Endogenous Morphine and Codeine As Possible Physiological Ligands of µ-Opiate Receptors

  • A. Tagliamonte
  • M. Guarna
  • E. Bianchi
Conference paper


Experiments carried out by indirect immunofluorescence and unlabelled antibody enzyme procedures revealed the presence of morphine-like immunoreactive material in the perikarya, fibers, and terminals of neurons in different, discrete areas of rat and human brain. The monoclonal and polyclonal anti-morphine antibodies used do not distinguish between morphine and codeine. Endogenous morphine seems to be stored in neurons as the 3-ethereal sulfate conjugate. This possibility is supported by the finding that, although active uptake of [3H]morphine has not been detected in brain synaptosomes, long-term i.c.v. injection of the tritiated opiate results in the accumulation of radioactivity inside the same neurons in which the endogenous alkaloids have been detected. Moreover, the sulfated compound showed a selective displacing effect toward [3H]DAMGO, although the affinity was lower than that of morphine HC1 and DAMGO. Finally, morphine-3-ethereal sulfate presented the same poor inhibitory action of morphine HC1 and DAMGO on rat striatal adenylate cyclase activity. Finally, striatal slices exposed to high K+ concentrations showed a rapid disappearance of the morphine-like immunoreactive material from neurons, indicating that endogenous alkaloids are released from neurons by depolarization.


Nerve Cell Body Striatal Slice Morphine Concentration Beef Brain Free Morphine 
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  1. 1.
    Bianchi E, Alessandrini C, Guarna M, Tagliamonte A. Endogenous codeine and morphine are stored in specific brain neurons. Brain Res 627: 210–215, 1993.PubMedCrossRefGoogle Scholar
  2. 2.
    Battersby A R, Binks R, Francis R J, McCaldin D J, Ramuz H. Alkaloid biosynthesis. 1Benzylisoquinolines as precursors of thebaine, codeine and morphine. J Chem Soc Part IV: 3600–3610, 1964.Google Scholar
  3. 3.
    Chen Y, Mestek A, Liu J, Yu L. Molecular cloning and functional expression of a µ-opioid receptor from rat brain. Brain Res 44: 8–12, 1993.Google Scholar
  4. 4.
    Donnerer J, Cardinale G, Coffey J, Lisek C A, Jardine I, Spector S. Chemical characterization and regulation of endogenous morphine and codeine in the rat. J Pharmacol Exp Ther 242: 583–587, 1987.PubMedGoogle Scholar
  5. 5.
    Donnerer J, Oka K, Brossi A, Rice K C, Spector S. Presence and formation of codeine and morphine in the rat. Proc Natl Acad Sci USA 83: 4566–4567, 1986.PubMedCrossRefGoogle Scholar
  6. 6.
    Evans C J, Keith D E Jr, Morrison H, Magendso K, Edwards R H. Cloning of a delta opioid receptor by functional expression. Science 258: 1952–1955, 1992.PubMedCrossRefGoogle Scholar
  7. 7.
    Fraser C M, Wang C D, Robinson D A, Gocayne J D, Venter C. Site-directed mutagenesis of M 1 muscarinic acetylcholine receptors: conserved aspartic acids play important roles in receptor function. Mol Pharmacol 36: 840–847, 1989.PubMedGoogle Scholar
  8. 8.
    Ginzler A R, Levy A, Spector S. Antibodies as a means of isolating and characterizing biologically active substances: presence of a non-peptide, morphine-like compound in the central nervous system. Proc Natl Acad Sci USA 73: 2132–2136, 1976.CrossRefGoogle Scholar
  9. 9.
    Ginzler A R, Gershon M D, Spector S. A non-peptide morphine-like compound: immunocytochemical in the mouse brain. Science 199: 447–448, 1978.CrossRefGoogle Scholar
  10. 10.
    Goldstein A, Barrett W, James F I, Lowney L I, Weitz C J, Knipmeyer L L, Rapaport H. Morphine and other opiates from beef brain and adrenal. Proc Natl Acad Sci USA 82: 52035207, 1985.Google Scholar
  11. 11.
    Hathaway C B, Epple A. Catecholamines, opioid peptides, and true opiates in chromaffin cells of the eel: immunohistochemical evidence. Gen Comp Endocrinol 79: 393–405, 1990.PubMedCrossRefGoogle Scholar
  12. 12.
    Kieffer B L, Befort K, Gaveriaux-Ruff C, Hirt C G. The a-opioid receptor: isolation of a cDNA by expression cloning and pharmacological characterization. Proc Natl Acad Sci USA 89: 12048–12052, 1992.PubMedCrossRefGoogle Scholar
  13. 13.
    Kirby G W. Biosynthesis of the morphine alkaloids. Science 155: 170–173, 1967.PubMedCrossRefGoogle Scholar
  14. 14.
    Knoche H W. Radioisotopic Methods for Biological and Medical Research, Oxford University, New York, 1991.Google Scholar
  15. 15.
    Lee C S, Spector S. Changes of endogenous morphine and codeine contents in the fasting rats. J Pharmacol Exp Ther 257: 647–650, 1991.PubMedGoogle Scholar
  16. 16.
    Matsubara K, Fukushima S, Akane A, Kobayashi S, Shiono H. Increased urinary morphine, codeine and tetrahydropapaveroline in parkinsonian patients undergoing 1–3,3dihydroxyphenyla’_anine therapy: a possible biosyntethic pathway of morphine from 1–3,4dihydroxyphenylalanine in humans. J Pharmacol Exp Ther 260: 974–978, 1992.PubMedGoogle Scholar
  17. 17.
    Mulder G J. Pharmacological effects of drug conjugates: is morphine 6-glucuronide an exception? TIPS 13: 302–304, 1992.PubMedGoogle Scholar
  18. 18.
    Schwartz J H. Chemical basis of synaptic transmission. In: Principles of neural Science, edited by Kandel E R, Schwartz J H. Elsevier, North Holland, 1981, pp 106–120.Google Scholar
  19. 19.
    Strader C D, Gaffney T, Sugg E E, Candelore M R, Keys R. Allele-specific activation of genetically engineered receptors. J Biol Chem 266: 5–8, 1991.PubMedGoogle Scholar
  20. 20.
    Turner A, Baker K, Algeri S, Frigerio A, Garattini S. Tetrahydropapaveroline: formation in vivo and in vitro in rat brain. Life Sci 14: 2247–2257, 1974.PubMedCrossRefGoogle Scholar
  21. 21.
    Verhoef J, Wiegant V M, De Wield D: Regional distribution ofα-and γ-type endorphins in rat brain. Europ J Pharmacol 231: 454–460, 1982.Google Scholar
  22. 22.
    Von Zastrow M, Keith D E, Evans C J. Agonist-induced state of the ∂-opioid receptor that discriminates between opioid peptides and opiate alkaloids. Brain Res 44: 166–172, 1993.Google Scholar
  23. 23.
    Weitz C J, Faull K F, Goldstein A. Synthesis of the skeleton of the morphine molecule by mammalian liver. Nature 330: 674–677, 1987.PubMedCrossRefGoogle Scholar
  24. 24.
    Yaksh T L, Harty G J. Pharmacology of the allodynia in rats evoked by high dose intrathecal morphine. J Pharmacol Exp Ther 244: 501–507, 1988.PubMedGoogle Scholar

Copyright information

© Springer-Verlag Wien 1995

Authors and Affiliations

  • A. Tagliamonte
    • 1
  • M. Guarna
    • 2
  • E. Bianchi
    • 1
  1. 1.Institute of PharmacologyUniversity of SienaItaly
  2. 2.Institute of Histology and General EmbryologyUniversity of SienaItaly

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