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Chronic morphine drinking establishes morphine tolerance, but not addiction in Wistar rats

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Abstract

Objective

Some animal models apply morphine in the drinking water to generate addiction, but related reports are not free of conflicting results. Accordingly, this study aimed to figure out if chronic consumption of morphine in the drinking water can induce morphine addiction in Wistar rats.

Methods

For 3 weeks, the animals received a daily morphine dose of 35 mg/kg by offering a calculated volume of sugar water (5% sucrose) with morphine (0.1 mg/ml) to each rat; animals receiving just sugar water served as controls. Immediately after the treatment phase, the tail immersion test was used to check for morphine tolerance, and all animals were then kept on tap water for one week (withdrawal phase). Afterwards, all rats were allowed to choose their drinking source by offering two bottles, containing sugar water without and with morphine, simultaneously for two days (preference phase).

Results

While the chronic consumption of morphine led to a reduction in body weight and to morphine tolerance, the morphine-treated Wistar rats did not show any preference for the opiate-containing sugar water.

Conclusion

Body weight loss and tolerance do not reveal a condition of drug craving, and current animal models should be re-evaluated regarding their potential to establish morphine addicted animals.

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References

  • Ammon-Treiber, S., Hollt, V., 2005. Morphine-induced changes of gene expression in the brain. Addict. Biol., 10(1):81–89. [doi:10.1080/13556210412331308994]

    Article  PubMed  CAS  Google Scholar 

  • Badawy, A.A., Evans, C.M., Evans, M., 1982. Production of tolerance and physical dependence in the rat by simple administration of morphine in drinking water. Br. J. Pharmacol., 75:485–491.

    PubMed  CAS  Google Scholar 

  • Bailey, C.P., Connor, M., 2005. Opioids: cellular mechanisms of tolerance and physical dependence. Curr. Opin. Pharmacol., 5(1):60–68. [doi:10.1016/j.coph.2004.08.012]

    Article  PubMed  CAS  Google Scholar 

  • Borg, P.J., Taylor, D.A., 1994. Voluntary oral morphine self-administration in rats: effects of haloperidol or ondansetron. Pharmacol. Biochem. Behav., 47(3):633–646. [doi:10.1016/0091-3057(94)90169-4]

    Article  PubMed  CAS  Google Scholar 

  • Cami, J., Farre, M., 2003. Drug addiction. N. Engl. J. Med., 349(10):975–986. [doi:10.1056/NEJMra023160]

    Article  PubMed  CAS  Google Scholar 

  • Contet, C., Kieffer, B.L., Befort, K., 2004. Mu opiod receptor: a gateway to drug addiction. Curr. Opin. Neurobiol., 14(3):370–378. [doi:10.1016/j.conb.2004.05.005]

    Article  PubMed  CAS  Google Scholar 

  • Dai, S., Hui, S.C.G., Ogle, C.W., 1984. Morphine preference in rats previously morphine dependent. Pharmacol. Res. Commun., 16(5):495–511. [doi:10.1016/S0031-6989(84)80018-1]

    Article  PubMed  CAS  Google Scholar 

  • Fábián, G., Tombor, B., Nemeth, I., Kicsi, E.G., Szikszay, M., Horvath, G., Szucs, M., 2003. Upregulation of mu opioid receptors by voluntary morphine administration in drinking water. Acta Biol. Hung., 54(2):157–166. [doi:10.1556/ABiol.54.2003.2.4]

    Article  PubMed  Google Scholar 

  • Gellert, V.F., Holtzman, S.G., 1978. Development and maintenance of morphine tolerance and dependence in the rat by scheduled access to morphine drinking solutions. J. Pharmacol. Exp. Ther., 205:536–546.

    PubMed  CAS  Google Scholar 

  • Gomaa, A., Hashem, T., Mohamed, M., Ashry, E., 2003. Matricaria chamomilla extract inhibits both development of morphine dependence and expression of abstinence syndrome in rats. J. Pharmacol. Sci., 92(1):50–55. [doi:10.1254/jphs.92.50]

    Article  PubMed  CAS  Google Scholar 

  • Hinson, R.E., Poulos, C.X., Thomas, W., Cappell, H., 1986. Pavlovian conditioning and addictive behavior: relapse to oral self-administration of morphine. Behav. Neurosci., 100(3):368–375. [doi:10.1037/0735-7044.100.3.368]

    Article  PubMed  CAS  Google Scholar 

  • Hui, S.C., Sevilla, E.L., Ogle, C.W., 1996. Prevention by the 5-HT3 receptor antagonist, ondansetron, of morphine-dependence and tolerance in the rat. Br. J. Pharmacol., 118:1044–1050.

    PubMed  CAS  Google Scholar 

  • Hutchings, D.E., Dow-Edwards, D., 1991. Animal models of opiate, cocaine and cannabis use. Clin. Perinatol., 18:1–22.

    PubMed  CAS  Google Scholar 

  • Itoh, A., Noda, Y., Mamiya, T., Hasegawa, T., Nabeshima, T., 1998. A therapeutic strategy to prevent morphine dependence and tolerance by coadministration of cAMP-related reagents with morphine. Methods Find. Exp. Clin. Pharmacol., 20(7):619–625. [doi:10.1358/mf.1998.20.7.485728]

    Article  PubMed  CAS  Google Scholar 

  • Jurna, I., Baldauf, J., Zenz, M., 1992. No psychological dependence after oral administration of morphine to rats. Neurosci. Lett., 138(1):77–80. [doi:10.1016/0304-3940(92)90476-N]

    Article  PubMed  CAS  Google Scholar 

  • Koob, G.F., Sanna, P.P., Bloom, F.E., 1998. Neuroscience of addiction. Neuron, 21(3):467–476. [doi:10.1016/S08966273(00)80557-7]

    Article  PubMed  CAS  Google Scholar 

  • Koob, G.F., Ahmed, S.H., Boutrel, B., Chen, S.A., Kenny, P.J., Markou, A., O’Dell, L.E., Parsons, L.H., Sanna, P.P., 2004. Neurobiological mechanisms in the transition from drug use to drug dependence. Neurosci. Behav. Rev., 27:739–749.

    CAS  Google Scholar 

  • Monteiro, M.G., 2001. A World Health Organization perspective on alcohol and illicit drug use and health. Eur. Addict. Res., 7(3):98–103. [doi:10.1159/000050727]

    Article  PubMed  CAS  Google Scholar 

  • Naidu, P.S., Singh, A., Joshi, D., Kulkani, S.H., 2003. Possible mechanisms of action in quercetin reversal of morphine tolerance and dependence. Addict. Biol., 8(3):327–336. [doi:10.1080/13556210310001602248]

    Article  PubMed  CAS  Google Scholar 

  • Nestler, E.J., 2004. Historical review: molecular and cellular mechanisms of opiate and cocaine addiction. Trends Pharmacol. Sci., 25(4):210–218. [doi:10.1016/j.tips.2004.02.005]

    Article  PubMed  CAS  Google Scholar 

  • Rezvani, A.H., Overstreet, D.H., Perfumi, M., Massi, M., 2003. Plant derivatives in the treatment of alcohol dependency. Pharm. Biochem. Behav., 75(3):593–606. [doi:10.1016/S0091-3057(03)00124-2]

    Article  CAS  Google Scholar 

  • Silva, M.T., Heyman, G.M., 2001. Chronic morphine consumption decreases wheel running and wheel running-reinforced behavior in rats. Pharmacol. Biochem. Behav., 69(1–2):51–57. [doi:10.1016/S0091-3057(01)00498-1]

    Article  PubMed  CAS  Google Scholar 

  • Tiong, G.K., Pierce, T.L., Olley, J.E., 1992. Sub-chronic exposure to opiates in the rat: effects on brain levels of substance P and calcitonin gene-related peptide during dependence and withdrawal. J. Neurosci. Res., 32(4):569–575. [doi:10.1002/jnr.490320412]

    Article  PubMed  CAS  Google Scholar 

  • van den Brink, W., van Ree, J.M., 2003. Pharmacological treatments for heroin and cocaine addiction. Eur. Neuropsychopharmacol., 13(6):476–487. [doi:10.1016/j.euroneuro.2003.08.008]

    Article  PubMed  Google Scholar 

  • West, J.P., Lysle, D.T., Dykstra, L.A., 1997. Tolerance development to morphine-induced alteration of immune status. Drug Alcohol Depend., 46(3):147–157. [doi:10.1016/S0376-8716(97)00059-8]

    Article  PubMed  CAS  Google Scholar 

  • Westerling, D., Perrson, C., Hoglund, P., 1995. Plasma concentrations of morphine, morphine-3-glucuronide, and morphine-6-glucuronide after intravenous and oral administration to healthy volunteers: relationship to nonanalgesic actions. Ther. Drug Monit., 17:287–301.

    PubMed  CAS  Google Scholar 

  • WHO (World Health Organization), 2002. The World Health Report 2002—Reducing Risk, Promoting Healthy Life. Geneva, WHO.

    Google Scholar 

  • Wolffgramm, J., Heyne, A., 1995. From controlled drug intake to loss of control: the irreversible development of drug addiction in the rat. Behav. Brain Res., 70(1):77–94. [doi:10.1016/0166-4328(95)00131-C]

    Article  PubMed  CAS  Google Scholar 

  • Yamamoto, T., Mizuguchi, T., 1992. Time-dependent effects of oral morphine on autotomy following brachial nerve section in the rat. Neurosci. Lett., 141(2):166–168. [doi:10.1016/0304-3940(92)90886-C]

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Zhu Yong-ping.

Additional information

Project supported by the National Basic Research Program (973) of China (No. 2003CB515402), and the Science and Technology Council of Zhejiang Province (No. 2005C23G2010166), China

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Binsack, R., Zheng, Ml., Zhang, Zs. et al. Chronic morphine drinking establishes morphine tolerance, but not addiction in Wistar rats. J. Zhejiang Univ. - Sci. B 7, 892–898 (2006). https://doi.org/10.1631/jzus.2006.B0892

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  • DOI: https://doi.org/10.1631/jzus.2006.B0892

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