomized, double-blind, noninferiority trial. Eur J Pain. 2019;23(3):577\u201388. https:\/\/doi.org\/10.1002\/ejp.1331.","journal-title":"Eur J Pain"},{"issue":"3","key":"794_CR165","doi-asserted-by":"publisher","first-page":"E193","DOI":"10.36076\/ppj.2018.3.E193","volume":"21","author":"A Scholz","year":"2018","unstructured":"Scholz A, Bothmer J, Kok M, Hoschen K, Daniels S. Cebranopadol: a novel, first-in-class, strong analgesic: results from a randomized phase IIa clinical trial in postoperative acute pain. Pain Physician. 2018;21(3):E193-206.","journal-title":"Pain Physician"},{"issue":"9","key":"794_CR166","doi-asserted-by":"publisher","first-page":"1813","DOI":"10.1097\/j.pain.0000000000000986","volume":"158","author":"A Christoph","year":"2017","unstructured":"Christoph A, Eerdekens MH, Kok M, Volkers G, Freynhagen R. Cebranopadol, a novel first-in-class analgesic drug candidate: first experience in patients with chronic low back pain in a randomized clinical trial. Pain. 2017;158(9):1813\u201324. https:\/\/doi.org\/10.1097\/j.pain.0000000000000986.","journal-title":"Pain"},{"key":"794_CR167","unstructured":"Eerdekens M, Koch ED, Kok M, Sohns M, Forst T. Cebranopadol, a novel first in class analgesic: efficacy safety and tolerability in patients with pain due to diabetic peripheral neuropathy (DPN). In: Presented at the World Institute of Pain; 2016."}],"container-title":["Pain and Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s40122-025-00794-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s40122-025-00794-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s40122-025-00794-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T15:24:55Z","timestamp":1768404295000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s40122-025-00794-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,5]]},"references-count":167,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,2]]}},"alternative-id":["794"],"URL":"https:\/\/doi.org\/10.1007\/s40122-025-00794-8","relation":{},"ISSN":["2193-8237","2193-651X"],"issn-type":[{"value":"2193-8237","type":"print"},{"value":"2193-651X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,5]]},"assertion":[{"value":"8 August 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 October 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 December 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Charles E. Argoff received royalties or licenses from Cambridge University Press and Elsevier; received consulting fees from Collegium, Gene Pharma, Ironwood, Lundbeck, Nevro, Rapport, Scilex, Tris Pharma, and Vertex; received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, Amgen, Averitas, Biohaven, Impel, and Lundbeck; received payment for expert testimony for Imperatore vs HSS; and participated on a Data Safety Monitoring Board or Advisory Board for Nevro and ShiraTronics. Roberto Ciccocioppo received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Tris Pharma. He also received honoraria as a consultant from Omeros Corp. and from Zambon Biotech. David Fam is an employee of Tris Pharma. Jeffrey Gudin received an in-kind grant from the National Institutes of Health National Center for Advancing Translational Sciences; received consulting fees from Acertis, Collegium, Hisamitsu America, Sanofi, and Tris Pharma; payment for expert testimony on various personal injury cases; participated on a Data Safety Monitoring Board or Advisory Board for Haisco; and received stock or stock options from Virpax Pharma. James Hackworth is an employee of Tris Pharma. Emanuela Offidani is an employee of Tris Pharma. Jim Potenziano is an employee of Tris Pharma.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}]}}