Sedative effect of U-49900 (3,4-dichloro-N- (2-(diethylamino)cyclohexyl)-N-methyl-benzamide) in adult Zebrafish

Abstract

BACKGROUND: U-49900 is a chemical analog of U-47700. Despite the growing abuse of synthetic opioids, including U-49900, its psychopharmacological and toxicological profiles remain poorly understood. The zebrafish (Danio rerio) is a promising model organism in neuroscience often used for the psychopharmacological evaluation of neurotropic drugs. OBJECTIVE: To evaluate the effects of U-49900 on the behavior of adult zebrafish in a new tank. MATERIALS AND METHODS: The effect of the test compound U-49900 at 1, 5, 10, and 25 mg/L concentrations (incubation for 20 minutes) on the behavior of adult zebrafish was assessed using the “new aquarium” test. U-49900 is 3.4-dichloro-N-(2-(diethylamino)cyclohexyl)-N-methylbenzamide and is considered an analog of the synthetic opioid U-47700, causing withdrawal in humans. RESULTS: The psychopharmacological profile of U-49900 at 1, 5, 10, and 25 mg/l concentrations (water immersion) in adult zebrafish was evaluated with the novel tank test. U-49900 at 25 mg/l for 20 min reduced the distance traveled and number of top entries in the novel tank test (p < 0.001 vs. control group), but unaltered other parameters. CONCLUSIONS: Overall, the sensitivity of zebrafish to synthetic non-fentanyl opioids such as U-49900 indicates the possibility of developing high-throughput screening platforms for finding effective therapies for pathological conditions caused by synthetic opioids.

Keywords

zebrafish / U-49900 / synthetic opioids / behavior / sedative effect

References

[1] Nutt D, King LA, Saulsbury W, Blakemore C. Development of a rational scale to assess the harm of drugs of potential misuse. Lancet. 2007;369(9566):1047–1053. doi: 10.1016/S0140-6736(07)60464-4

[2] Nutt D., King L.A., Saulsbury W., Blakemore C. Development of a rational scale to assess the harm of drugs of potential misuse // Lancet. 2007. Vol. 369, N 9566. P. 1047–1053. doi: 10.1016/S0140-6736(07)60464-4

[3] Fabregat-Safont D, Carbón X, Ventura M, et al. Updating the list of known opioids through identification and characterization of the new opioid derivative 3, 4-dichloro-N-(2-(diethylamino) cyclohexyl)-N-methylbenzamide (U-49900). Sci Rep. 2017;7(1):6338. doi: 10.1038/s41598-017-06778-9

[4] Fabregat-Safont D., Carbón X., Ventura M., et al. Updating the list of known opioids through identification and characterization of the new opioid derivative 3, 4-dichloro-N-(2-(diethylamino) cyclohexyl)-N-methylbenzamide (U-49900) // Sci Rep. 2017. Vol. 7, N 1. ID 6338 doi: 10.1038/s41598-017-06778-9

[5] Krotulski AJ, Papsun DM, Friscia M, et al. Fatality following ingestion of tetrahydrofuranylfentanyl, U-49900 and methoxy-phencyclidine. J Anal Toxicol. 2018;42(3):e27–e32. doi: 10.1093/jat/bkx092

[6] Krotulski A.J., Papsun D.M., Friscia M., et al. Fatality following ingestion of tetrahydrofuranylfentanyl, U-49900 and methoxy-phencyclidine // J Anal Toxicol. 2018. Vol. 42, N 3. P. e27–e32. doi: 10.1093/jat/bkx092

[7] Kalueff AV, Echevarria D, Stewart AM. Gaining translational momentum: more zebrafish models for neuroscience research. Prog Neuro-Psychopharmacol Biol Psychiatry. 2014;55:1–6. doi: 10.1016/j.pnpbp.2014.01.022

[8] Kalueff A.V., Echevarria D., Stewart A.M. Gaining translational momentum: more zebrafish models for neuroscience research // Prog Neuro-Psychopharmacol Biol Psychiatry. 2014. Vol. 55. P. 1–6. doi: 10.1016/j.pnpbp.2014.01.022

[9] Gerlai R. Learning and memory in zebrafish (Danio rerio). Methods Cell Biolol. 2016;134:551–586. doi: 10.1016/bs.mcb.2016.02.005

[10] Gerlai R. Learning and memory in zebrafish (Danio rerio) // Methods Cell Biolol. 2016. Vol. 134. P. 551–586. doi: 10.1016/bs.mcb.2016.02.005

[11] Gerlai R. Social behavior of zebrafish: from synthetic images to biological mechanisms of shoaling. J Neurosci Methods. 2014;234:59–65. doi: 10.1016/j.jneumeth.2014.04.028

[12] Gerlai R. Social behavior of zebrafish: from synthetic images to biological mechanisms of shoaling // J Neurosci Methods. 2014. Vol. 234. P. 59–65. doi: 10.1016/j.jneumeth.2014.04.028

[13] Jesuthasan S. Fear, anxiety, and control in the zebrafish. Dev Neurobiol. 2012;72(3):395–403. doi: 10.1002/dneu.20873

[14] Jesuthasan S. Fear, anxiety, and control in the zebrafish // Dev Neurobiol. 2012. Vol. 72, N 3. P. 395–403. doi: 10.1002/dneu.20873

[15] Filimonov DA, Lagunin AA, Gloriozova TA, et al. Prediction of the biological activity spectra of organic compounds using the PASS online web resource. Chem Heterocycl Compd. 2014;50:444–457. doi: 10.1007/s10593-014-1496-1

[16] Filimonov D.A., Lagunin A.A., Gloriozova T.A., et al. Prediction of the biological activity spectra of organic compounds using the PASS online web resource // Chem Heterocycl Compd. 2014. Vol. 50. P. 444–457. doi: 10.1007/s10593-014-1496-1

[17] Westerfield M. The zebrafish book: A guide for the laboratory use of zebrafish Danio (Brachydanio Rerio). 5th ed. University of Oregon, 2007.

[18] Stewart AM, Kalueff AV. The behavioral effects of acute Δ9-tetrahydrocannabinol and heroin (diacetylmorphine) exposure in adult zebrafish. Brain Res. 2014;1543:109–119. doi: 10.1016/j.brainres.2013.11.002

[19] Stewart A.M., Kalueff A.V. The behavioral effects of acute Δ9-tetrahydrocannabinol and heroin (diacetylmorphine) exposure in adult zebrafish // Brain Res. 2014. Vol. 1543. P. 109–119. doi: 10.1016/j.brainres.2013.11.002

[20] Goldsmith P. Zebrafish as a pharmacological tool: the how, why and when. Curr Opin Pharmacol. 2004;4(5):504–512. doi: 10.1016/j.coph.2004.04.005

[21] Goldsmith P. Zebrafish as a pharmacological tool: the how, why and when // Curr Opin Pharmacol. 2004. Vol. 4, N 5. P. 504–512. doi: 10.1016/j.coph.2004.04.005

[22] Kalueff AV, Gebhardt M, Stewart AM, et al. Towards a comprehensive catalog of zebrafish behavior 1.0 and beyond. Zebrafish. 2013;10(1):70–86. doi: 10.1089/zeb.2012.0861

[23] Kalueff A.V., Gebhardt M., Stewart A.M., et al. Towards a comprehensive catalog of zebrafish behavior 1.0 and beyond // Zebrafish. 2013. Vol. 10, N 1. P. 70–86. doi: 10.1089/zeb.2012.0861

[24] Stewart A, Wu N, Cachat J, et al. Pharmacological modulation of anxiety-like phenotypes in adult zebrafish behavioral models. Prog Neuro-Psychopharmacol Biol Psychiatry. 2011;35(6):1421–1431. doi: 10.1016/j.pnpbp.2010.11.035

[25] Stewart A., Wu N., Cachat J., et al. Pharmacological modulation of anxiety-like phenotypes in adult zebrafish behavioral models // Prog Neuro-Psychopharmacol Biol Psychiatry. 2011. Vol. 35, N 6. P. 1421–1431. doi: 10.1016/j.pnpbp.2010.11.035

[26] Douglas A. The dose-response relationship of morphine in a zebrafish (Danio rerio) model. University of Prince Edward Island, 2012.

[27] Volgin AD, Yakovlev OA, Demin KA, et al. Zebrafish models for personalized psychiatry: Insights from individual, strain and sex differences, and modeling gene x environment interactions. J Neurosci Res. 2019;97(4):402–413. doi: 10.1002/jnr.24337

[28] Volgin A.D., Yakovlev O.A., Demin K.A., et al. Zebrafish models for personalized psychiatry: Insights from individual, strain and sex differences, and modeling gene x environment interactions // J Neurosci Res. 2019. Vol. 97, N 4. P. 402–413. doi: 10.1002/jnr.24337

[29] Suzuki J, El-Haddad S. A review: fentanyl and non-pharmaceutical fentanyls. Drug And Alcohol Dependence. 2017;171:107–116. doi: 10.1016/j.drugalcdep.2016.11.033

[30] Suzuki J., El-Haddad S. A review: fentanyl and non-pharmaceutical fentanyls // Drug And Alcohol Dependence. 2017. Vol. 171. P. 107–116. doi: 10.1016/j.drugalcdep.2016.11.033

[31] Bachour R-L, Golovko O, Kellner M, Pohl J. Behavioral effects of citalopram, tramadol, and binary mixture in zebrafish (Danio rerio) larvae. Chemosphere. 2020;238:124587. doi: 10.1016/j.chemosphere.2019.124587

[32] Bachour R.-L., Golovko O., Kellner M., Pohl J. Behavioral effects of citalopram, tramadol, and binary mixture in zebrafish (Danio rerio) larvae // Chemosphere. 2020. Vol. 238. ID 124587. doi: 10.1016/j.chemosphere.2019.124587

[33] Stewart AM, Ullmann JF, Norton WHJ, et al. Molecular psychiatry of zebrafish. Mol Psychiatry. 2015;20(1):2–17. doi: 10.1038/mp.2014.128

[34] Stewart A.M., Ullmann J.F., Norton W.H.J., et al. Molecular psychiatry of zebrafish // Mol Psychiatry. 2015. Vol. 20, N 1. P. 2–17. doi: 10.1038/mp.2014.128

[35] Galstyan DS, Kolesnikova TO, Kositsyn YM, et al. Assessment of general locomotor activity and anxiety in zebrafish (Danio rerio) in the light-dark box (tank), the shoaling test, in the novel tank and the open field tests. Reviews on Clinical Pharmacology and Drug Therapy. 2022;20(2):123–133. EDN: AKINGC doi: 10.17816/RCF202123-133

[36] Галстян Д.С., Колесникова Т.О., Косицын Ю.М., и др. Оценка общей двигательной активности и тревожности зебраданио (Danio rerio) с использованием тестов незнакомого аквариума, открытого поля, черно-белого аквариума и построения косяка // Обзоры по клинической фармакологии и лекарственной терапии. 2022. Т. 20, № 2. С. 123–133. EDN: AKINGC doi: 10.17816/RCF202123-133

[37] Alzghari SK, Amin ZM, Chau S, et al. On the horizon: the synthetic opioid U-49900. Cureus. 2017;9(9):e1679. doi: 10.7759/cureus.1679

[38] Alzghari S.K., Amin Z.M., Chau S., et al. On the horizon: the synthetic opioid U-49900 // Cureus. 2017. Vol. 9, N 9. ID e1679. doi: 10.7759/cureus.1679

RIGHTS & PERMISSIONS

Eco-Vector