Skip to main content

Advertisement

SpringerLink
Log in

Norlaudanosoline and Nicotine Increase Endogenous Ganglionic Morphine Levels: Nicotine Addiction

  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Summary

1. Given the presence of morphine, its metabolites and precursors, e.g., norlaudanosoline, in mammalian and invertebrate tissues, it became important to determine if exposing normal excised ganglia to norlaudanosoline would result in increasing endogenous morphine levels.

2. Mytilus edulis pedal ganglia contain 2.2 ± 0.41 ng/g wet weight morphine as determined by high pressure liquid chromatography coupled to electrochemical detection and radioimmunoassay.

3. Incubation of M. edulis pedal ganglia with norlaudanosoline, a morphine precursor, resulted in a concentration- and time-dependent statistical increase in endogenous morphine levels (6.9 ± 1.24 ng/g).

4. Injection of animals with nicotine also increased endogenous morphine levels in a manner that was antagonized by atropine, suggesting that nicotine addiction may be related to altering endogenous morphine levels in mammals.

5. We surmise that norlaudanosoline is being converted to morphine, demonstrating that invertebrate neural tissue can synthesize morphine.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.
Fig. 3.

Similar content being viewed by others

Abbreviations

HPLC:

High pressure liquid chromatography

THP:

tetrahydropapoverine/norlaudanosoline

PBS:

phosphate buffered saline

RIA:

radioimmunoassay

REFERENCES

  • Amann, T., and Zenk, M. H. (1991). Formation of the morphine precursor salutaridine is catalyzed by a cytochrome P-450 enzyme mammalian liver. Tetrahedron Lett. 32:3675–3678.

    Article  CAS  Google Scholar 

  • Amann, T., Roos, P. H., Huh, H., and Zenk, M. H. (1995). Purification and characterization of a cytochrome P450 enzyme from pig liver, catalyzing the phenol oxidative coupling of (R)-reticuline to salutaridine, the critical step in morphine biosynthesis. Heterocycles 40:425–440.

    Article  CAS  Google Scholar 

  • Brochmann-Hanssen, E. (1985). Biosynthesis of morphinan alkaloids. In Phillipson, J. D., Roberts, M. F., and Zenk, M. H. (eds). The Chemistry and Biology of Isoquinoline Alkaloids. Springer-Verlag, Berlin, Heidelberg, pp. 229–239.

    Google Scholar 

  • Cadet, P., Mantione, K. J., and Stefano, G. B. (2003). Molecular identification and functional expression of mu3, a novel alternatively spliced variant of the human mu opiate receptor gene. J. Immunol. 170:5118–5123.

    PubMed  CAS  Google Scholar 

  • Casares, F. M., McElroy, A., Mantione, K. J., Baggerman, G., Zhu, W., and Stefano, G. B. (2005). The American lobster, Homarus americanus, contains morphine that is coupled to nitric oxide release in its nervous and immune tissues: Evidence for neurotransmitter and hormonal signaling. Neuroendocrinol. Lett. 26:89–97.

    PubMed  CAS  Google Scholar 

  • Dani, J. A., and Harris, R. A. (2005). Nicotine addiction and comorbidity with alcohol abuse and mental illness. Nat. Neurosci. 8:1465–1470.

    Article  PubMed  CAS  Google Scholar 

  • Davis, V. E., and Walsh, M. J. (1970). Alcohol, amines and alkaloids: A possible biochemical basis for alcohol addiction. Science 167:1005–1007.

    Article  PubMed  CAS  Google Scholar 

  • Donnerer, J., Oka, K., Brossi, A., Rice, K. C., and Spector, S. (1986). Presence and formation of codeine and morphine in the rat. Proc. Natl. Acad. Sci. USA 83:4566–4567.

    Article  PubMed  CAS  Google Scholar 

  • Dowell, C., Olivera, B. M., Garrett, J. E., Staheli, S. T., Watkins, M., Kuryatov, A., Yoshikami, D., Lindstrom, J. M., and McIntosh, J. M. (2003). Alpha-conotoxin PIA is selective for alpha6 subunit-containing nicotinic acetylcholine receptors. J. Neurosci. 23:8445–8452.

    PubMed  CAS  Google Scholar 

  • Epple, A., Nibbio, B., Spector, S., and Brinn, J. (1994). Endogenous codeine: autocrine regulator of catecholamine release from chromaffin cells. Life Sci. 54:695–702.

    Article  PubMed  CAS  Google Scholar 

  • Esch, T., and Stefano, G. B. (2004). The neurobiology of pleasure, reward processes, addiction and their health implications. Neuroendocrinol. Lett. 25:235–251.

    Article  PubMed  CAS  Google Scholar 

  • Fricchione,, G. L., and Stefano,, G. B. (2005). Placebo neural systems: Nitric oxide, morphine and the dopamine brain reward and motivation circuitries. Med. Sci. Monit. 11:MS54–MS65.

    PubMed  CAS  Google Scholar 

  • Goldstein, A., Barrett, R. W., James, I. F., Lowney, L. I., Weitz, C., Knipmeyer, L. I., and Rapoport, H. (1985). Morphine and other opiates from beef brain and adrenal. Proc. Natl. Acad. Sci. USA 82:5203–5207.

    Article  PubMed  CAS  Google Scholar 

  • Goumon, Y., and Stefano, G. B. (2000). Identification of morphine in the rat adrenal gland. Mol. Brain Res. 77:267–269.

    Article  PubMed  CAS  Google Scholar 

  • Goumon, Y., Casares, F. Pryor, S., Ferguson, L. Brownwell, B., Cadet, P., Rialas, C. M., Welters, I., Sonetti, D., and Stefano, G. B. (2000). Ascaris suum, an internal parasite, produces morphine. J. Immunol. 165:339–343.

    PubMed  CAS  Google Scholar 

  • Goumon, Y., Casares, F., Zhu, W., and Stefano, G. B. (2001). The presence of morphine in ganglionic tissues of Modiolus deminissus: A highly sensitive method of quantitation for morphine and its derivatives. Mol. Brain Res. 86:184–188.

    Article  PubMed  CAS  Google Scholar 

  • Greenberg, R. S., and Cohen, G. (1973). Tetrahydroisoquinoline alkaloids: stimulated secretion from the adrenal medulla. J. Pharmacol. Exp. Ther. 184:119–128.

    PubMed  CAS  Google Scholar 

  • Guarna, M., Ghelardini, C., Galeotti, N., Stefano, G. B., and Bianchi, E. (2005). Neurotransmitter role of endogenous morphine in CNS. Med. Sci. Monit. 11:RA190–RA193.

    PubMed  CAS  Google Scholar 

  • Heikkila, R., Cohen, G., and Dembiec, D. (1971). Tetrahydroisoquinoline alkaloids: uptake by rat brain homogenates and inhibition of catecholamine uptake. J. Pharmacol. Exp. Ther. 179:250–258.

    PubMed  CAS  Google Scholar 

  • Hellwig, G., and Achazi, R. K. (1991). ACh and 5-HT induced changes in the concentration of cytosolic inositol trisphosphate (InsP3) and inositol bisphosphate (InsP2) in the ABRM of Mytilus edulis L. Comp. Biochem Physiol C. 100:343–348.

    Article  PubMed  CAS  Google Scholar 

  • Kodaira, H., and Spector, S. (1988). Transformation of thebaine to oripavine, codeine, and morphine by rat liver, kidney, and brain microsomes. Proc. Natl. Acad. Sci. USA 85:1267–1271.

    Article  PubMed  Google Scholar 

  • Kodaira, H., Listek, C. A., Jardine, I., Arimura, A., and Spector, S. (1989). Identification of the convusant opiate thebaine in the mammalian brain. Proc. Natl. Acad. Sci. USA 86:716–719.

    Article  PubMed  CAS  Google Scholar 

  • Lee, C. M., Lin, J. T., and Hwang, J. C. (1998). Pharmacological properties of ACh receptors on the heart of the marine bivalve Meretrix lusoria. Chin. J. Physiol. 41:19–24.

    PubMed  CAS  Google Scholar 

  • Lee, S. C. and Spector, S. (1991). DON’T USE Changes in Endogenous Morphine and Codeine contents in the fasting rat. J. Pharmacol. Exp. Ther. 257:647–652.

    PubMed  CAS  Google Scholar 

  • Leung, M. K., Dissous, C., Capron, A., Woldegaber, H., Duvaux-Miret, O., Pryor, S. C., and Stefano, G. B. (1995). Schistosoma mansoni: The presence and potential use of opiate-like substances. Exp. Parasit. 81:208–215.

    Article  PubMed  CAS  Google Scholar 

  • Mantione, K. J., Goumon, Y. Esch, T., and Stefano, G. B. (2005). Morphine 6β glucuronide: Fortuitous morphine metabolite or preferred peripheral regulatory opiate? Med. Sci. Monit. 11:MS43–MS46.

    PubMed  CAS  Google Scholar 

  • Nakajima, M., and Yokoi, T. (2005). Interindividual variability in nicotine metabolism: C-oxidation and glucuronidation. Drug Metab Pharmacokinet 20:227–235.

    Article  PubMed  CAS  Google Scholar 

  • Neri, C., Guarna, M., Bianchi, E., Sonetti, D., Matteucci, G., and Stefano, G. B. (2004). Endogenous morphine and codeine in the brain of non-human primate. Med. Sci. Monit. 10:MS1–MS5.

    PubMed  CAS  Google Scholar 

  • Poeaknapo, C., Schmidt, J., Brandsch, M. Dräger, B., and Zenk, M. H. (2004). Endogenous formation of morphine in human cells. Proc. Natl. Acad. Sci. USA 101:14091–14096.

    Article  PubMed  CAS  Google Scholar 

  • Pryor, S. C., Zhu, W., Cadet, P., Bianchi, E., Guarna, M., and Stefano, G. B. (2005). Endogenous morphine: opening new doors for the treatment of pain and addiction. Expert. Opin. Biol. Ther. 5:893–906.

    Article  PubMed  CAS  Google Scholar 

  • Sindrup, S. H., Poulsen, L., Brosen, K., Arendt-Nielsen, L., and Gram, L. F. (1993). Are poor metabolisers of sparteine/debrisoquine less pain tolerant than extensive metabolisers? Pain 53:335–339.

    Article  PubMed  CAS  Google Scholar 

  • Sonetti, D., Mola, L., Casares, F., Bianchi, E., Guarna, M., and Stefano, G. B. (1999). Endogenous morphine levels increase in molluscan neural and immune tissues after physical trauma. Brain Res. 835:137–147.

    Article  PubMed  CAS  Google Scholar 

  • Sonetti, D., Peruzzi, E., and Stefano, G. B. (2005). Endogenous morphine and ACTH association in neural tissues. Med. Sci. Monit. 11:MS22–MS30.

    PubMed  CAS  Google Scholar 

  • Stefano, G. B. (1998). Autoimmunovascular regulation: Morphine and anandamide stimulated nitric oxide release. J. Neuroimmunol. 83:70–76.

    Article  PubMed  CAS  Google Scholar 

  • Stefano, G. B., and Scharrer, B. (1994). Endogenous morphine and related opiates, a new class of chemical messengers. Adv. Neuroimmunol. 4:57–68.

    PubMed  CAS  Google Scholar 

  • Stefano, G. B., Teoh, M. B., Grant, A., Reid, C., Teoh, H., and Hughes, T. K. (1994). Electric field exposure activates immunocytes: Evidence for calcium dependency. Electro. Magnetobiol. 13:123–136.

    Google Scholar 

  • Stefano, G. B., Digenis, A., Spector, S., Leung, M. K., Bilfinger, T. V., Makman, M. H., Scharrer, B., and Abumrad, N. N. (1993). Opiate-like substances in an invertebrate, a novel opiate receptor on invertebrate and human immunocytes, and a role in immunosuppression. Proc. Natl. Acad. Sci. USA 90:11099–11103.

    Article  PubMed  CAS  Google Scholar 

  • Stefano, G. B., Goumon, Y., Bilfinger, T. V., Welters, I., and Cadet, P. (2000a). Basal nitric oxide limits immune, nervous and cardiovascular excitation: Human endothelia express a mu opiate receptor. Prog. Neurobiol. 60:531–544.

    Article  Google Scholar 

  • Stefano, G. B., Goumon, Y., Casares, F., Cadet, P., Fricchione, G. L., Rialas, C., Peter, D., Sonetti, D., Guarna, M., Welters, I., and Bianchi, E. (2000b). Endogenous morphine. Trends in Neurosci. 9:436–442.

    Article  Google Scholar 

  • Stefano, G. B., Burrill, J. D., Labur, S., Blake, J., and Cadet, P. (2005a). Regulation of various genes in human leukocytes acutely exposed to morphine: Expression microarray analysis. Med. Sci. Monit. 11:MS35–MS42.

    PubMed  CAS  Google Scholar 

  • Stefano, G. B., Fricchione, G. L., Goumon, Y., and Esch, T. (2005b). Pain, immunity, opiate and opioid compounds and health. Med. Sci. Monit. 11:MS47–MS53.

    PubMed  CAS  Google Scholar 

  • Turner, A. J., Baker, K. M., Algeri, S., Erigerio, A., and Garattini, S. (1974). Tetrahydropapaveroline: Formation in vivo and in vitro in rat brain. Life Sci. 14:2247–2257.

    Article  PubMed  CAS  Google Scholar 

  • Vehovszky, A, and Salanki, J. (1983). Pharmacological characterization of postsynaptic potentials evoked in the bimodal pacemaker neuron of Helix pomatia L. Acta Physiol. Hung. 62:35–46.

    PubMed  CAS  Google Scholar 

  • Wright, T. J., and Huddart, H. (2002). The nature of the acetylcholine and 5-hydroxytryptamine receptors in buccal smooth muscle of the pest slug Deroceras reticulatum. J. Comp. Physiol. [B] 172:237–249.

    CAS  Google Scholar 

  • Yamano, S., Kageura, E., Ishida, T., and Toki, S. (1985). Purification and characterization of guinea pig liver morphine 6-dehydrogenase. J. Biol. Chem. 260:5259–5264.

    PubMed  CAS  Google Scholar 

  • Zhu, W., and Stefano, G. B. (2004). Reticuline exposure to invertebrate ganglia increases endogenous morphine levels. Neuro. Endocrinol Lett. 25:323–330.

    PubMed  CAS  Google Scholar 

  • Zhu, W., Baggerman, G., Goumon, Y., Casares, F., Brownawell, B., and Stefano, G. B. (2001a). Presence of morphine and morphine-6-glucuronide in the marine mollusk Mytilus edulis ganglia determined by GC/MS and Q-TOF-MS. Starvation increases opiate alkaloid levels. Brain Res. Mol. Brain Res. 88:155–160.

    Article  PubMed  CAS  Google Scholar 

  • Zhu, W., Baggerman, G., Goumon, Y., Zenk, M. H., and Stefano, G. B. (2001b). Identification of morphine and morphine-6-glucuronide in the adrenal medullary chromaffin PC-12 cell line by nano electrospray ionization double quadrupole orthogonal acceleration time of flight mass spectrometry. Eur. J. of Mass Spect. 7:25–28.

    CAS  Google Scholar 

  • Zhu, W., Baggerman, G., Secor, W. E., Casares, F., Pryor, S. C., Fricchione, G. L., Ruiz-Tiben, E., Eberhard, M. L., Bimi, L., and Stefano, G. B. (2002a). Dracunculus medinensis and Schistosoma mansoni contain opiate alkaloids. Annal. Trop. Med. Parasitol. 96:309–316.

    Article  CAS  Google Scholar 

  • Zhu, W., Ma, Y., and Stefano, G. B. (2002b). Presence of isoquinoline alkaloids in molluscan ganglia. Neuroendocrinol. Lett. 23:329–334.

    PubMed  CAS  Google Scholar 

  • Zhu, W., Ma, Y., Cadet, P., Yu, D., Bilfinger, T. V., Bianchi, E., and Stefano, G. B. (2003). Presence of reticuline in rat brain: A pathway for morphine biosynthesis. Mol. Brain Res. 117:83–90.

    Article  PubMed  CAS  Google Scholar 

  • Zhu, W., Ma, Y., Bell, A., Esch, T., Guarna, M., Bilfinger, T. V., Bianchi, E., and Stefano, G. B. (2004a). Presence of morphine in rat amygdala: Evidence for the mu3 opiate receptor subtype via nitric oxide release in limbic structures. Med. Sci. Monit. 10:BR433–BR439.

    PubMed  CAS  Google Scholar 

  • Zhu, W., Pryor, S. C., Putnam, J., Cadet, P., and Stefano, G. B. (2004b). Opiate alkaloids and nitric oxide production in the nematode Ascaris suum. J. Parasitol. 90:15–22.

    Article  PubMed  CAS  Google Scholar 

  • Zhu, W., Cadet, P., Baggerman, G., Mantione, K. J., and Stefano, G. B. (2005a). Human white blood cells synthesize morphine: CYP2D6 modulation. J. Immunol. 175:7357–7362.

    Google Scholar 

  • Zhu, W., Mantione, K. J., Shen, L., Cadet, P., Esch, T., Goumon, Y., Bianchi, E., Sonetti, D., and Stefano, G. B. (2005b). Tyrosine and tyramine increase endogenous ganglionic morphine and dopamine levels in vitro and in vivo: CYP2D6 and tyrosine hydroxylase modulation demonstrates a dopamine coupling. Med. Sci. Monit. 11:BR397–BR404.

    PubMed  CAS  Google Scholar 

  • Zhu, W., Mantione, K. J., Shen, L., and Stefano, G. B. (2005c). In vivo and in vitro L-DOPA exposure increases ganglionic morphine levels. Med. Sci. Monit. 11:MS1–MS5.

    PubMed  CAS  Google Scholar 

Download references

ACKNOWLEDGMENTS

This work was supported, in part, by the following grants: NIMH 47392. Mr. Brian Lee is a member of a High School Research Program in association with the Long Island Conservatory.

Author information

Authors and Affiliations

  1. Neuroscience Research Institute, State University of New York, College at Old Westbury, P.O. Box 210, Old Westbury, New York, 11568, USA

    Wei Zhu, Kirk J. Mantione, Lihua Shen, Brian Lee & George B. Stefano

Authors
  1. Wei Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kirk J. Mantione
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lihua Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Brian Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. George B. Stefano
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to George B. Stefano.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhu, W., Mantione, K.J., Shen, L. et al. Norlaudanosoline and Nicotine Increase Endogenous Ganglionic Morphine Levels: Nicotine Addiction. Cell Mol Neurobiol 26, 1035–1043 (2006). https://doi.org/10.1007/s10571-006-9021-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10571-006-9021-4

KEY WORDS:

Search

Navigation