Potentiating Effect of Methylmorphine on Flunitrazepam-induced Cholesterogenesis in Brain: A rat Model

Authors

  • Esther Abam Biochemistry Unit, Chemical and Food Sciences, Bells University of Technology, Ota Author

Keywords:

Methylmorphine, flunitrazepam, ATPases, hyperbilirubinemia, hypercholesterolemia, cholesterogenesis

Abstract

Methylmorphine (codeine) and flunitrazepam (rohypnol) are central nervous system depressants and common drugs of abuse among youths, despite the restriction in production and distribution placed on these drugs in Nigeria. The aim of this study is to assess the toxic effects of combined abuse of these drugs. Thirty-five (35) male Wistar rats were divided into five (5) groups of seven animals each. Group 1 served as control and was administered distilled water only, groups 2 and 3 received a daily dose of 3.25mg kg-1 bw of codeine and 0.03mg kg-1 bw rohypnol respectively. Groups 4 and 5 both received combined doses of 3.25mg kg-1 bw of codeine and 0.03mg kg-1 bw of codeine and 0.03mg kg-1bw of rohypnol daily. All groups were exposed for 28days except group 5 which was sacrificed after one week of withdrawal of treatments (day 35). At the end of the exposure, some liver and brain function biomarkers were studied spectrophotometrically. Exposure to either codeine or rohypnol resulted in significantly reduced (p<0.05) plasma creatinine levels, and reduced activities of Ca2+-Mg2+- and total ATPases in the brain. Hyperbilirubinemia, hypercholesterolemia, elevated plasma and liver transaminases and a 5-fold increase in brain cholesterol were observed as a result of combined exposure to both toxicants. Interaction between codeine and rohypnol was mostly additive and synergistic in the biomarkers studied with a potentiating effect of codeine on rohypnol with regards to brain cholesterol. The enhanced psychoactivity produced in co-abuse of both drugs may be mediated by enhanced cholesterogenesis in the brain.

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References

Abam, E. O., Kuyooro, S. E., Shawai, A. and Dim, E. C. (2021). Hepatotoxic and neurotoxic effects of combined lead and di-(2- ethylhexyl) phthalate exposure: Activation of total -, Ca2+ - and Na+ K+ - ATPases in the liver of male rats. Journal of Toxicological and Environmental Health Science, 13(1), 18-27.

Achukwu, P. U., Omorodion, N. T., Tosan, E., Aloh, H. E., Charles, E. and Okoyeocha, O. M. E. (2019). Codeine and its histopathological effect on brain of albino rats: An experimental study. Acta Scientific Nutritional Health, 3 (2), 125-133.

Ademuyiwa, O., Agarwal, R., Chandra, R., Behari, J. R. (2009). Lead-induced phospholipidosis and cholesterogenesis in rat tissues. Chemico--Biological Interactions, 179, 314-320.

Afolabi, O. K., Ugbaja, R. N. and Ademuyiwa, O. (2016). Combined arsenic and di-(2-ethylhexyl) phthalate exposure elicits responses in brain ATPases different from hepatic and renal activities in rats. Journal of Toxicological and Environmental Health Sciences, 8(2), 6-14.

Ator, N. A. and Griffiths, R. R. (1987). Self-administration of barbiturates and benzodiazepines: A review. Pharmacology Biochemistry and Behavior, 27(2), 391–398.

BBC News (2018). “Nigeria bans cough syrup with codeine after addiction outcry”. Retrieved from https://www.bbc.com/news/world-africa-43961738.

Carson-DeWitt, R., Carrol, K. M., Fagan, J., Kranzler, H. R. and Kuhar, M. J. (2001). Encyclopedia of Drugs, Alcohol and Addictive Behavior, 1, A-D. January 1, 2001.

Comer, S. D., Sullivan, M. A., Whittington, R.A, Vosburg, S. K. and Kowalczyk, W. J. (2008). Abuse liability of prescription opioids compared to heroin in morphine-maintained heroin abusers. Neuropsychopharmacology, 33, 1179–1191.

Dietschy, J. M. (2009). Central nervous system: cholesterol turnover, brain development and neurodegeneration. Biological Chemistry, 390(4), 287–293.

Druid, H., Holmgren, P. and Ahlner, J. (2001). Flunitrazepam: an evaluation of use, abuse and toxicity. Forensic Science International, 122(2-3), 136-141.

Evans, D. J. (1969). Membrane adenosine triphosphatase of Escherichia coli: activation by calcium ions and inhibition by monovalent cations. Journal of Bacteriology, 100, 914-922.

Folch, M., Lees, M. and Stanley, G. H. (1957). A simple method for the isolation and purification of total lipids from animal tissues. Journal of Biological Chemistry, 226, 497-509.

Giboney, P. (2005). Mildly elevated liver transaminase levels in the asymptomatic patient. American Family Physician, 71(6), 1105-1110.

Habeck, M., Haviv, H., Katz, A., Kapri-Pardes, E. and Ayciriex, S. (2015). Stimulation, Inhibition, or Stabilization of Na,K-ATPase. The Journal of Biological Chemisty, 290(8), 4829–4842.

Haney. M. and Spealman, R. (2008). Controversies in translational research: drug self-administration. Psychopharmacology (Berl), 199, 403–419.

Hesketh, J. E., Loudon, J. B., Reading, H. W. and Glen, I. M. (1978). The effect of lithium treatment on erythrocyte membrane ATPase activities and erythrocyte ion content. British Journal of Clinical Pharmacology, 5(4), 323-329.

Hitchings, A., Lonsdale, D., Burrage, D. and Baker, E. (2015). Top 100 drugs: Clinical pharmacology and practical prescribing. 1st edition. Churchill Livingstone (Ed). p. 168.

Hjerten, S. and Pan, H. (1983). Purification and characterization of two forms of a low-affinity Ca2+-ATPase from erythrocyte membrane. Biochimica et Biophysica Acta, 728, 281-288.

Hussaini, S. H., O'Brien, C. S., Despott, E. J. and Dalton, H. R. (2007). Antibiotic therapy: a major cause of drug-induced jaundice in southwest England. European Journal of Gastroenterology and Hepatology, 19(1), 15-20.

Jones, D. J., Mogali, S. and Comer, S. D. (2012). Polydrug abuse: A review of opioid and benzodiazepine combination use. Drug and Alcohol Dependence, 125(1-2), 8–18.

Kathiramalainathan, K., Kaplan, H. L., Romach, M. K., Busto, U. E., Li, N. Y., Säwe, J., Tyndale, R. F. and Sellers, E. M. (2000). Inhibition of cytochrome P450 2D6 modifies codeine abuse liability. Journal of Clinical Psychopharmacology. 20 (4), 435–44.,

Kieffer, B. L. and Gavériaux-Ruff, C. (2002). Exploring the opioid system by gene knockout. Progress in Neurobiology, 66, 285–306.

Lars Bastiaanse, E. M., Höld, K. M., and Van der Laarse, A. (1997). The effect of membrane cholesterol content on ion transport processes in plasma membranes. Cardiovascular Research, 33(2), 272–283.

Lloyd, J. (2003). Rohypnol. Executive Office of the President. Office of National Drug Control Policy (ONDCP): Drug Policy Information Clearinghouse Factsheet: Washington, DC. Retrieved from https://popcenter.asu.edu/sites/default/files/problems/rape/PDFs/rohypnol.pdf

Lodish, H., Berk, A. and Zipursky, S. L. (2000). Active Transport by ATP-Powered Pumps In: Molecular cell Biology, 4th edition..W. H. Freeman, ed. New York: 2000. Section 15.5, Available from: https://www.ncbi.nlm.nih.gov/books/NBK21481/

Lowry, O. H., Rosbrough, N. J., Farr, A. L. and Randall, R. J. (1951). Journal of Biological Chemistry, 193, 265.

Mandrioli, R., Mercolini, L. and Raggi, M. A. (2008). Benzodiazepine metabolism: An Analytical perspective. Current Drug Metabolism, 9(8), 827-844(18).

Matthes, H. W., Maldonado, R., Simonin, F., Valverde, O. and Slowe, S. (1996). Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the mu-opioid-receptor gene. Nature, 383, 819–823.

Mehta, N., Ozick, L. A. and Gbadehan, E. (2019). Drug-induced hepatotoxicity. Medscape. Retrieved from https://emedicine.medscape.com/article/169814-overview.

Mizuno, K., Katoh, M., Okumura, K. Nakagawa, N. and Negishi, T. (2009). Metabolic activation of benzodiazepines by CYP3A4. Drug Metabolism and Disposition, 37 (2), 345-351.

NAFDAC (2018). “Codeine Syrup Crisis: NAFDAC Shuts Down Peace Standard Pharmaceutical Limited, Bioraj Pharmaceutical Limited, Both In Ilorin, And Emzor Pharmaceuticals Ind. Ltd, Lagos. Retrieved from https://www.nafdac.gov.ng/codeine-syrup-crisis-nafdac-shuts-down-peace-standard-pharmaceutical-limited-bioraj-pharmaceutical-limited-both-in-ilorin-and-emzor-pharmaceuticals-ind-ltd-lagos/

NNEUROtiker, (2007). Chemical Structure of codeine. Retrieved from https://en.wikipedia.org/wiki/File:Codein-Codeine.svg

Ohnishi, T., Suzuki, T., Suzuki, Y., Ozawa, K. (1982). A comparative study of plasma membrane Mg2+- ATPase activities in normal, regenerating and malignant cells. Biochemica Biophysica Acta, 684, 67-74.

Olaniyan, M. F., Ozuruoke, D. F. N., Fapohunda, J. S and Afolabi, T. (2017). Immunological effect of tramadol, codeine, flunitrazepam on plasma cortisol (anti-inflammatory agent), cortisol binding globulin (acute phase protein) and total bile acid in rabbits. Journal of Advances in Medicine and Medical Research, 23(4), 1-8.

Ostapowicz, G., Fontana, R. J., Schiødt, F. V., Larson, A. and Davern, T. J. (2002). U.S. Acute Liver Failure Study Group; Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Annals of Internal Medicine, 137(12), 947.

Ostermann, M., Kashani, K., Forni, L. G. (2016). The two sides of creatinine: both as bad as each other? Journal of Thoracic Disease, 8(7), E628-E630.

Papich, M. G. (2016). "Codeine". Saunders Handbook of Veterinary Drugs (4th Edition). W.B. Saunders: pp 183–184.

Petrov, A. M., Kasimov, M. R. and Zefirov, A. L. (2016). Brain cholesterol metabolism and its defects: Linkage to neurodegenerative diseases and synaptic dysfunction. Acta Naturae, 8(1), 58–73.

Rosenbaum, J. F. (2005). Attitudes toward benzodiazepines over the years. Journal of Clinical Psychiatry, 66:4–8.

Ross, J. and Darke, S. (2000). The nature of benzodiazepine dependence among heroin users in Sydney. Australia Addiction, 95, 1785–1793.

Russel, D. W., Halford, R. W., Ramirez, D. M. O., Shah, R. and Kotti, T. (2009). Cholesterol 24-Hydroxylase: An Enzyme of Cholesterol Turnover in the Brain. Annual Review of Biochemistry, 78, 1017-1040.

Smith, K. M., Larive, L. L. and Romanelli, F. (2002). Club drugs: methylenedioxymethamphetamine, flunitrazepam, ketamine hydrochloride, and gamma-hydroxybutyrate. American Journal of Health Systems Pharmocology, 59, 1067–1076.

Stefano, G. B., Ptáček R, Kuželová H, and Kream R. M. (2012). "Endogenous morphine: up-to-date review 2011". Folia Biologica (Praha), 58 (2), 49–56/

Strang, J., Griffiths, P., Abbey, J. and Gossop, M. (1994). Survey of use of injected benzodiazepines among drug users in Britain. British Medical Journal, 308:1082.

Substance Abuse and Mental Health Services Administration (SAMHSA) (2011a) The DAWN Report: Drug-Related Emergency Department Visits Attributed to Intentional Poisoning. Center for Behavioral Health Quality and Statistics; Rockville, MD. Retrieved from http://dawninfo.samhsa.gov/.

Substance Abuse and Mental Health Services Administration (SAMHSA) (2011b) The TEDS Report: Substance Abuse Treatment Admissions for Abuse of Benzodiazepines. Center for Behavioral Health Statistics and Quality; Rockville, MD. Retrieved from http://dawninfo.samhsa.gov/

Tori, M. E., Larochelle, M. R. and Naimi, T. S. (2020). Alcohol or benzodiazepine co-involvement with opioid overdose deaths in the United States, 1999-2017. Journal of the American Medical Association Network Open, 3(4), e202361.

Trigo, J. M., Martin-García, E., Berrendero, F., Robledo, P. and Maldonado, R. (2010). The endogenous opioid system: a common substrate in drug addiction. Drug and Alcohol Dependence, 108,183–194.

Vaccinationist (2013). Chemical Structure of Flunitrazepam. Retrievedfromhttps://en.wikipedia.org/wiki/File:Flunitrazepam_structure.svg

Wisniak, J. (2013). Pierre-jean robiquet. Educación Química, 24, 139-149.

Xu, J. J., Diaz, D., O'Brien, P. J. (2004). Applications of cytotoxicity assays and pre-lethal mechanistic assays for assessment of human hepatotoxicity potential. Chemico-Biological Interactions, 150(1), 115.

Published

2022-07-01

How to Cite

Potentiating Effect of Methylmorphine on Flunitrazepam-induced Cholesterogenesis in Brain: A rat Model. (2022). Nigerian Journal of Biochemistry and Molecular Biology, 37(2), 111-121. https://www.nsbmb.org.ng/journals/index.php/njbmb/article/view/10