{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T03:55:05Z","timestamp":1774583705897,"version":"3.50.1"},"reference-count":47,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2020,2,27]],"date-time":"2020-02-27T00:00:00Z","timestamp":1582761600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"},{"start":{"date-parts":[[2020,2,27]],"date-time":"2020-02-27T00:00:00Z","timestamp":1582761600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"}],"funder":[{"name":"Nektar Therapeutics"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Mol Neurobiol"],"published-print":{"date-parts":[[2021,7]]},"DOI":"10.1007\/s10571-020-00816-3","type":"journal-article","created":{"date-parts":[[2020,2,27]],"date-time":"2020-02-27T20:02:41Z","timestamp":1582833761000},"page":"949-960","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Preclinical Assessment of the Analgesic Pharmacology of NKTR-181 in Rodents"],"prefix":"10.1007","volume":"41","author":[{"given":"Caroline M.","family":"Kopruszinski","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juliana","family":"Swiokla","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yeon Sun","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edita","family":"Navratilova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laurie","family":"VanderVeen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miao","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takahiro","family":"Miyazaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William K.","family":"Schmidt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan","family":"Zalevsky","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2267-0617","authenticated-orcid":false,"given":"Frank","family":"Porreca","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,2,27]]},"reference":[{"key":"816_CR1","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1007\/s002130000624","volume":"154","author":"ME Abreu","year":"2001","unstructured":"Abreu ME, Bigelow GE, Fleisher L, Walsh SL (2001) Effect of intravenous injection speed on responses to cocaine and hydromorphone in humans. Psychopharmacology 154:76\u201384","journal-title":"Psychopharmacology"},{"key":"816_CR2","doi-asserted-by":"publisher","first-page":"188","DOI":"10.4103\/0976-500X.162015","volume":"6","author":"T Anantharamu","year":"2015","unstructured":"Anantharamu T, Sharma S, Gupta AK, Dahiya N, Singh Brashier DB, Sharma AK (2015) Naloxegol: First oral peripherally acting mu opioid receptor antagonists for opioid-induced constipation. J Pharmacol Pharmacother 6:188\u2013192","journal-title":"J Pharmacol Pharmacother"},{"key":"816_CR3","doi-asserted-by":"publisher","first-page":"570","DOI":"10.1097\/00000542-200603000-00025","volume":"104","author":"MS Angst","year":"2006","unstructured":"Angst MS, Clark JD (2006) Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology 104:570\u2013587","journal-title":"Anesthesiology"},{"key":"816_CR4","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1056\/NEJMra1802148","volume":"380","author":"ASB Bohnert","year":"2019","unstructured":"Bohnert ASB, Ilgen MA (2019) Understanding Links among opioid use, overdose, and suicide. N Engl J Med 380:71\u201379","journal-title":"N Engl J Med"},{"key":"816_CR5","doi-asserted-by":"publisher","first-page":"j5790","DOI":"10.1136\/bmj.j5790","volume":"360","author":"GA Brat","year":"2018","unstructured":"Brat GA, Agniel D, Beam A et al (2018) Postsurgical prescriptions for opioid naive patients and association with overdose and misuse: retrospective cohort study. BMJ 360:j5790","journal-title":"BMJ"},{"key":"816_CR6","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1016\/j.pbb.2006.11.012","volume":"85","author":"CD Bryant","year":"2006","unstructured":"Bryant CD, Roberts KW, Byun JS, Fanselow MS, Evans CJ (2006) Morphine analgesic tolerance in 129P3\/J and 129S6\/SvEv mice. Pharmacol Biochem Behav 85:769\u2013779","journal-title":"Pharmacol Biochem Behav"},{"key":"816_CR7","doi-asserted-by":"publisher","first-page":"1016","DOI":"10.1016\/j.tips.2017.08.004","volume":"38","author":"HCS Chan","year":"2017","unstructured":"Chan HCS, McCarthy D, Li J, Palczewski K, Yuan S (2017) Designing safer analgesics via mu-opioid receptor pathways. Trends Pharmacol Sci 38:1016\u20131037","journal-title":"Trends Pharmacol Sci"},{"key":"816_CR8","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/0165-0270(94)90144-9","volume":"53","author":"SR Chaplan","year":"1994","unstructured":"Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL (1994) Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 53:55\u201363","journal-title":"J Neurosci Methods"},{"key":"816_CR9","doi-asserted-by":"publisher","first-page":"203","DOI":"10.5055\/jom.2009.0022","volume":"5","author":"SD Comer","year":"2009","unstructured":"Comer SD, Ashworth JB, Sullivan MA, Vosburg SK, Saccone PA, Foltin RW (2009) Relationship between rate of infusion and reinforcing strength of oxycodone in humans. J Opioid Manag 5:203\u2013212","journal-title":"J Opioid Manag"},{"key":"816_CR10","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1056\/NEJMra1508490","volume":"374","author":"WM Compton","year":"2016","unstructured":"Compton WM, Jones CM, Baldwin GT (2016) Relationship between nonmedical prescription-opioid use and heroin use. N Engl J Med 374:154\u2013163","journal-title":"N Engl J Med"},{"key":"816_CR11","doi-asserted-by":"publisher","first-page":"1638","DOI":"10.1021\/acschemneuro.7b00195","volume":"8","author":"G Del Vecchio","year":"2017","unstructured":"Del Vecchio G, Spahn V, Stein C (2017) Novel Opioid analgesics and side effects. ACS Chem Neurosci 8:1638\u20131640","journal-title":"ACS Chem Neurosci"},{"key":"816_CR12","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1111\/j.1365-2125.2012.04317.x","volume":"75","author":"AM Drewes","year":"2013","unstructured":"Drewes AM, Jensen RD, Nielsen LM et al (2013) Differences between opioids: pharmacological, experimental, clinical and economical perspectives. Br J Clin Pharmacol 75:60\u201378","journal-title":"Br J Clin Pharmacol"},{"key":"816_CR13","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1208\/s12248-008-9056-1","volume":"10","author":"EO Dumas","year":"2008","unstructured":"Dumas EO, Pollack GM (2008) Opioid tolerance development: a pharmacokinetic\/pharmacodynamic perspective. AAPS J 10:537\u2013551","journal-title":"AAPS J"},{"key":"816_CR14","doi-asserted-by":"publisher","first-page":"1601","DOI":"10.1111\/j.1360-0443.1991.tb01754.x","volume":"86","author":"M Farre","year":"1991","unstructured":"Farre M, Cami J (1991) Pharmacokinetic considerations in abuse liability evaluation. Br J Addict 86:1601\u20131606","journal-title":"Br J Addict"},{"key":"816_CR15","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1016\/j.tins.2015.01.002","volume":"38","author":"HL Fields","year":"2015","unstructured":"Fields HL, Margolis EB (2015) Understanding opioid reward. Trends Neurosci 38:217\u2013225","journal-title":"Trends Neurosci"},{"key":"816_CR16","doi-asserted-by":"publisher","first-page":"1026","DOI":"10.1126\/science.aan0088","volume":"355","author":"T Grosser","year":"2017","unstructured":"Grosser T, Woolf CJ, FitzGerald GA (2017) Time for nonaddictive relief of pain. Science 355:1026\u20131027","journal-title":"Science"},{"key":"816_CR17","doi-asserted-by":"publisher","DOI":"10.1093\/pm\/pnz169","author":"J Gudin","year":"2019","unstructured":"Gudin J, Rauck R, Argoff C et al (2019) Long-term safety and tolerability of NKTR-181 in patients with moderate to severe chronic low back pain or chronic noncancer pain: a phase 3 multicenter, open-label, 52-week study (SUMMIT-08 LTS). Pain Med. https:\/\/doi.org\/10.1093\/pm\/pnz169","journal-title":"Pain Med"},{"key":"816_CR18","doi-asserted-by":"publisher","first-page":"546","DOI":"10.1093\/cid\/ciy977","volume":"69","author":"R Heimer","year":"2018","unstructured":"Heimer R, Hawk K, Vermund SH (2018) Prevalent misconceptions about opioid use disorders in the United States produce failed policy and public health responses. Clin Infect Dis 69:546\u2013551","journal-title":"Clin Infect Dis"},{"key":"816_CR19","doi-asserted-by":"publisher","first-page":"1145","DOI":"10.1097\/j.pain.0000000000000170","volume":"156","author":"WM Hooten","year":"2015","unstructured":"Hooten WM, Lamer TJ, Twyner C (2015) Opioid-induced hyperalgesia in community-dwelling adults with chronic pain. Pain 156:1145\u20131152","journal-title":"Pain"},{"key":"816_CR20","first-page":"355","volume":"260","author":"PD Kanof","year":"1992","unstructured":"Kanof PD, Handelsman L, Aronson MJ, Ness R, Cochrane KJ, Rubinstein KJ (1992) Clinical characteristics of naloxone-precipitated withdrawal in human opioid-dependent subjects. J Pharmacol Exp Ther 260:355\u2013363","journal-title":"J Pharmacol Exp Ther"},{"key":"816_CR21","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1016\/S0306-4522(02)00458-X","volume":"115","author":"B Kest","year":"2002","unstructured":"Kest B, Palmese CA, Hopkins E, Adler M, Juni A, Mogil JS (2002) Naloxone-precipitated withdrawal jumping in 11 inbred mouse strains: evidence for common genetic mechanisms in acute and chronic morphine physical dependence. Neuroscience 115:463\u2013469","journal-title":"Neuroscience"},{"key":"816_CR22","doi-asserted-by":"publisher","first-page":"754","DOI":"10.1037\/0735-7044.111.4.754","volume":"111","author":"TE King","year":"1997","unstructured":"King TE, Joynes RL, Grau JW (1997) Tail-flick test: II. The role of supraspinal systems and avoidance learning. Behav Neurosci 111:754\u2013767","journal-title":"Behav Neurosci"},{"key":"816_CR23","doi-asserted-by":"publisher","first-page":"121","DOI":"10.3389\/fphar.2012.00121","volume":"3","author":"SM Kousik","year":"2012","unstructured":"Kousik SM, Napier TC, Carvey PM (2012) The effects of psychostimulant drugs on blood brain barrier function and neuroinflammation. Front Pharmacol 3:121","journal-title":"Front Pharmacol"},{"key":"816_CR24","doi-asserted-by":"publisher","first-page":"736","DOI":"10.1177\/1756283X16648869","volume":"9","author":"W Leppert","year":"2016","unstructured":"Leppert W, Woron J (2016) The role of naloxegol in the management of opioid-induced bowel dysfunction. Ther Adv Gastroenterol 9:736\u2013746","journal-title":"Ther Adv Gastroenterol"},{"key":"816_CR25","doi-asserted-by":"publisher","first-page":"1374","DOI":"10.1097\/j.pain.0000000000001517","volume":"160","author":"J Markman","year":"2019","unstructured":"Markman J, Gudin J, Rauck R et al (2019) Summit-07: A randomized trial of NKTR-181, a new molecular entity, full mu-opioid receptor agonist for chronic low-back pain. Pain 160:1374\u20131382","journal-title":"Pain"},{"key":"816_CR26","first-page":"1056","volume":"299","author":"LA Marsch","year":"2001","unstructured":"Marsch LA, Bickel WK, Badger GJ et al (2001) Effects of infusion rate of intravenously administered morphine on physiological, psychomotor, and self-reported measures in humans. J Pharmacol Exp Ther 299:1056\u20131065","journal-title":"J Pharmacol Exp Ther"},{"key":"816_CR27","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1124\/jpet.117.243030","volume":"363","author":"T Miyazaki","year":"2017","unstructured":"Miyazaki T, Choi IY, Rubas W et al (2017) NKTR-181: a novel mu-opioid analgesic with inherently low abuse potential. J Pharmacol Exp Ther 363:104\u2013113","journal-title":"J Pharmacol Exp Ther"},{"key":"816_CR28","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1016\/0014-2999(94)90543-6","volume":"263","author":"C Nath","year":"1994","unstructured":"Nath C, Gupta MB, Patnaik GK, Dhawan KN (1994) Morphine-induced straub tail response: mediated by central mu2-opioid receptor. Eur J Pharmacol 263:203\u2013205","journal-title":"Eur J Pharmacol"},{"key":"816_CR29","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1016\/j.pain.2004.01.035","volume":"109","author":"KV Nemmani","year":"2004","unstructured":"Nemmani KV, Grisel JE, Stowe JR, Smith-Carliss R, Mogil JS (2004) Modulation of morphine analgesia by site-specific N-methyl-D-aspartate receptor antagonists: dependence on sex, site of antagonism, morphine dose, and time. Pain 109:274\u2013283","journal-title":"Pain"},{"key":"816_CR30","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1002\/neu.20091","volume":"61","author":"MH Ossipov","year":"2004","unstructured":"Ossipov MH, Lai J, King T et al (2004) Antinociceptive and nociceptive actions of opioids. J Neurobiol 61:126\u2013148","journal-title":"J Neurobiol"},{"key":"816_CR31","doi-asserted-by":"publisher","first-page":"3779","DOI":"10.1172\/JCI43766","volume":"120","author":"MH Ossipov","year":"2010","unstructured":"Ossipov MH, Dussor GO, Porreca F (2010) Central modulation of pain. J Clin Invest 120:3779\u20133787","journal-title":"J Clin Invest"},{"key":"816_CR32","doi-asserted-by":"publisher","first-page":"654","DOI":"10.1111\/j.1526-4637.2009.00583.x","volume":"10","author":"F Porreca","year":"2009","unstructured":"Porreca F, Ossipov MH (2009) Nausea and vomiting side effects with opioid analgesics during treatment of chronic pain: mechanisms, implications, and management options. Pain Med 10:654\u2013662","journal-title":"Pain Med"},{"key":"816_CR33","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1016\/j.neuroscience.2016.06.029","volume":"338","author":"LA Roeckel","year":"2016","unstructured":"Roeckel LA, Le Coz GM, Gaveriaux-Ruff C, Simonin F (2016) Opioid-induced hyperalgesia: cellular and molecular mechanisms. Neuroscience 338:160\u2013182","journal-title":"Neuroscience"},{"key":"816_CR34","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1097\/j.pain.0000000000001420","volume":"160","author":"SF Rosen","year":"2019","unstructured":"Rosen SF, Ham B, Haichin M et al (2019) Increased pain sensitivity and decreased opioid analgesia in T-cell-deficient mice and implications for sex differences. Pain 160:358\u2013366","journal-title":"Pain"},{"key":"816_CR35","doi-asserted-by":"publisher","first-page":"2512","DOI":"10.1056\/NEJMp1710862","volume":"377","author":"L Rutkow","year":"2017","unstructured":"Rutkow L, Vernick JS (2017) Emergency Legal authority and the opioid crisis. N Engl J Med 377:2512\u20132514","journal-title":"N Engl J Med"},{"key":"816_CR36","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1186\/s12987-017-0080-3","volume":"14","author":"CP Schaefer","year":"2017","unstructured":"Schaefer CP, Tome ME, Davis TP (2017) The opioid epidemic: a central role for the blood brain barrier in opioid analgesia and abuse. Fluids Barriers CNS 14:32","journal-title":"Fluids Barriers CNS"},{"key":"816_CR37","doi-asserted-by":"publisher","first-page":"1374","DOI":"10.1016\/j.jpain.2017.06.010","volume":"18","author":"A Shah","year":"2017","unstructured":"Shah A, Hayes CJ, Martin BC (2017) Factors Influencing long-term opioid use among opioid naive patients: an examination of initial prescription characteristics and pain etiologies. J Pain 18:1374\u20131383","journal-title":"J Pain"},{"key":"816_CR38","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1016\/j.neuron.2016.09.051","volume":"92","author":"P Skolnick","year":"2016","unstructured":"Skolnick P, Volkow ND (2016) Re-energizing the Development of pain therapeutics in light of the opioid epidemic. Neuron 92:294\u2013297","journal-title":"Neuron"},{"key":"816_CR39","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1146\/annurev-med-062613-093100","volume":"67","author":"C Stein","year":"2016","unstructured":"Stein C (2016) Opioid receptors. Annu Rev Med 67:433\u2013451","journal-title":"Annu Rev Med"},{"key":"816_CR40","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1007\/s11916-010-0171-1","volume":"15","author":"DA Tompkins","year":"2011","unstructured":"Tompkins DA, Campbell CM (2011) Opioid-induced hyperalgesia: clinically relevant or extraneous research phenomenon? Curr Pain Headache Rep 15:129\u2013136","journal-title":"Curr Pain Headache Rep"},{"key":"816_CR41","doi-asserted-by":"publisher","first-page":"2587","DOI":"10.2147\/JPR.S170269","volume":"11","author":"E Treillet","year":"2018","unstructured":"Treillet E, Laurent S, Hadjiat Y (2018) Practical management of opioid rotation and equianalgesia. J Pain Res 11:2587\u20132601","journal-title":"J Pain Res"},{"key":"816_CR42","unstructured":"US Food and Drug Administration (2015) Guidance for industry: abuse-deterrent opioids\u2013evaluation and labeling. US Department of Health and Human Services website. https:\/\/www.fda.gov\/downloads\/drugs\/guidancecomplianceregulatoryinformation\/guidances\/ucm334743.pdf. Accessed: 2019"},{"key":"816_CR43","doi-asserted-by":"publisher","first-page":"3041","DOI":"10.1111\/ejn.12709","volume":"40","author":"CM Vander Weele","year":"2014","unstructured":"Vander Weele CM, Porter-Stransky KA, Mabrouk OS et al (2014) Rapid dopamine transmission within the nucleus accumbens: dramatic difference between morphine and oxycodone delivery. Eur J Neurosci 40:3041\u20133054","journal-title":"Eur J Neurosci"},{"key":"816_CR44","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1358\/dot.2018.54.4.2812620","volume":"54","author":"G Walker","year":"2018","unstructured":"Walker G (2018) The opioid crisis: a 21st century pain. Drugs Today (Barc) 54:283\u2013286","journal-title":"Drugs Today (Barc)"},{"key":"816_CR45","doi-asserted-by":"publisher","first-page":"790","DOI":"10.1111\/j.1526-4637.2012.01380.x","volume":"13","author":"LR Webster","year":"2012","unstructured":"Webster LR, Bath B, Medve RA, Marmon T, Stoddard GJ (2012) Randomized, double-blind, placebo-controlled study of the abuse potential of different formulations of oral oxycodone. Pain Med 13:790\u2013801","journal-title":"Pain Med"},{"key":"816_CR46","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1093\/pm\/pnw344","volume":"19","author":"L Webster","year":"2018","unstructured":"Webster L, Henningfield J, Buchhalter AR et al (2018) Human abuse potential of the new opioid analgesic molecule NKTR-181 compared with oxycodone. Pain Med 19:307\u2013318","journal-title":"Pain Med"},{"key":"816_CR47","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1007\/978-3-540-33823-9_2","volume":"177","author":"C Zollner","year":"2007","unstructured":"Zollner C, Stein C (2007) Opioids. Handb Exp Pharmacol 177:31\u201363","journal-title":"Handb Exp Pharmacol"}],"container-title":["Cellular and Molecular Neurobiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10571-020-00816-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10571-020-00816-3\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10571-020-00816-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,27]],"date-time":"2021-05-27T17:42:47Z","timestamp":1622137367000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10571-020-00816-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,27]]},"references-count":47,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2021,7]]}},"alternative-id":["816"],"URL":"https:\/\/doi.org\/10.1007\/s10571-020-00816-3","relation":{},"ISSN":["0272-4340","1573-6830"],"issn-type":[{"value":"0272-4340","type":"print"},{"value":"1573-6830","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2,27]]},"assertion":[{"value":"5 November 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 February 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 February 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}]}}