Effects of Magnesium sulfate and Bupropion on Morphine Induced tolerance in mice

Bohlool Habibi-asl, Saeed Ghanbarzadeh, Haleh Vaez, Mina Khodabandeh


Introduction: Chronic opiate exposure induces tolerance to opiate analgesic effects. Glutamate system is believed to play a major role in morphine induced tolerance. The inhibitory effects of magnesium sulfate and bupropion on this system are well-studied. The aim of this study was to evaluate the effects of magnesium sulfate and bupropion on the prevention of morphine induced tolerance in mice.

Materials and Methods: Animals were divided into the nine groups which received drugs intraperitoneally for four consecutive days according to the following protocol: saline (10 ml/kg) + saline (10 ml/kg), morphine (50 mg/kg) + saline (10 ml/kg), morphine (50 mg/kg) + magnesium sulfate (20, 40 and 60 mg/kg), morphine (50 mg/kg) + bupropion (2, 4 and 8 mg/kg) and morphine (50 mg/kg) + magnesium sulfate (20 mg/kg) + bupropion (2 mg/kg). To evaluate the effects of mentioned drugs on morphine tolerance, a test dose of morphine (9 mg/kg) was administered on the fifth day in all groups. In the hot-plate test, thermal stimulation was measured at time intervals of 0, 15, 30, 45 and 60 minutes.

Results: Administration of magnesium sulfate, bupropion and their combination before daily injection of morphine, significantly attenuated tolerance to morphine. Also, the highest tolerance reduction was observed at the 30th minute of the study (P<0.001).

Conclusion: Magnesium sulfate and bupropion can be used to attenuate morphine induced tolerance. The possible mechanisms are antagonist behavior on N-methyl-D-aspartate (NMDA) receptor and inhibition of glutamate release, respectively.


Key words: Bupropion; Hot plate; Magnesium sulfate; Morphine; Tolerance

Full Text:



Liu JG AK. Protein kinase modulate the cellular adaptation associated with opioid tolerance and dependence. Brain Res Rev. 2001;38:1-19.

Mayer D.J MJ. mechanisms of opioid tolerance current view of cellular mechanisms. Pain Forum. 1999;8:14-8.

Kramer HK, Simon EJ. Role of protein kinase C (PKC) in agonist-induced mu-opioid receptor down-regulation: II. Activation and involvement of the alpha, epsilon, and zeta isoforms of PKC. Journal of neurochemistry. 1999 Feb;72(2):594-604.

Fundytus ME, Coderre TJ. Chronic inhibition of intracellular Ca2+ release or protein kinase C activation significantly reduces the development of morphine dependence. European journal of pharmacology. 1996 Apr 11;300(3):173-81.

Kaymak C YE, Basar H, Ozcakir S, Apan A, Batislam E. Use of the NMDA antagonist magnesium sulfate during monitored anesthesia care for shockwave lithotripsy. J Endourol. 2007;21:145-50.

Mendes IA TK. NMDA reseptor antagonists inhibit opiate antinociceptive tolerance and locomotor sensitization in rats. Psychopharmacology. 2008;196:497-509.

Kozela E, Popik P. The effects of NMDA receptor antagonists on acute morphine antinociception in mice. Amino acids. 2002;23(1-3):163-8. doi: 10.1007/s00726-001-0123-5.

Bisaga A, Popik P. In search of a new pharmacological treatment for drug and alcohol addiction: N-methyl-D-aspartate (NMDA) antagonists. Drug and alcohol dependence. 2000 Apr 1;59(1):1-15.

Smetana R SH, Kiss K, Glogar DH. Intravenous magnesium sulphate in acute myocardial infarction. Magnes Res. 2003;16:65-9.

Wiswell TE GL, Caddell JL, Vecchione N, Stanley C, Spitzer AR. The possible role of magnesium in protection of premature infants from neurological syndromes and visual impairments and a review of survival of magnesium-exposed premature infants. Magnes Res. 1999:201-16.

Trescot AM DS, Lee M, Hansen H Opioid pharmacology. Pain Physician. 2008;11:133-53.

McCarthy RJ, Kroin JS, Tuman KJ, Penn RD, Ivankovich AD. Antinociceptive potentiation and attenuation of tolerance by intrathecal co-infusion of magnesium sulfate and morphine in rats. Anesthesia and analgesia. 1998 Apr;86(4):830-6.

Habibi-Asl B, Hassanzadeh K, Vafai H, Mohammadi S. Development of morphine induced tolerance and withdrawal symptoms is attenuated by lamotrigine and magnesium sulfate in mice. Pakistan journal of biological sciences: PJBS. 2009 May 15;12(10):798-803.

KA T. Are NMDA receptors involved in opiate-induced neural and behavioral plasticity? A review of preclinical studies. Psychopharmacology. 2000;151:121-41.

Joshi D, Singh A, Naidu PS, Kulkarni SK. Protective effect of bupropion on morphine tolerance and dependence in mice. Methods and findings in experimental and clinical pharmacology. 2004 Oct;26(8):623-6.

Vanderah TW, Suenaga NM, Ossipov MH, Malan TP, Jr., Lai J, Porreca F. Tonic descending facilitation from the rostral ventromedial medulla mediates opioid-induced abnormal pain and antinociceptive tolerance. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2001 Jan 1;21(1):279-86.

Prommer EE. Opioid-induced pain. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2008 Jul 10;26(20):3464-5; author reply 5. doi: 10.1200/JCO.2008.17.3633.

Chen L, Huang LY. Protein kinase C reduces Mg2+ block of NMDA-receptor channels as a mechanism of modulation. Nature. 1992 Apr 9;356(6369):521-3. doi: 10.1038/356521a0.

Granados-Soto V, Kalcheva I, Hua X, Newton A, Yaksh TL. Spinal PKC activity and expression: role in tolerance produced by continuous spinal morphine infusion. Pain. 2000 Apr;85(3):395-404.

Li Y, Roerig SC. Alteration of spinal protein kinase C expression and kinetics in morphine, but not clonidine, tolerance. Biochemical pharmacology. 1999 Aug 1;58(3):493-501.

Fan GH, Zhao J, Wu YL, Lou LG, Zhang Z, Jing Q, et al. N-Methyl-D-aspartate attenuates opioid receptor-mediated G protein activation and this process involves protein kinase C. Molecular pharmacology. 1998 Apr;53(4):684-90.

Zhao M, Joo DT. Subpopulation of dorsal horn neurons displays enhanced N-methyl-D-aspartate receptor function after chronic morphine exposure. Anesthesiology. 2006 Apr;104(4):815-25.

Trujillo KA. The neurobiology of opiate tolerance, dependence and sensitization: mechanisms of NMDA receptor-dependent synaptic plasticity. Neurotoxicity research. 2002 Jun;4(4):373-91. doi: 10.1080/10298420290023954.

Adam F, Bonnet F, Le Bars D. Tolerance to morphine analgesia: Evidence for stimulus intensity as a key factor and complete reversal by a glycine site-specific NMDA antagonist. Neuropharmacology. 2006;51(2):191-202. doi: http://dx.doi.org/10.1016/j.neuropharm.2006.03.018.

Fischer BD, Ward SJ, Henry FE, Dykstra LA. Attenuation of morphine antinociceptive tolerance by a CB1 receptor agonist and an NMDA receptor antagonist: Interactive effects. Neuropharmacology. 2010;58(2):544-50. doi: http://dx.doi.org/10.1016/j.neuropharm.2009.08.005.

Ghasemi M, Shafaroodi H, Nazarbeiki S, Meskar H, Ghasemi A, Bahremand A, et al. Inhibition of NMDA receptor/NO signaling blocked tolerance to the anticonvulsant effect of morphine on pentylenetetrazole-induced seizures in mice. Epilepsy Research. 2010;91(1):39-48. doi: http://dx.doi.org/10.1016/j.eplepsyres.2010.06.010.

Guo R-x, Zhang M, Liu W, Zhao C-m, Cui Y, Wang C-h, et al. NMDA receptors are involved in upstream of the spinal JNK activation in morphine antinociceptive tolerance. Neuroscience Letters. 2009;467(2):95-9. doi: http://dx.doi.org/10.1016/j.neulet.2009.10.013.

Wen ZH, Wu GJ, Chang YC, Wang JJ, Wong CS. Dexamethasone modulates the development of morphine tolerance and expression of glutamate transporters in rats. Neuroscience. 2005;133(3):807-17. doi: http://dx.doi.org/10.1016/j.neuroscience.2005.03.015.

Zhou Q, Wang J, Zhang X, Zeng L, Wang L, Jiang W. Effect of metabotropic glutamate 5 receptor antagonists on morphine efficacy and tolerance in rats with neuropathic pain. European journal of pharmacology. 2013;718(1–3):17-23. doi: http://dx.doi.org/10.1016/j.ejphar.2013.09.009.

Lin TY, Yang TT, Lu CW, Wang SJ. Inhibition of glutamate release by bupropion in rat cerebral cortex nerve terminals. Progress in neuro-psychopharmacology & biological psychiatry. 2011 Mar 30;35(2):598-606. doi: 10.1016/j.pnpbp.2010.12.029.

Trujillo KA, Akil H. Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science. 1991 Jan 4;251(4989):85-7.

Gutstein HB, Trujillo KA. MK-801 inhibits the development of morphine tolerance at spinal sites. Brain research. 1993 Oct 29;626(1-2):332-4.

Allen RM, Dykstra LA. The competitive NMDA receptor antagonist LY235959 modulates the progression of morphine tolerance in rats. Psychopharmacology (Berl). 1999 Feb;142(2):209-14.

Habibi-Asl B, Hassanzadeh K, Khezri E, Mohammadi S. Evaluation the effects of dextromethorphan and midazolam on morphine induced tolerance and dependence in mice. Pakistan journal of biological sciences: PJBS. 2008 Jul 1;11(13):1690-5.

Habibi-Asl B, Hassanzadeh K, Moosazadeh S. Effects of ketamine and magnesium on morphine induced tolerance and dependence in mice. DARU. 2005;13:110-5.

Habibi-Asl B, Hassanzadeh K. Effects of ketamine and midazolam on morphine induced dependence and tolerance in mice. DARU. 2004;12:101-5.

Ferry LH BR. Efficacy of bupropion for smoking cessation in non-depressed smokers. J Addict Dis. 1994;13:249.

Gadde K M PCB, Maner L.G. Bupropion for weight loss: an investigation of efficacy and tolerability in overweight and obese women. Obes Res. 2001;9:544-51.

Learned-Coughlin SM BM, Savitcheva I, Ascher J, Schmith VD, Langstrom B. In vivo activity of bupropion at the human dopamine transporter. Biol Psychiatry 2003;54:800-5.

Lin TY YT, Lu CW, Wang SJ. Inhibition of glutamate release by bupropion in rat cerebral cortex nerve terminals. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35:598-606.

Wollmuth LP, Kuner T, Sakmann B. Intracellular Mg2+ interacts with structural determinants of the narrow constriction contributed by the NR1-subunit in the NMDA receptor channel. The Journal of physiology. 1998 Jan 1;506 ( Pt 1):33-52.

Ruppersberg JP, Kitzing Ev, Schoepfer R. The mechanism of magnesium block of NMDA receptors. Seminars in Neuroscience. 1994 ;6(2):87-96. doi: http://dx.doi.org/10.1006/smns.1994.1012.

Martin G, Ahmed SH, Blank T, Spiess J, Koob GF, Siggins GR. Chronic morphine treatment alters NMDA receptor-mediated synaptic transmission in the nucleus accumbens. The Journal of neuroscience : the official journal of the Society for Neuroscience. 1999 Oct 15;19(20):9081-9.

Begon S, Pickering G, Eschalier A, Dubray C. Magnesium increases morphine analgesic effect in different experimental models of pain. Anesthesiology. 2002 Mar;96(3):627-32.

Kalipatnapu S, Jafurulla M, Chandrasekaran N, Chattopadhyay A. Effect of Mg2+ on guanine nucleotide sensitivity of ligand binding to serotonin1A receptors from bovine hippocampus. Biochemical and biophysical research communications. 2004 Oct 15;323(2):372-6. doi: 10.1016/j.bbrc.2004.08.120.

Papierkowski A, Pasternak K. The effect of a single dose of morphine and ethanol on magnesium level in blood serum and tissues in mice. Magnes Res. 1998 Jun;11(2):85-9.

Nechifor M, Chelarescu D, Miftode M. Magnesium influence on morphine--induced pharmacodependence in rats. Magnes Res. 2004 Mar;17(1):7-13.


  • There are currently no refbacks.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

2013-2019 (CC-BY) Australian International Academic Centre PTY.LTD.

Advances in Bioscience and Clinical Medicine