Morphine was provided to rats in drinking water for 21 days. Profound analgesic tolerance was detected both in hot-plate and tail-flick tests. The density of [3H]DAMGO binding sites increased by 76% in spinal cord membranes due to morphine exposure compared to those in opioid naive animals. Slightly augmented [3H]DAMGO binding was measured in the synaptic plasma membranes, with a concomitant decrease in the microsomal membranes, of morphine tolerant/dependent brains. These observations suggest that the regulation of spinal mu opioid receptors might be different from those in the brain. It is emphasized that the molecular changes underlying tolerance/dependence are influenced by several factors, such as the tissue or subcellular fractions used, besides the obvious importance of the route of drug administration. Results obtained after voluntary morphine intake further support the growing number of experimental data that chronic morphine does not internalize/downregulate the mu opioid receptors in the central nervous system.
Adams, J. U., Andrews, J. S., Hiller, J. M., Simon, E. J., Holtzman, S. G. (1987) Effects of stress and beta-funaltrexamine pretreatment on morphine analgesia and opioid binding in rats. Life Sci. 41, 2835–2844.
Badawy, A. A.-B., 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. Pharmac. 75, 485–491.
Bohn, L. M., Lefkowitz, R. J., Caron, M. G. (2002) Differential mechanisms of morphine anti-nociceptive tolerance revealed in β arrestin-2 knock-out mice. J. Neurosci. 22, 10494–10500.
Bradford, M. M. (1986) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of dye-binding. Anal. Biochem. 72, 248–254.
Christie, M. J., Williams, J. T., North, R. A. (1987) Mechanisms of tolerance to opiates in locus coeruleus neurons. NIDA Res Monogr. 78, 158–168.
Cox, B. M. (1993) Opioid receptor-G protein interactions: acute and chronic effects of opioids. In: Born et al. (eds) Handbook of Exp. Pharmacol. Opioids I. Springer-Verlag, London, 145–188.
Craft, R. M., Stratmann, J. A., Bartok, R. E., Walpole, T. I., King, S. J. (1999) Sex differences in the development of morphine tolerance and dependence in rat. Psychopharmacology 143, 1–7.
Dafters, R. I., Odber, J. (1989) Effects of dose, interdose interval, and drug-signal parameters on morphine analgesic tolerance: Implications for current theories of tolerance. Behav. Neurosci. 103, 1082–1090.
Du, X., Skopp, G., Aderjan, R. (1999) The influence of the route of administration: a comparative study at steady state of oral sustained release morphine and morphine sulfate suppositories. Ther. Drug Monit. 21, 208–214.
Duttaroy, A., Yoburn, B. C. (1995) The effect of intrinsic efficacy on opioid tolerance. Anesthesiology 82, 1226–1236.
Fábián, G., Bozó, B., Szikszay, M., Horváth, G., Coscia, C. J., Szűcs, M. (2002) Changes in the sub-cellular distribution of mu opioid receptors and G-proteins in morphine-tolerant rat brains. J. Pharmacol. Exp. Therap. 302, 774–780.
Gintzler, A. R., Chakrabarti, S. (2000) Opioid tolerance and the emergence of new opioid receptorcoupled signaling. Mol. Neurobiol. 21, 21–33.
He, L., Fong, J., von Zastrow, M., Whistler, J. L. (2002) Regulation of opioid receptor trafficking and morphine tolerance by receptor oligomerization. Cell 108, 271–282.
Ingram, S. L., Vaughan, C. W., Bagley, E. E., Connor, M., Christie, M. J. (1998) Enhanced opioid efficacy in opioid dependence is caused by an altered signal transduction pathway. J. Neurosci. 18, 10269–10276.
Munson, P. J., Rodbard, D. (1980) Ligand, a versatile computerized approach for characterization of ligand binding systems. Anal. Biochem. 107, 220–239.
Nestler, E. J., Aghajanian, G. K. (1997) Molecular and cellular basis of addiction. Science 278, 58–63.
Noble, F., Szűcs, M., Kieffer, B., Roques, B. P. (2000) Overexpression of dynamin is induced by chronic stimulation of mu but not delta opioid receptors: relationship with mu-related morphine dependence. Mol. Pharmacol. 58, 159–166.
Paul, D., Bodnar, R. J., Gistrak, M. A., Pasternak, G. W. (1989) Different mu receptor subtypes mediate spinal and supraspinal analgesia in mice. Eur. J. Pharmacol. 168, 307–314.
Seevers, M. H., Deneau, G. A. (1963) Physiological aspects of tolerance and physical dependence. In: Root, W. S., Hoffmann, F. G. (eds) Physiological Pharmacology. Academic Press, New York, 565–640.
Selley, D. E., Nestler, E. J., Breivogel, C. S., Childers, S. R. (1997) Opioid receptor coupled G-proteins in rat locus coeruleus membranes: decrease in activity after chronic morphine treatment. Brain Res. 746, 10–18.
Szűcs, M., Coscia, C. J. (1992) Differential coupling of opioid binding sites to guanosine triphos-phate binding regulatory proteins in subcellular fractions of rat brain. J. Neurosci. Res. 31, 565–572.
Tao, P. L., Lee, C. R., Law, P. Y., Loh, H. H. (1993) The interaction of the mu-opioid receptor and G protein is altered after chronic morphine treatment in rats. Naunyn Schmiedebergs Arch. Pharmacol. 348, 504–508.
Taylor, D. A., Fleming, W. W. (2000) Unifying perspectives of the mechanisms underlying the development of tolerance and physical dependence to opioids. J. Pharmacol. Exp. Therap. 297, 11–18.
Tkachuk, V. A., Wollemann, M. (1979) Hypersensitivity to isoproterenol in rabbit heart decreases guanine nucleotide effect on adenylate cyclase. Biochem Pharmacol. 28, 2097–2100.
Williams, J. T., Christie, M. J., Manzoni, O. (2001) Cellular and synaptic adaptations mediating opioid dependence. Physiol. Rev. 81, 299–343.
Zadina, J. E., Kastin, A. J., Harrison, L. M., Chang, S. L. (1995) Opiate receptor changes after chronic exposure to agonists and antagonists. Annals N.Y. Acad. Sci. 757, 353–360.
The interest and helpful comments of Mária Wollemann are highly appreciated. Thanks are due to Mrs. Ildikó Dobos for excellent technical assistance. This work was supported by OTKA T-033062, T-34741 and ETT 042/2001 research funds.
Dedicated to Professor Maria Wollemann on the occasion of her 80th birthday.
About this article
Cite this article
Fábián, G., Tombor, B., Németh, I. et al. Upregulation of Mu Opioid Receptors by Voluntary Morphine Administration in Drinking Water. BIOLOGIA FUTURA 54, 157–166 (2003). https://doi.org/10.1556/ABiol.54.2003.2.4
- spinal cord