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Preclinical Studies on Nalfurafine (TRK-820), a Clinically Used KOR Agonist

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The Kappa Opioid Receptor

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 271))

Abstract

Nalfurafine has been used clinically in Japan for treatment of itch in kidney dialysis patients and in patients with chronic liver diseases. A one-year post-marketing study showed nalfurafine to be safe and efficacious without producing side effects of typical KOR agonists such as anhedonia and psychotomimesis. In this chapter, we summarize in vitro characterization and in vivo preclinical studies on nalfurafine. In vitro, nalfurafine is a highly potent and moderately selective KOR full agonist; however, whether it is a biased KOR agonist is a matter of debate. In animals, nalfurafine produced anti-pruritic effects in a dose range lower than that caused side effects, including conditioned place aversion (CPA), hypolocomotion, motor incoordination, consistent with the human data. In addition, nalfurafine showed antinociceptive effects in several pain models at doses that did not cause the side effects mentioned above. It appears to be effective against inflammatory pain and mechanical pain, but less so against thermal pain, particularly high-intensity thermal pain. U50,488H and nalfurafine differentially modulated several signaling pathways in a brain region-specific manners. Notably, U50,488H, but not nalfurafine, activated the mTOR pathway, which contributed to U50,488H-induced CPA. Because of its lack of side effects associated with typical KOR agonists, nalfurafine has been investigated as a combination therapy with an MOR ligand for pain treatment and for its effects on opioid use disorder and alcohol use disorder, and results indicate potential usefulness for these indications. Thus, although in vitro data regarding uniqueness of nalfurafine in terms of signaling at the KOR are somewhat equivocal, in vivo results support the assertion that nalfurafine is an atypical KOR agonist with a significantly improved side-effect profile relative to typical KOR agonists.

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References

  • Akiyama T, Carstens MI, Piecha D, Steppan S, Carstens E (2015) Nalfurafine suppresses pruritogen- and touch-evoked scratching behavior in models of acute and chronic itch in mice. Acta Derm Venereol 95:147–150. https://doi.org/10.2340/00015555-1879

    Article  PubMed  PubMed Central  Google Scholar 

  • Anderson RI, Becker HC (2017) Role of the dynorphin/kappa opioid receptor system in the motivational effects of ethanol alcohol. Clin Exp Res 41:1402–1418. https://doi.org/10.1111/acer.13406

    Article  CAS  Google Scholar 

  • Bart G, Schluger JH, Borg L, Ho A, Bidlack JM, Kreek MJ (2005) Nalmefene induced elevation in serum prolactin in normal human volunteers: partial kappa opioid agonist activity? Neuropsychopharmacology 30:2254–2262. https://doi.org/10.1038/sj.npp.1300811

    Article  CAS  PubMed  Google Scholar 

  • Bloodgood DW, Hardaway JA, Stanhope CM, Pati D, Pina MM, Neira S, Desai S, Boyt KM, Palmiter RD, Kash TL (2020) Kappa opioid receptor and dynorphin signaling in the central amygdala regulates alcohol intake. Mol Psychiatry. https://doi.org/10.1038/s41380-020-0690-z

  • Bruchas MR, Land BB, Aita M, Xu M, Barot SK, Li S, Chavkin C (2007) Stress-induced p38 mitogen-activated protein kinase activation mediates kappa-opioid-dependent dysphoria. J Neurosci 27:11614–11623

    Article  CAS  Google Scholar 

  • Cao D, Huang P, Chiu YT, Chen C, Wang H, Li M, Zheng Y, Ehlert FJ, Zhang Y, Liu-Chen LY (2020) Comparison of pharmacological properties between the kappa opioid receptor agonist nalfurafine and 42B, its 3-dehydroxy analogue: disconnect between in vitro agonist bias and in vivo pharmacological effects. ACS Chem Neurosci 11:3036–3050. https://doi.org/10.1021/acschemneuro.0c00407

    Article  CAS  PubMed  Google Scholar 

  • Che T, Majumdar S, Zaidi SA, Ondachi P, McCorvy JD, Wang S, Mosier PD, Uprety R, Vardy E, Krumm BE, Han GW, Lee MY, Pardon E, Steyaert J, Huang XP, Strachan RT, Tribo AR, Pasternak GW, Carroll FI, Stevens RC, Cherezov V, Katritch V, Wacker D, Roth BL (2018) Structure of the nanobody-stabilized active state of the kappa opioid receptor cell 172:55–67 e15. https://doi.org/10.1016/j.cell.2017.12.011

  • Cosgrove KP, Carroll ME (2002) Effects of bremazocine on self-administration of smoked cocaine base and orally delivered ethanol, phencyclidine, saccharin, and food in rhesus monkeys: a behavioral economic analysis. J Pharmacol Exp Ther 301:993–1002. https://doi.org/10.1124/jpet.301.3.993

    Article  CAS  PubMed  Google Scholar 

  • Cowan A, Gmerek DE (1986) In-vivo studies on kappa opioid receptors. Trends Pharmacol Sci 7:69–72

    Article  CAS  Google Scholar 

  • D’Addario C, Caputi FF, Rimondini R, Gandolfi O, Del Borrello E, Candeletti S, Romualdi P (2013) Different alcohol exposures induce selective alterations on the expression of dynorphin and nociceptin systems related genes in rat brain. Addict Biol 18:425–433. https://doi.org/10.1111/j.1369-1600.2011.00326.x

    Article  CAS  PubMed  Google Scholar 

  • Dunn AD, Reed B, Erazo J, Ben-Ezra A, Kreek MJ (2019) Signaling properties of structurally diverse kappa opioid receptor ligands: toward in vitro models of in vivo responses. ACS Chem Neurosci 10:3590–3600. https://doi.org/10.1021/acschemneuro.9b00195

    Article  CAS  PubMed  Google Scholar 

  • Dunn A, Windisch K, Ben-Ezra A, Pikus P, Morochnik M, Erazo J, Reed B, Kreek MJ (2020) Modulation of cocaine-related behaviors by low doses of the potent KOR agonist nalfurafine in male C57BL6 mice. Psychopharmacology 237:2405–2418. https://doi.org/10.1007/s00213-020-05543-7

    Article  CAS  PubMed  Google Scholar 

  • Elliott G, Vanwersch R, Soeberdt M, Metze D, Lotts T, Stander S, Abels C (2016) Topical nalfurafine exhibits anti-inflammatory and anti-pruritic effects in a murine model of AD. J Dermatol Sci 84:351–354. https://doi.org/10.1016/j.jdermsci.2016.09.008

    Article  CAS  PubMed  Google Scholar 

  • Endoh T, Matsuura H, Tajima A, Izumimoto N, Tajima C, Suzuki T, Saitoh A, Suzuki T, Narita M, Tseng L, Nagase H (1999) Potent antinociceptive effects of TRK-820, a novel kappa-opioid receptor agonist. Life Sci 65:1685–1694

    Article  CAS  Google Scholar 

  • Endoh T, Tajima A, Suzuki T, Kamei J, Narita M, Tseng L, Nagase H (2000) Characterization of the antinociceptive effects of TRK-820 in the rat. Eur J Pharmacol 387:133–140

    Article  CAS  Google Scholar 

  • Endoh T, Tajima A, Izumimoto N, Suzuki T, Saitoh A, Suzuki T, Narita M, Kamei J, Tseng LF, Mizoguchi H, Nagase H (2001) TRK-820, a selective kappa-opioid agonist, produces potent antinociception in cynomolgus monkeys. Jpn J Pharmacol 85:282–290

    Article  CAS  Google Scholar 

  • Freeman KB, Naylor JE, Prisinzano TE, Woolverton WL (2014) Assessment of the kappa opioid agonist, salvinorin a, as a punisher of drug self-administration in monkeys. Psychopharmacology 231:2751–2758. https://doi.org/10.1007/s00213-014-3436-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gillis A, Gondin AB, Kliewer A, Sanchez J, Lim HD, Alamein C, Manandhar P, Santiago M, Fritzwanker S, Schmiedel F, Katte TA, Reekie T, Grimsey NL, Kassiou M, Kellam B, Krasel C, Halls ML, Connor M, Lane JR, Schulz S, Christie MJ, Canals M (2020) Low intrinsic efficacy for G protein activation can explain the improved side effect profiles of new opioid agonists. Sci Signal 13:eaaz3140. https://doi.org/10.1126/scisignal.aaz3140

    Article  CAS  PubMed  Google Scholar 

  • Hasebe K, Kawai K, Suzuki T, Kawamura K, Tanaka T, Narita M, Nagase H, Suzuki T (2004) Possible pharmacotherapy of the opioid kappa receptor agonist for drug dependence. Ann N Y Acad Sci 1025:404–413. https://doi.org/10.1196/annals.1316.050

    Article  CAS  PubMed  Google Scholar 

  • Haun HL, Griffin WC, Lopez MF, Becker HC (2020) Kappa opioid receptors in the bed nucleus of the stria terminalis regulate binge-like alcohol consumption in male and female mice. Neuropharmacology 167:107984. https://doi.org/10.1016/j.neuropharm.2020.107984

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huskinson SL, Platt DM, Brasfield M, Follett ME, Prisinzano TE, Blough BE, Freeman KB (2020) Quantification of observable behaviors induced by typical and atypical kappa-opioid receptor agonists in male rhesus monkeys. Psychopharmacology 237:2075–2087. https://doi.org/10.1007/s00213-020-05519-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Inan S, Cowan A (2004) Kappa opioid agonists suppress chloroquine-induced scratching in mice. Eur J Pharmacol 502:233–237

    Article  CAS  Google Scholar 

  • Inan S, Cowan A (2006) Nalfurafine, a kappa opioid receptor agonist, inhibits scratching behavior secondary to cholestasis induced by chronic ethynylestradiol injections in rats. Pharmacol Biochem Behav 85:39–43

    Article  CAS  Google Scholar 

  • Inan S, Dun NJ, Cowan A (2009a) Nalfurafine prevents 5′-guanidinonaltrindole- and compound 48/80-induced spinal c-fos expression and attenuates 5′-guanidinonaltrindole-elicited scratching behavior in mice. Neuroscience 163:23–33

    Article  CAS  Google Scholar 

  • Inan S, Lee DY, Liu-Chen LY, Cowan A (2009b) Comparison of the diuretic effects of chemically diverse kappa opioid agonists in rats: nalfurafine, U50,488H, and salvinorin a. Naunyn Schmiedeberg's Arch Pharmacol 379:263–270

    Article  CAS  Google Scholar 

  • Iwamoto ET (1981) Locomotor activity and antinociception after putative mu, kappa and sigma opioid receptor agonists in the rat: influence of dopaminergic agonists and antagonists. J Pharmacol Exp Ther 217:451–460

    CAS  PubMed  Google Scholar 

  • Kardon AP, Polgar E, Hachisuka J, Snyder LM, Cameron D, Savage S, Cai X, Karnup S, Fan CR, Hemenway GM, Bernard CS, Schwartz ES, Nagase H, Schwarzer C, Watanabe M, Furuta T, Kaneko T, Koerber HR, Todd AJ, Ross SE (2014) Dynorphin acts as a neuromodulator to inhibit itch in the dorsal horn of the spinal cord. Neuron 82:573–586. https://doi.org/10.1016/j.neuron.2014.02.046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kaski SW, White AN, Gross JD, Trexler KR, Wix K, Harland AA, Prisinzano TE, Aube J, Kinsey SG, Kenakin T, Siderovski DP, Setola V (2019) Preclinical testing of nalfurafine as an opioid-sparing adjuvant that potentiates analgesia by the mu opioid receptor-targeting agonist morphine. J Pharmacol Exp Ther 371:487–499. https://doi.org/10.1124/jpet.118.255661

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kissler JL, Sirohi S, Reis DJ, Jansen HT, Quock RM, Smith DG, Walker BM (2014) The one-two punch of alcoholism: role of central amygdala dynorphins/kappa-opioid receptors. Biol Psychiatry 75:774–782. https://doi.org/10.1016/j.biopsych.2013.03.014

    Article  CAS  PubMed  Google Scholar 

  • Ko MC, Husbands SM (2009) Effects of atypical kappa-opioid receptor agonists on intrathecal morphine-induced itch and analgesia in primates. J Pharmacol Exp Ther 328:193–200. https://doi.org/10.1124/jpet.108.143925

    Article  CAS  PubMed  Google Scholar 

  • Koob GF (2021) Drug addiction: hyperkatifeia/negative reinforcement as a framework for medications development. Pharmacol Rev 73:163–201. https://doi.org/10.1124/pharmrev.120.000083

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kozono H, Yoshitani H, Nakano R (2018) Post-marketing surveillance study of the safety and efficacy of nalfurafine hydrochloride (Remitch((R)) capsules 2.5 mug) in 3,762 hemodialysis patients with intractable pruritus. Int J Nephrol Renovasc Dis 11:9–24. https://doi.org/10.2147/IJNRD.S145720

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kumagai H, Ebata T, Takamori K, Muramatsu T, Nakamoto H, Suzuki H (2010) Effect of a novel kappa-receptor agonist, nalfurafine hydrochloride, on severe itch in 337 haemodialysis patients: a phase III, randomized, double-blind, placebo-controlled study. Nephrol Dial Transplant 25:1251–1257. https://doi.org/10.1093/ndt/gfp588

    Article  CAS  PubMed  Google Scholar 

  • Kumagai H, Ebata T, Takamori K, Miyasato K, Muramatsu T, Nakamoto H, Kurihara M, Yanagita T, Suzuki H (2012) Efficacy and safety of a novel k-agonist for managing intractable pruritus in dialysis patients. Am J Nephrol 36:175–183. https://doi.org/10.1159/000341268

    Article  CAS  PubMed  Google Scholar 

  • Lam MP, Gianoulakis C (2011) Effects of corticotropin-releasing hormone receptor antagonists on the ethanol-induced increase of dynorphin A1-8 release in the rat central amygdala. Alcohol 45:621–630. https://doi.org/10.1016/j.alcohol.2011.05.001

    Article  CAS  PubMed  Google Scholar 

  • Lazenka ML, Moerke MJ, Townsend EA, Freeman KB, Carroll FI, Negus SS (2018) Dissociable effects of the kappa opioid receptor agonist nalfurafine on pain/itch-stimulated and pain/itch-depressed behaviors in male rats. Psychopharmacology 235:203–213. https://doi.org/10.1007/s00213-017-4758-7

    Article  CAS  PubMed  Google Scholar 

  • Lindholm S, Werme M, Brené S, Franck J (2001) The selective kappa-opioid receptor agonist U50,488H attenuates voluntary ethanol intake in the rat. Behav Brain Res 120:137–146. https://doi.org/10.1016/s0166-4328(00)00368-5

    Article  CAS  PubMed  Google Scholar 

  • Liu JJ, Sharma K, Zangrandi L, Chen C, Humphrey SJ, Chiu YT, Spetea M, Liu-Chen LY, Schwarzer C, Mann M (2018) In vivo brain GPCR signaling elucidated by phosphoproteomics. Science 360:eaao4927. https://doi.org/10.1126/science.aao4927

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu JJ, Chiu YT, DiMattio KM, Chen C, Huang P, Gentile TA, Muschamp JW, Cowan A, Mann M, Liu-Chen LY (2019) Phosphoproteomic approach for agonist-specific signaling in mouse brains: mTOR pathway is involved in kappa opioid aversion. Neuropsychopharmacology 44:939–949. https://doi.org/10.1038/s41386-018-0155-0

    Article  CAS  PubMed  Google Scholar 

  • Mello NK, Negus SS (1998) Effects of kappa opioid agonists on cocaine- and food-maintained responding by rhesus monkeys. J Pharmacol Exp Ther 286:812–824

    CAS  PubMed  Google Scholar 

  • Morani AS, Kivell B, Prisinzano TE, Schenk S (2009) Effect of kappa-opioid receptor agonists U69593, U50488H, spiradoline and salvinorin a on cocaine-induced drug-seeking in rats. Pharmacol Biochem Behav 94:244–249. https://doi.org/10.1016/j.pbb.2009.09.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mori T, Nomura M, Nagase H, Narita M, Suzuki T (2002) Effects of a newly synthesized kappa-opioid receptor agonist, TRK-820, on the discriminative stimulus and rewarding effects of cocaine in rats. Psychopharmacology (Berlin) 161:17–22

    Article  CAS  Google Scholar 

  • Mucha RF, Herz A (1985) Motivational properties of kappa and mu opioid receptor agonists studied with place and taste preference conditioning. Psychopharmacology 86:274–280

    Article  CAS  Google Scholar 

  • Nagase H, Fujii H (2013) Essential structure of the kappa opioid receptor agonist nalfurafine for binding to the kappa receptor. Curr Pharm Des 19:7400–7414

    Google Scholar 

  • Nagase H, Hayakawa J, Kawamura K, Kawai K, Takezawa Y, Matsuura H, Tajima C, Endo T (1998) Discovery of a structurally novel opioid kappa-agonist derived from 4,5-epoxymorphinan. Chem Pharm Bull (Tokyo) 46:366–369

    Article  CAS  Google Scholar 

  • Nakao K, Mochizuki H (2009a) Nalfurafine hydrochloride: a new drug for the treatment of uremic pruritus in hemodialysis patients. Drugs Today (Barc) 45:323–329. https://doi.org/10.1358/dot.2009.45.5.1362067

    Article  CAS  Google Scholar 

  • Nakao K, Mochizuki H (2009b) Nalfurafine hydrochloride: a new drug for the treatment of uremic pruritus in hemodialysis patients. Drugs Today (Barc) 45:323–329

    Article  CAS  Google Scholar 

  • Nakao K, Ikeda K, Kurokawa T, Togashi Y, Umeuchi H, Honda T, Okano K, Mochizuki H (2008) Effect of TRK-820, a selective kappa opioid receptor agonist, on scratching behavior in an animal model of atopic dermatitis. Nihon Shinkei Seishin Yakurigaku Zasshi 28:75–83

    CAS  PubMed  Google Scholar 

  • Negus SS, Schrode K, Stevenson GW (2008) Micro/kappa opioid interactions in rhesus monkeys: implications for analgesia and abuse liability. Exp Clin Psychopharmacol 16:386–399. https://doi.org/10.1037/a0013088

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pande AC, Pyke RE, Greiner M, Wideman GL, Benjamin R, Pierce MW (1996) Analgesic efficacy of enadoline versus placebo or morphine in postsurgical pain. Clin Neuropharmacol 19:451–456

    Article  CAS  Google Scholar 

  • Pfeiffer A, Brantl V, Herz A, Emrich HM (1986) Psychotomimesis mediated by kappa opiate receptors. Science 233:774–776. https://doi.org/10.1126/science.3016896

    Article  CAS  PubMed  Google Scholar 

  • Rose JH, Karkhanis AN, Chen R, Gioia D, Lopez MF, Becker HC, McCool BA, Jones SR (2016) Supersensitive kappa opioid receptors promotes ethanol withdrawal-related behaviors and reduce dopamine signaling in the nucleus accumbens. Int J Neuropsychopharmacol 19. https://doi.org/10.1093/ijnp/pyv127

  • Sakakihara M, Imamachi N, Saito Y (2016) Effects of intrathecal kappa-opioid receptor agonist on morphine-induced itch and antinociception in mice. Reg Anesth Pain Med 41:69–74. https://doi.org/10.1097/AAP.0000000000000326

    Article  CAS  PubMed  Google Scholar 

  • Schattauer SS, Kuhar JR, Song A, Chavkin C (2017) Nalfurafine is a G-protein biased agonist having significantly greater bias at the human than rodent form of the kappa opioid receptor. Cell Signal 32:59–65. https://doi.org/10.1016/j.cellsig.2017.01.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Seki T, Awamura S, Kimura C, Ide S, Sakano K, Minami M, Nagase H, Satoh M (1999) Pharmacological properties of TRK-820 on cloned mu-, delta- and kappa-opioid receptors and nociceptin receptor. Eur J Pharmacol 376:159–167

    Article  CAS  Google Scholar 

  • Shippenberg TS, Herz A (1986) Differential effects of mu and kappa opioid systems on motivational processes NIDA. Res Monogr 75:563–566

    CAS  Google Scholar 

  • Simonson B, Morani AS, Ewald AW, Walker L, Kumar N, Simpson D, Miller JH, Prisinzano TE, Kivell BM (2015) Pharmacology and anti-addiction effects of the novel κ opioid receptor agonist Mesyl Sal B, a potent and long-acting analogue of salvinorin a. Br J Pharmacol 172:515–531. https://doi.org/10.1111/bph.12692

    Article  CAS  PubMed  Google Scholar 

  • Snyder LM, Chiang MC, Loeza-Alcocer E, Omori Y, Hachisuka J, Sheahan TD, Gale JR, Adelman PC, Sypek EI, Fulton SA, Friedman RL, Wright MC, Duque MG, Lee YS, Hu Z, Huang H, Cai X, Meerschaert KA, Nagarajan V, Hirai T, Scherrer G, Kaplan DH, Porreca F, Davis BM, Gold MS, Koerber HR, Ross SE (2018) Kappa opioid receptor distribution and function in primary afferents. Neuron 99:1274–1288.e1276. https://doi.org/10.1016/j.neuron.2018.08.044

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takasaki I, Suzuki T, Sasaki A, Nakao K, Hirakata M, Okano K, Tanaka T, Nagase H, Shiraki K, Nojima H, Kuraishi Y (2004) Suppression of acute herpetic pain-related responses by the kappa-opioid receptor agonist (−)-17-cyclopropylmethyl-3,14beta-dihydroxy-4,5alpha-epoxy-beta-[n-methyl-3-trans −3-(3-furyl) acrylamido] morphinan hydrochloride (TRK-820) in mice. J Pharmacol Exp Ther 309:36–41. https://doi.org/10.1124/jpet.103.059816

    Article  CAS  PubMed  Google Scholar 

  • Togashi Y, Umeuchi H, Okano K, Ando N, Yoshizawa Y, Honda T, Kawamura K, Endoh T, Utsumi J, Kamei J, Tanaka T, Nagase H (2002) Antipruritic activity of the kappa-opioid receptor agonist, TRK-820. Eur J Pharmacol 435:259–264

    Article  CAS  Google Scholar 

  • Townsend EA, Naylor JE, Negus SS, Edwards SR, Qureshi HN, McLendon HW, McCurdy CR, Kapanda CN, do Carmo JM, da Silva FS, Hall JE, Sufka KJ, Freeman KB (2017) Effects of nalfurafine on the reinforcing, thermal antinociceptive, and respiratory-depressant effects of oxycodone: modeling an abuse-deterrent opioid analgesic in rats. Psychopharmacology 234:2597–2605. https://doi.org/10.1007/s00213-017-4652-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tsuji M, Takeda H, Matsumiya T, Nagase H, Yamazaki M, Narita M, Suzuki T (2000a) A novel kappa-opioid receptor agonist, TRK-820, blocks the development of physical dependence on morphine in mice. Life Sci 66:L353–L358

    Article  Google Scholar 

  • Tsuji M, Yamazaki M, Takeda H, Matsumiya T, Nagase H, Tseng LF, Narita M, Suzuki T (2000b) The novel kappa-opioid receptor agonist TRK-820 has no affect on the development of antinociceptive tolerance to morphine in mice. Eur J Pharmacol 394:91–95

    Article  CAS  Google Scholar 

  • Tsuji M, Takeda H, Matsumiya T, Nagase H, Narita M, Suzuki T (2001) The novel kappa-opioid receptor agonist TRK-820 suppresses the rewarding and locomotor-enhancing effects of morphine in mice. Life Sci 68:1717–1725

    Article  CAS  Google Scholar 

  • Umeuchi H, Togashi Y, Honda T, Nakao K, Okano K, Tanaka T, Nagase H (2003) Involvement of central mu-opioid system in the scratching behavior in mice, and the suppression of it by the activation of kappa-opioid system. Eur J Pharmacol 477:29–35

    Article  CAS  Google Scholar 

  • Umeuchi H, Kawashima Y, Aoki CA, Kurokawa T, Nakao K, Itoh M, Kikuchi K, Kato T, Okano K, Gershwin ME, Miyakawa H (2005) Spontaneous scratching behavior in MRL/lpr mice, a possible model for pruritus in autoimmune diseases, and antipruritic activity of a novel kappa-opioid receptor agonist nalfurafine hydrochloride. Eur J Pharmacol 518:133–139. https://doi.org/10.1016/j.ejphar.2005.06.019

    Article  CAS  PubMed  Google Scholar 

  • von Voigtlander PF, Lahti RA, Ludens JH (1983) U-50,488: a selective and structurally novel non-mu (kappa) opioid agonist. J Pharmacol Exp Ther 224:7–12

    Google Scholar 

  • Wadenberg ML (2003) A review of the properties of spiradoline: a potent and selective kappa-opioid receptor agonist. CNS Drug Rev 9:187–198

    Article  CAS  Google Scholar 

  • Wakasa Y, Fujiwara A, Umeuchi H, Endoh T, Okano K, Tanaka T, Nagase H (2004) Inhibitory effects of TRK-820 on systemic skin scratching induced by morphine in rhesus monkeys. Life Sci 75:2947–2957. https://doi.org/10.1016/j.lfs.2004.05.033

    Article  CAS  PubMed  Google Scholar 

  • Walsh SL, Strain EC, Abreu ME, Bigelow GE (2001) Enadoline, a selective kappa opioid agonist: comparison with butorphanol and hydromorphone in humans. Psychopharmacology 157:151–162. https://doi.org/10.1007/s002130100788

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Tang K, Inan S, Siebert D, Holzgrabe U, Lee DY, Huang P, Li JG, Cowan A, Liu-Chen L-Y (2005) Comparison of pharmacological activities of three distinct k ligands (Salvinorin a, TRK-820 and 3FLB) on k opioid receptors in vitro and their antipruritic and antinociceptive activities in vivo. J Pharmacol Exp Ther 312:220–230

    Article  CAS  Google Scholar 

  • White KL, Robinson JE, Zhu H, DiBerto JF, Polepally PR, Zjawiony JK, Nichols DE, Malanga CJ, Roth BL (2015) The G protein-biased kappa-opioid receptor agonist RB-64 is analgesic with a unique spectrum of activities in vivo. J Pharmacol Exp Ther 352:98–109. https://doi.org/10.1124/jpet.114.216820

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zamarripa CA, Naylor JE, Huskinson SL, Townsend EA, Prisinzano TE, Freeman KB (2020a) Kappa opioid agonists reduce oxycodone self-administration in male rhesus monkeys. Psychopharmacology 237:1471–1480. https://doi.org/10.1007/s00213-020-05473-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zamarripa CA, Patel TR, Williams BC, Pareek T, Schrock HM, Prisinzano TE, Freeman KB (2020b) The kappa-opioid receptor agonist, nalfurafine, blocks acquisition of oxycodone self-administration and oxycodone's conditioned rewarding effects in male rats. Behav Pharmacol. https://doi.org/10.1097/FBP.0000000000000581

  • Zhang Y, Kreek MJ (2020) Nalfurafine modulates the reinforcing effects of oxycodone in male and female adolescent C57BL/6J mice. Neuropharmacology 176:108244. https://doi.org/10.1016/j.neuropharm.2020.108244

    Article  CAS  PubMed  Google Scholar 

  • Zhou Y, Kreek MJ (2019a) Clinically utilized kappa-opioid receptor agonist nalfurafine combined with low-dose naltrexone prevents alcohol relapse-like drinking in male and female mice. Brain Res 1724:146410. https://doi.org/10.1016/j.brainres.2019.146410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou Y, Kreek MJ (2019b) Combination of clinically utilized kappa-opioid receptor agonist nalfurafine with low-dose naltrexone reduces excessive alcohol drinking in male and female mice. Alcohol Clin Exp Res 43:1077–1090. https://doi.org/10.1111/acer.14033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou Y, Colombo G, Gessa GL, Kreek MJ (2013) Effects of voluntary alcohol drinking on corticotropin-releasing factor and preprodynorphin mRNA levels in the central amygdala of Sardinian alcohol-preferring rats. Neurosci Lett 554:110–114. https://doi.org/10.1016/j.neulet.2013.08.071

    Article  CAS  PubMed  Google Scholar 

  • Zhou Y, Liang Y, Kreek MJ (2020) mTORC1 pathway is involved in the kappa opioid receptor activation-induced increase in excessive alcohol drinking in mice. Pharmacol Biochem Behav 195:172954. https://doi.org/10.1016/j.pbb.2020.172954

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The writing of this manuscript was supported by the NIH grants F30DA044711 (SK), R01DA039167 (KBF), R01DA041359, R21DA045274 and P30DA013429 (LYLC). YZ and MJK thank the support of Dr. Miriam and Sheldon G. Adelson Medical Research Foundation and Robertson Therapeutic Discover Fund at the Rockefeller University. We are grateful to NIDA Division of Drug Supply and Analytical Services for nalfurafine used in the experiments.

Conflict of Interests

The authors declare no conflict of interests.

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Author notes

  1. Yan Zhou, Kevin Freeman, Vincent Setola, and Danni Cao contributed equally to this work.

Authors and Affiliations

  1. Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, NY, USA

    Yan Zhou & Mary Jeanne Kreek

  2. Division of Neurobiology and Behavior Research, Department of Psychiatry and Human Behavior, The University of Mississippi Medical Center, Jackson, MS, USA

    Kevin Freeman

  3. Departments of Neuroscience, and Behavioral Medicine and Psychiatry, West Virginia University School of Medicine, Morgantown, WV, USA

    Vincent Setola & Shane Kaski

  4. Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA

    Danni Cao & Lee-Yuan Liu-Chen

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  1. Yan Zhou
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  2. Kevin Freeman
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  3. Vincent Setola
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  4. Danni Cao
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  5. Shane Kaski
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  6. Mary Jeanne Kreek
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  7. Lee-Yuan Liu-Chen
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Correspondence to Lee-Yuan Liu-Chen .

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Editors and Affiliations

  1. Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA

    Lee-Yuan Liu-Chen

  2. Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA

    Saadet Inan

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Zhou, Y. et al. (2021). Preclinical Studies on Nalfurafine (TRK-820), a Clinically Used KOR Agonist. In: Liu-Chen, LY., Inan, S. (eds) The Kappa Opioid Receptor. Handbook of Experimental Pharmacology, vol 271. Springer, Cham. https://doi.org/10.1007/164_2021_443

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