Investigation of the Inhibitory Effect of Naringin on the Development of Morphine Physical Dependency in Male Rats

Document Type : Original Article

Authors

1 Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran

2 Department of Biology, Faculty of Sciences, Shahid Bahonar University of Kerman, Kerman, Iran

3 Leishmaniasis Research Center, Kerman University of Medical Sciences, Kerman, Iran

10.34172/ahj.1543

Abstract

Background: Morphine dependence is a significant concern because of its potential for inducing addiction and adverse withdrawal symptoms. Naringin, a flavonoid compound found in citrus fruits, has shown promise in various pharmacological activities, including analgesic and anti-inflammatory effects. However, its potential role in inhibiting or reducing morphine dependence has not been extensively investigated yet. This study aimed to determine whether naringin can inhibit or reduce physical morphine dependence in rats.
Methods: Morphine dependence was induced in rats through chronic injection of the drug for 7 days. Also, different doses of naringin (10, 25, and 50 mg/kg) were administered 15 minutes prior to morphine injection in three experimental groups. The effect of naringin pretreatment on drug withdrawal-associated symptoms, including body weight, jumping, abdominal contraction, grooming, ptosis, diarrhea, and teeth chattering, was evaluated.
Finding: The animals experiencing morphine dependence exhibited significant body weight loss. However, administration of naringin before morphine injection prevented this loss by 50%. Also, drug withdrawal symptoms such as jumping, abdominal contraction, grooming, diarrhea, and teeth chattering were significantly increased in the rats. Interestingly, the prescription of naringin significantly reduced these symptoms. Ptosis was observed in all rats receiving morphine, while naringin did not significantly affect this symptom. Furthermore, the inhibitory effect of naringin on morphine physical dependence was found to be dose-dependent.
Conclusion: Naringin pretreatment demonstrated potential in inhibiting or reducing physical morphine dependence in rats. These findings suggest that naringin may have therapeutic potential in managing morphine dependence and associated withdrawal symptoms

Keywords


  1. Wang F, Meng J, Zhang L, Johnson T, Chen C, Roy S. Morphine induces changes in the gut microbiome and metabolome in a morphine dependence model. Sci Rep. 2018;8(1):3596. doi: 10.1038/s41598-018-21915-8.
  2. Khorrami S, Dogani M, Esmaeili Mahani S, Moosazadeh Moghaddam M, Taheri RA. Neuroprotective activity of green synthesized silver nanoparticles against methamphetamine-induced cell death in human neuroblastoma SH-SY5Y cells. Sci Rep. 2023;13(1):11867. doi: 10.1038/s41598-023-37917-0.
  3. Darvishzadeh-Mahani F, Esmaeili-Mahani S, Komeili G, Sheibani V, Zare L. Ginger (Zingiber officinale Roscoe) prevents the development of morphine analgesic tolerance and physical dependence in rats. J Ethnopharmacol. 2012;141(3):901-7. doi: 10.1016/j.jep.2012.03.030.
  4. Degenhardt L, Glantz M, Evans-Lacko S, Sadikova E, Sampson N, Thornicroft G, et al. Estimating treatment coverage for people with substance use disorders: an analysis of data from the World Mental Health Surveys. World Psychiatry. 2017;16(3):299-307. doi: 10.1002/wps.20457.
  5. Lefevre EM, Gauthier EA, Bystrom LL, Scheunemann J, Rothwell PE. Differential patterns of synaptic plasticity in the nucleus accumbens caused by continuous and interrupted morphine exposure. J Neurosci. 2023;43(2):308-18. doi: 10.1523/jneurosci.0595-22.2022.
  6. Koob GF, Volkow ND. Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry. 2016;3(8):760-73. doi: 10.1016/s2215-0366(16)00104-8.
  7. Zhang JJ, Song CG, Wang M, Zhang GQ, Wang B, Chen X, et al. Monoclonal antibody targeting mu-opioid receptor attenuates morphine tolerance via enhancing morphine-induced receptor endocytosis. J Pharm Anal. 2023;13(10):1135-52. doi: 10.1016/j.jpha.2023.06.008.
  8. Motallebi M, Bhia M, Rajani HF, Bhia I, Tabarraei H, Mohammadkhani N, et al. Naringenin: a potential flavonoid phytochemical for cancer therapy. Life Sci. 2022;305:120752. doi: 10.1016/j.lfs.2022.120752.
  9. Rivoira MA, Rodriguez V, Talamoni G, Tolosa de Talamoni N. New perspectives in the pharmacological potential of naringin in medicine. Curr Med Chem. 2021;28(10):1987-2007. doi: 10.2174/0929867327666200604171351.
  10. Han G, Lee DG. Naringin generates three types of reactive oxygen species contributing differently to apoptosis-like death in Escherichia coli. Life Sci. 2022;304:120700. doi: 10.1016/j. lfs.2022.120700.
  11. Salehi B, Fokou PVT, Sharifi-Rad M, Zucca P, Pezzani R, Martins N, et al. The therapeutic potential of naringenin: a review of clinical trials. Pharmaceuticals (Basel). 2019;12(1):11. doi: 10.3390/ph12010011.
  12. Bhia M, Motallebi M, Abadi B, Zarepour A, Pereira-Silva M, Saremnejad F, et al. Naringenin nano-delivery systems and their therapeutic applications. Pharmaceutics. 2021;13(2):291. doi: 10.3390/pharmaceutics13020291.
  13. Heidary Moghaddam R, Samimi Z, Moradi SZ, Little PJ, Xu S, Farzaei MH. Naringenin and naringin in cardiovascular disease prevention: a preclinical review. Eur J Pharmacol. 2020;887:173535. doi: 10.1016/j.ejphar.2020.173535.
  14. Smith MA, Armas SP, Schmidt KT. Modulation of morphine physical dependence and discriminative stimulus effects by ovarian hormones: role of estradiol. Pharmacol Biochem Behav. 2022;218:173431. doi: 10.1016/j.pbb.2022.173431.
  15. Fattahi M, Ashabi G, Karimian SM, Riahi E. Preventing morphine reinforcement with high-frequency deep brain stimulation of the lateral hypothalamic area. Addict Biol. 2019;24(4):685-95. doi: 10.1111/adb.12634.
  16. Rueda-Ruzafa L, Cruz F, Cardona D, Hone AJ, Molina-Torres G, Sánchez-Labraca N, et al. Opioid system influences gut-brain axis: dysbiosis and related alterations. Pharmacol Res. 2020;159:104928. doi: 10.1016/j.phrs.2020.104928.
  17. Kang M, Mischel RA, Bhave S, Komla E, Cho A, Huang C, et al. The effect of gut microbiome on tolerance to morphine mediated antinociception in mice. Sci Rep. 2017;7:42658. doi: 10.1038/srep42658.
  18. López-Almada G, Domínguez-Avila JA, Mejía-León ME, Robles-Sánchez M, González-Aguilar GA, Salazar-López NJ. Could naringenin participate as a regulator of obesity and satiety? Molecules. 2023;28(3):1450. doi: 10.3390/ molecules28031450.
  19. Rufino AT, Costa VM, Carvalho F, Fernandes E. Flavonoids as antiobesity agents: a review. Med Res Rev. 2021;41(1):556- 85. doi: 10.1002/med.21740.
  20. Raasmaja A, Lecklin A, Li XM, Zou J, Zhu GG, Laakso I, et al. A water-alcohol extract of Citrus grandis whole fruits has beneficial metabolic effects in the obese Zucker rats fed with high fat/high cholesterol diet. Food Chem. 2013;138(2- 3):1392-9. doi: 10.1016/j.foodchem.2012.09.140.
  21. Park M, Kim K, Lee YM, Rhyu MR, Kim HY. Naringenin stimulates cholecystokinin secretion in STC-1 cells. Nutr Res Pract. 2014;8(2):146-50. doi: 10.4162/nrp.2014.8.2.146.
  22. Esmaeili-Mahani S, Fathi Y, Motamedi F, Hosseinpanah F, Ahmadiani A. L-type calcium channel blockade attenuates morphine withdrawal: in vivo interaction between L-type calcium channels and corticosterone. Horm Behav. 2008;53(2):351-7. doi: 10.1016/j.yhbeh.2007.10.012.
  23. Rock EM, Ayoub SM, Limebeer CL, Gene A, Wills KL, DeVuono MV, et al. Acute naloxone-precipitated morphine withdrawal elicits nausea-like somatic behaviors in rats in a manner suppressed by N-oleoylglycine. Psychopharmacology (Berl). 2020;237(2):375-84. doi: 10.1007/s00213-019-05373- 2.
  24. Chtourou Y, Aouey B, Aroui S, Kebieche M, Fetoui H. Anti-apoptotic and anti-inflammatory effects of naringin on cisplatin-induced renal injury in the rat. Chem Biol Interact. 2016;243:1-9. doi: 10.1016/j.cbi.2015.11.019.
  25. Cavia-Saiz M, Busto MD, Pilar-Izquierdo MC, Ortega N, Perez-Mateos M, Muñiz P. Antioxidant properties, radical scavenging activity and biomolecule protection capacity of flavonoid naringenin and its glycoside naringin: a comparative study. J Sci Food Agric. 2010;90(7):1238-44. doi: 10.1002/ jsfa.3959.
  26. Khorrami S, Zarepour A, Zarrabi A. Green synthesis of silver nanoparticles at low temperature in a fast pace with unique DPPH radical scavenging and selective cytotoxicity against MCF-7 and BT-20 tumor cell lines. Biotechnol Rep (Amst). 2019;24:e00393. doi: 10.1016/j.btre.2019.e00393.
  27. Song P, Zhang R, Wang X, He P, Tan L, Ma X. Dietary grape-seed procyanidins decreased postweaning diarrhea by modulating intestinal permeability and suppressing oxidative stress in rats. J Agric Food Chem. 2011;59(11):6227-32. doi: 10.1021/jf200120y.
  28. Lauridsen C. From oxidative stress to inflammation: redox balance and immune system. Poult Sci. 2019;98(10):4240-6. doi: 10.3382/ps/pey407.
  29. Yang Z, Pan A, Zuo W, Guo J, Zhou W. Relaxant effect of flavonoid naringenin on contractile activity of rat colonic smooth muscle. J Ethnopharmacol. 2014;155(2):1177-83. doi: 10.1016/j.jep.2014.06.053.
  30. Shi R, Xu JW, Xiao ZT, Chen RF, Zhang YL, Lin JB, et al. Naringin and naringenin relax rat tracheal smooth by regulating BK(Ca) activation. J Med Food. 2019;22(9):963-70. doi: 10.1089/jmf.2018.4364.
  31. Kim HJ, Kim BJ. Naringenin inhibits pacemaking activity in interstitial cells of Cajal from murine small intestine. Integr Med Res. 2017;6(2):149-55. doi: 10.1016/j.imr.2017.02.001.
  32. Sadraei H, Ghasemi M, Saranji S. Evaluation of spasmolytic effects of naringenin on ileum contraction and intestinal charcoal meal transit: involvement of ATP-sensitive K + channels. J Herbmed Pharmacol. 2022;11(2):262-8. doi: 10.34172/jhp.2022.31.
  33. Greenwood-Van Meerveld B, Johnson AC, Grundy D. Gastrointestinal physiology and function. Handb Exp Pharmacol. 2017;239:1-16. doi: 10.1007/164_2016_118.
  34. Pereira da Silva EA, Martín-Aragón Baudel M, Navedo MF, Nieves-Cintrón M. Ion channel molecular complexes in vascular smooth muscle. Front Physiol. 2022;13:999369. doi: 10.3389/fphys.2022.999369.
  35. Thorneloe KS, Nelson MT. Ion channels in smooth muscle: regulators of intracellular calcium and contractility. Can J Physiol Pharmacol. 2005;83(3):215-42. doi: 10.1139/y05- 016.
  36. Manchope MF, Ferraz CR, Borghi SM, Rasquel-Oliveira FS, Franciosi A, Bagatim-Souza J, et al. Therapeutic role of naringenin to alleviate inflammatory pain. In: Rajendram R, Patel VB, Preedy VR, Martin CR, eds. Treatments, Mechanisms, and Adverse Reactions of Anesthetics and Analgesics. Academic Press; 2022. p. 443-55. doi: 10.1016/ b978-0-12-820237-1.00038-7.
  37. Liu P, Chu Z, Lei G, Deng LS, Yang L, Dang YH. The role of HINT1 protein in morphine addiction: an animal model-based study. Addict Biol. 2021;26(2):e12897. doi: 10.1111/ adb.12897.
  38. Ramesh D, Ross GR, Schlosburg JE, Owens RA, Abdullah RA, Kinsey SG, et al. Blockade of endocannabinoid hydrolytic enzymes attenuates precipitated opioid withdrawal symptoms in mice. J Pharmacol Exp Ther. 2011;339(1):173-85. doi: 10.1124/jpet.111.181370.
  39. Abbasi Maleki N, Abbasi Maleki S, Bekhradi R. Suppressive effects of Rosa damascena essential oil on naloxone-precipitated morphine withdrawal signs in male mice. Iran J Pharm Res. 2013;12(3):357-61.
  40. Listos J, Łupina M, Talarek S, Mazur A, Orzelska-Górka J, Kotlińska J. The mechanisms involved in morphine addiction: an overview. Int J Mol Sci. 2019;20(17):4302. doi: 10.3390/ ijms20174302.
  41. Okur ME, Köksal Karayıldırım Ç. Central possible antinociceptive mechanism of naringin. Istanbul J Pharm. 2021;51(2):204-11.
  42. Shen CL, Castro L, Fang CY, Castro M, Sherali S, White S, et al. Bioactive compounds for neuropathic pain: an update on preclinical studies and future perspectives. J Nutr Biochem. 2022;104:108979. doi: 10.1016/j.jnutbio.2022.108979.
  43. Joseph MH, Datla K, Young AM. The interpretation of the measurement of nucleus accumbens dopamine by in vivo dialysis: the kick, the craving or the cognition? Neurosci Biobehav Rev. 2003;27(6):527-41. doi: 10.1016/j. neubiorev.2003.09.001.
  44. Volkow ND, Michaelides M, Baler R. The neuroscience of drug reward and addiction. Physiol Rev. 2019;99(4):2115-40. doi: 10.1152/physrev.00014.2018.
  45. Torkzadeh-Mahani S, Nasri S, Esmaeili-Mahani S. Ginger (Zingiber officinale Roscoe) prevents morphine-induced addictive behaviors in conditioned place preference test in rats.