Skip to main content
Log in

Ajoene restored behavioral patterns and liver glutathione level in morphine treated C57BL6 mice

  • Research Article
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

Oxidative stress exacerbates drug dependence induced by administration of opiate analgesics such as morphine-induced tolerance and physical dependence associated with the reduction in hepatic glutathione (GSH) level. Ajoene obtained from garlic (Allium sativum L.) has been reported for anti-tumorigenic, anti-oxidative and neuroprotective properties, however, little is known about its effect on morphine-induced dependence. Therefore, this study aimed at the effect of ajoene on physical and/or psychological dependence and liver GSH content in morphine-treated mice. Conditioned place preference (CPP) test and measurement of morphine withdrawal syndrome were performed in C57BL6 mice for behavioral experiments. Thereafter, mice were sacrificed for measurement of serum and liver GSH levels. Ajoene restored CPP and naloxone-precipitated jumping behavior in mice exposed to morphine. Moreover, the reduced level of liver GSH content in morphine treated mice was back to normal after ajoene administration. Taken together, ajoene improved behavioral patterns in mice exposed to morphine suggesting its potential therapeutic benefit against morphine-induced dependence.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Abdel-Zaher AO, Mostafa MG, Farghaly HS, Hamdy MM, Abdel-Hady RH (2013) Role of oxidative stress and inducible nitric oxide synthase in morphine-induced tolerance and dependence in mice. Effect of alpha-lipoic acid. Behav Brain Res 247:17–26

    Article  CAS  PubMed  Google Scholar 

  • Benavides M, Laorden ML, Marin MT, Milanes MV (2005) Role of PKC-alpha, gamma isoforms in regulation of c-Fos and TH expression after naloxone-induced morphine withdrawal in the hypothalamic PVN and medulla oblongata catecholaminergic cell groups. J Neurochem 95:1249–1258

    Article  CAS  PubMed  Google Scholar 

  • Berland D, Rodgers P (2012) Rational use of opioids for management of chronic nonterminal pain. Am Fam Physician 86:252–258

    PubMed  Google Scholar 

  • Che Y, Cui YH, Tan H, Andreazza AC, Young LT, Wang JF (2013) Abstinence from repeated amphetamine treatment induces depressive-like behaviors and oxidative damage in rat brain. Psychopharmacology 227:605–614

    Article  CAS  PubMed  Google Scholar 

  • Dirsch VM, Kiemer AK, Wagner H, Vollmar AM (1998) Effect of allicin and ajoene, two compounds of garlic, on inducible nitric oxide synthase. Atherosclerosis 139:333–339

    Article  CAS  PubMed  Google Scholar 

  • Doyle T, Bryant L, Batinic-Haberle I, Little J, Cuzzocrea S, Masini E, Spasojevic I, Salvemini D (2009) Supraspinal inactivation of mitochondrial superoxide dismutase is a source of peroxynitrite in the development of morphine antinociceptive tolerance. Neuroscience 164:702–710

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Galbes O, Bourret A, Nouette-Gaulain K, Pillard F, Matecki S, Py G, Mercier J, Capdevila X, Philips A (2010) N-acetylcysteine protects against bupivacaine-induced myotoxicity caused by oxidative and sarcoplasmic reticulum stress in human skeletal myotubes. Anesthesiology 113:560–569

    CAS  PubMed  Google Scholar 

  • Gallwitz H, Bonse S, Martinez-Cruz A, Schlichting I, Schumacher K, Krauth-Siegel RL (1999) Ajoene is an inhibitor and subversive substrate of human glutathione reductase and Trypanosoma cruzi trypanothione reductase: crystallographic, kinetic, and spectroscopic studies. J Med Chem 42:364–372

    Article  CAS  PubMed  Google Scholar 

  • Gunduz O, Karadag CH, Ulugol A (2010) Modulatory role of the endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine (ADMA), in morphine tolerance and dependence in mice. J Neural Transm 117:1027–1032

    Article  CAS  PubMed  Google Scholar 

  • Gutowicz M, Kazmierczak B, Baranczyk-Kuzma A (2011) The influence of heroin abuse on glutathione-dependent enzymes in human brain. Drug Alcohol Depend 113:8–12

    Article  CAS  PubMed  Google Scholar 

  • Han CY, Ki SH, Kim YW, Noh K, Da Lee Y, Kang B, Ryu JH, Jeon R, Kim EH, Hwang SJ, Kim SG (2011) Ajoene, a stable garlic by-product, inhibits high fat diet-induced hepatic steatosis and oxidative injury through LKB1-dependent AMPK activation. Antioxid Redox Signal 14:187–202

    Article  CAS  PubMed  Google Scholar 

  • Hosztafi S (2011) Heroin addiction. Acta Pharm Hung 81:173–183

    PubMed  Google Scholar 

  • Ibi M, Matsuno K, Matsumoto M, Sasaki M, Nakagawa T, Katsuyama M, Iwata K, Zhang J, Kaneko S, Yabe-Nishimura C (2011) Involvement of NOX1/NADPH oxidase in morphine-induced analgesia and tolerance. J Neurosci 31:18094–18103

    Article  CAS  PubMed  Google Scholar 

  • Jung JC, Oh S (2011) Practical synthesis of hydroxychromenes and evaluation of their biological activity. Molecules 17:240–247

    Article  PubMed  Google Scholar 

  • Kay HY, Won Yang J, Kim TH, Da Lee Y, Kang B, Ryu JH, Jeon R, Kim SG (2010) Ajoene, a stable garlic by-product, has an antioxidant effect through Nrf2-mediated glutamate-cysteine ligase induction in HepG2 cells and primary hepatocytes. J Nutr 140:1211–1219

    Article  CAS  PubMed  Google Scholar 

  • Kim HS, Jang CG, Lee MK (1990) Antinarcotic effects of the standardized ginseng extract G115 on morphine. Planta Med 56:158–163

    Article  CAS  PubMed  Google Scholar 

  • Kim HC, Shin EJ, Jang CG, Lee MK, Eun JS, Hong JT, Oh KW (2005) Pharmacological action of Panax ginseng on the behavioral toxicities induced by psychotropic agents. Arch Pharm Res 28:995–1001

    Article  CAS  PubMed  Google Scholar 

  • Kovatsi L, Njau S, Nikolaou K, Topouridou K, Papamitsou T, Koliakos G (2010) Evaluation of prooxidant–antioxidant balance in chronic heroin users in a single assay: an identification criterion for antioxidant supplementation. Am J Drug Alcohol Abuse 36:228–232

    Article  PubMed  Google Scholar 

  • Oh KW, Eun JS, Kwon HN, Cho EY, Kim KM (2007) Effects of (−)-epigallocatechin gallate on the development of morphine-induced physical dependence. Arch Pharm Res 30:1111–1115

    Article  CAS  PubMed  Google Scholar 

  • Patel K, Bhaskaran M, Dani D, Reddy K, Singhal PC (2003) Role of heme oxygenase-1 in morphine-modulated apoptosis and migration of macrophages. J Infect Dis 187:47–54

    Article  CAS  PubMed  Google Scholar 

  • Payabvash S, Beheshtian A, Salmasi AH, Kiumehr S, Ghahremani MH, Tavangar SM, Sabzevari O, Dehpour AR (2006) Chronic morphine treatment induces oxidant and apoptotic damage in the mice liver. Life Sci 79:972–980

    Article  CAS  PubMed  Google Scholar 

  • Romero A, Hernandez L, Garcia-Nogales P, Puig MM (2010) Deletion of the inducible nitric oxide synthase gene reduces peripheral morphine tolerance in a mouse model of chronic inflammation. Fundam Clin Pharmacol 24:317–323

    Article  CAS  PubMed  Google Scholar 

  • Rozisky JR, Laste G, De Macedo IC, Santos VS, Krolow R, Noschang C, Vanzella C, Bertoldi K, Lovatel GA, De Souza IC, Siqueira IR, Dalmaz C, Caumo W, Torres IL (2013) Neonatal morphine administration leads to changes in hippocampal BDNF levels and antioxidant enzyme activity in the adult life of rats. Neurochem Res 38:494–503

    Article  CAS  PubMed  Google Scholar 

  • Skrabalova J, Drastichova Z, Novotny J (2013) Morphine as a potential oxidative stress-causing agent. Mini Rev Org Chem 10:367–372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Song Z, Zou W, Liu C, Guo Q (2010) Gene knockdown with lentiviral vector-mediated intrathecal RNA interference of protein kinase C gamma reverses chronic morphine tolerance in rats. J Gene Med 12:873–880

    Article  CAS  PubMed  Google Scholar 

  • Todaka T, Ishida T, Kita H, Narimatsu S, Yamano S (2005) Bioactivation of morphine in human liver: isolation and identification of morphinone, a toxic metabolite. Biol Pharm Bull 28:1275–1280

    Article  CAS  PubMed  Google Scholar 

  • Toki S, Yamano S (1999) Production of morphinone as a metabolite of morphine and its physiological role. Yakugaku Zasshi 119:249–267

    CAS  PubMed  Google Scholar 

  • Trescot AM (2010) Review of the role of opioids in cancer pain. J Natl Compr Cancer Netw 8:1087–1094

    CAS  Google Scholar 

  • Yamano S, Takahashi A, Todaka T, Toki S (1997) In vivo and in vitro formation of morphinone from morphine in rat. Xenobiotica 27:645–656

    Article  CAS  PubMed  Google Scholar 

  • Yun J, Lee Y, Yun K, Oh S (2015) Bergenin decreases the morphine-induced physical dependence via antioxidative activity in mice. Arch Pharm Res 38:1248–1254

    Article  CAS  PubMed  Google Scholar 

  • Zhang YT, Zheng QS, Pan J, Zheng RL (2004) Oxidative damage of biomolecules in mouse liver induced by morphine and protected by antioxidants. Basic Clin Pharmacol Toxicol 95:53–58

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This research was supported by the National Research Foundation of Korea (NRF) Grant funded by the Ministry of Science, ICT and Future Planning (SO, MRC, 2010-0029355; JR, 2011-0030074) and Ministry of Food and Drug Safety Grant (14182MFDS979).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Seikwan Oh.

Ethics declarations

Conflict of interest

No conflict to disclose.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (TIFF 271 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yun, J., Oliynyk, S., Lee, Y. et al. Ajoene restored behavioral patterns and liver glutathione level in morphine treated C57BL6 mice. Arch. Pharm. Res. 40, 106–111 (2017). https://doi.org/10.1007/s12272-016-0773-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12272-016-0773-1

Keywords

Navigation