Health  Vol.5 No.11 A , November 2013
Further studies on the effects of acamprosate on tolerance to the analgesic effects of morphine and NO synthesis in the brain
Abstract: The aim of this work was to investigate whether acamprosate modifies the expression of the enzyme responsible for neuronal NO synthesis (nNOS) in the nucleus accumbens (NAc) of mice chronically treated with morphine and during the abstinence syndrome induced by naloxone. The enzyme was monitored by the NADPH diaphorase method. The number of cells stained for NADPH diaphorase in the NAc of mice was counted in 40 μm thick coronal brain slices at 40X. The intensity of the histochemical reaction of stained cells from naive morphine plus saline and morphine plus acamprosate treated mice was analyzed by Image Pro Plus 4.5.1. Morphine administered in a slow release preparation increased the stain intensity of the positive neurons. The increase in the NADPH staining persisted after naloxone was given to mice chronically treated with morphine. Acamprosate antagonized the effects induced by chronic morphine treatment in the NAc of mice. These results indicate that up-regulation of nNOS in the NAc is a consequence of the sustained effects of morphine stimulation, which, in turn, may result from an increased in glutamate release during the abstinence syndrome.
Cite this paper: Sepúlveda, J. , Ortega, A. , Roa, J. and Contreras, E. (2013) Further studies on the effects of acamprosate on tolerance to the analgesic effects of morphine and NO synthesis in the brain. Health, 5, 1-6. doi: 10.4236/health.2013.511A1001.

[1]   Lhuintre, J., Daoust, M., Moore, N.D., Chretien, P., Saligaut, C., Tran, G., Bosimare, F. and Hillemand, B. (1985) Ability of calcium bis acetyl homotaurine, a GABA agonist, to prevent relapse in weaned alcoholics. Lancet, 1, 1014-1016.

[2]   Sass, H., Soyka, M., Mann, K. and Zieglgansberger, W. (1996) Relapse prevention by acamprosate: Results from a placebo-controlled study on alcohol dependence. Archives of General Psychiatry, 53, 673-680.

[3]   Wilde, M.I. and Wagstaff, A.J. (1997) Acamprosate: A review of its pharmacology and clinical potential in the management of alcoholic dependence after detoxification. Drugs, 53, 1038-1053.

[4]   Chick, J., Howlett, H., Morgan, M.Y. and Ritson, B. (2000) United Kingdom Multicentre Acamprosate Study (UKMAS): A 6-month prospective study of acamprosate versus placebo in preventing relapse after withdrawal from alcohol. Alcohol and Alcoholism, 35, 176-187.

[5]   Han, D.H., Lyool, I.K., Sung, Y.H., Lee, S.H. and Renshaw, P.F. (2008) The effect of acamprosate on alcohol and food craving in patients with alcohol dependence. Drug and Alcohol Dependence, 93, 279-283.

[6]   Spanagel, R. and Zieglgansberger, W. (1997) Anti-craving compounds for ethanol: New pharmacological tools to study addictive processes. Trends in Pharmacological Sciences, 18, 54-59.

[7]   Allgaier, C., Franke, H., Sobottka, H. and Scheibler, P. (2000) Acamprosate inhibits Ca2+ influx mediated by NMDA receptors and voltage-sensitive Ca2+ channels in cultured rat mesencephalicneurones. Naunyn-Schmiedeberg’s Archives of Pharmacology, 362, 440-443.

[8]   Bachteler, D., Economidou, D., Danysz, W., Ciccocioppo, R. and Spanagel, R. (2005) The effects of acamprosate and neramexane on cue-induced reinstatement of ethanol-seeking behavior in rat. Neuropsychopharmacology, 30, 1104-1110.

[9]   Zeise, M.L., Kasparov, S., Capogna, M. and Zieglgansberger, W. (1993) Acamprosate (calcium acetyl homotaurinate) decreases postsynaptic potentials in the rat neocortex: Possible involvement of excitatory amino acid receptors. European Journal of Pharmacology, 231, 47-52.

[10]   Popp, R.L. and Lovinger, D.M. (2000) Interaction of acamprosate with ethanol and spermine on NMDA receptors in primary cultured neurons. European Journal of Pharmacology, 394, 221-231.

[11]   Koob, G.F., Wall, T.L. and Bloom, F.E. (1989) Nucleus accumbens as a substrate for the aversive stimulus effects of opiate withdrawal. Psychopharmacology, 98, 530-534.

[12]   Stinus, L., Le Moal, M. and Koob, G.F. (1990) Nucleus accumbens and amygdale are possible substrate for the aversive stimulus effects of opiate withdrawal. Neuroscience, 37, 767-773.

[13]   Pothos, E., Rada, P., Mark, G. and Hoebel, B.G. (1991) Dopamine microdialysis in the nucleus accumbens during acute and chronic morphine, naloxone precipitated withdrawal and clonidine treatment. Brain Research, 566, 348-350.

[14]   Rada, P.V., Mark, G.P., Taylor, K.M. and Hoebel, B.G. (1996) Morphine and naloxone ip or locally affect extracellular acetylcholine in accumbens and prefrontal cortex. Pharmacology Biochemistry and Behavior, 53, 809-816.

[15]   Sepúlveda, M.J., Hernandez, L., Rada, P., Tucci, S. and Contreras, E. (1998) Effect of precipitated withdrawal on extracellular glutamate and aspartate in the nucleus accumbens of chronically morphine-treated rats: An in vivo microdialysis study. Pharmacology Biochemistry and Behavior, 60, 255-262.

[16]   Kielstein, A., Tsikas, D., Galloway, G.P., Mendelson, J.E. (2007) Asymmetric dimethylarginine (ADMA)—A modulator of nociception in opiate tolerance and addiction? Nitric Oxide, 17, 55-59.

[17]   Komatsu, T., Sakurada, C., Sasaki, M., Sanai, K., Tsuzuki, M., Bagetta, G., Sakurada, S., Sakurada, T. (2007) Extracellular signal-regulated kinase (ERK) and nitric oxide synthase mediate intrathecal morphine-induced nociceptive behavior. Neuropharmacology, 52, 1237-1243.

[18]   Harlan, R.E., Webber, D.S. and Garcia, M.M. (2001) Involvement of nitric oxide in morphine induced c-Fos expression in the rat striatum. Brain Research Bulletin, 54, 207-212.

[19]   Garthwaite, J. (1991) Glutamate, nitric oxide and cell-cell signaling in the nervous system. Trends in Neuroscience, 14, 60-67.

[20]   Nestler, E., Alreja, M. and Aghajanian, M. (1994) Molecular and cellular mechanisms of opiate action: Studies in the rat locus coeruleus. Brain Research Bulletin, 35, 521-528.

[21]   Hope, B.T., Michael, G.J., Knigge, K.M. and Vincent, S.R. (1991) Neuronal NADPH diaphorase is a nitric oxide synthase. Proceedings of the National Academy of Sciences of the United States of America, 88, 2811-2814.

[22]   Vincent, S.R. and Kimura, H. (1992) Histochemical mapping of nitric oxide synthase in the rat brain. Neuroscience, 46, 755-784.

[23]   Sepúlveda, M.J., Ortega, A., Zapata, G. and Contreras, E. (2002) Acamprosate decreases the induction of tolerance and physical dependence in morphine-treated mice. European Journal of Pharmacology, 445, 87-91.

[24]   Sepúlveda, J., Oliva, P. and Contreras, E. (2004) Neurochemical changes of the extracellular concentrations of glutamate and aspartate in the nucleus accumbens of rats after chronic administration of morphine. European Journal of Pharmacology, 483, 249-258.

[25]   Paxinos, G. and Franklin, K.B.J. (2001) The mouse brain in stereotaxic coordinates. 2nd Edition, Elsevier, New York.

[26]   Bredt, D.S., Hwang, P.M., Glatt, C.E., Lowenstein, C., Reed, R.R. and Snyder, S.H. (1991) Cloned and expressed nitric oxide synthase structurally resembles cytochrome P450 reductase. Nature, 351, 714-718.

[27]   Garthwaite, J., Charles, S.L. and Chess-Williams, R. (1988) Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain. Nature, 33, 385.

[28]   Bredt, D.S. and Snyder, S.H. (1992) Nitric oxide, a novel neuronal messenger. Neuron, 8, 3-11.

[29]   Leza, J.C., Lizasoain, I., San Martin-Clark, O. and Lorenzo, P. (1995) Morphine-induced changes on cerebral and cerebellar nitric oxide synthase activity. European Journal of Pharmacology, 285, 95-98.

[30]   Cuellar, B., Fernandez, A.P., Lizasoain, I., Moro, M.A., Lorenzo, P., Bentura, M.L., Rodrigo, J. and Leza, J.C. (2000) Up-regulation of neuronal NO synthase immunoreactivity in opiate dependence and withdrawal. Psychopharmacology, 148, 66-73.

[31]   Santamarta, M.T., Ulibarri, I. and Pineda, J. (2005) Inhibition of neuronal nitric oxide synthase attenuates the development of morphine tolerance in rats. Synapse, 57, 38-46.

[32]   Mori, T., Ito, S., Matsubayashi, K. and Sawaguchi, T. (2007) Comparison of nitric oxidesynthase inhibitors, phospholipase A2 inhibitor and free radical scavengers as attenuators of opioid withdrawal syndrome. Behavioural Pharmacology, 18, 725-729.

[33]   Smart, D. and Lambert, D.G. (1996) The stimulatory effects of opioids and their possible role in the development of tolerance. Trends in Pharmacological Sciences, 7, 264-269.

[34]   Chen, L. and Huang, L.Y. (1991) Sustained potentiation of NMDA receptor-mediated glutamate responses through activation of protein kinase C by a mu opioid. Neuron, 7, 319-326.

[35]   Naassila, M., Hammoumi, S., Legrand, E., Durbin, P. and Daoust, M. (1998) Mechanism of action of acamprosate. Part I Characterization of spermidine-sensitive acamprosate binding site in rat brain. Alcoholism: Clinical and Experimental Research, 22, 802-809.

[36]   Mayer, S., Harris, B., Gibson, D.A., Blanchard, J., Prendergast, M.A., Holley, R.C. and Littleton, J. (2002) Acamprosate has no effect on NMDA-induced toxicity but reduces toxicity induced by spermidine or by changing the medium in organotypic hippocampal slice cultures from rat. Alcoholism: Clinical and Experimental Research, 26, 655-662.