The Scientist
September 21, 2004
Human cells produce morphine - Results of biosynthesis studies may
improve understanding of pain, immunity, and behavior | By Charles Q
Choi
Researchers in Germany have found solid evidence that human cells can
generate morphine. Their findings, reported this week in PNAS, may help
resolve years of debate.
"If this morphine [that] humans produce interacts with opiate receptors
in the body, this could open up a whole new era for understanding the
pharmacological modulation of pain, of immune response, and of
behavior," author Meinhart Zenk of Martin Luther University in Halle,
Germany, told The Scientist.
George Stefano, director of the Old Westbury Neuroscience Institute in
New York and a leading proponent of endogenous morphine's debated
existence, said the study, which he did not participate in, confirms
nearly 30 years of theories. In 2003, his group cloned an opiate
receptor from human tissues, mu3, that only reacts with morphine and is
found in immune, vascular, and neural tissues.
"This could demonstrate how endogenous morphine may work," Stefano told
The Scientist. "This could represent a brand new signaling pathway."
Morphine has been discovered for decades in trace amounts in animal
organs and fluids such as toad skin, cow brain, and human heart and
urine, as well as in invertebrates such as mussels. The most widely
accepted explanation was such morphine was of environmental origin,
since it also occurs in hay, lettuce, and milk.
To resolve the issue in animals, Zenk and colleagues used
isotope-labeled precursors to demonstrate the biosynthesis de novo of
morphine and its intermediates in human neuroblastoma and pancreas
carcinoma cells.
In the plant kingdom, a pair of oxygen atoms is incorporated into each
morphine molecule during the transformation of two molecules of
L-tyrosine into a pair of dopamine molecules. In the latest study, Zenk
and colleagues found that neuroblastoma cells raised in an
oxygen-18-enriched atmosphere generated morphine with a molecular weight
4 mass units higher than morphine produced in cells grown in a regular
oxygen-16 atmosphere, which indicated the presence of two atoms of
oxygen-18 per morphine molecule. Pancreas cells grown in an oxygen-18
atmosphere also yielded isotope-labeled reticuline and norlaudanosoline,
which are morphine precursors.
The researchers also supplied carbon-13-labeled morphine precursor L-
tyramine to neuroblastoma cells. The resulting morphine was 6 mass units
heavier than normal, corresponding to the incorporation of one molecule
of carbon-13-labeled tyramine. Ion chromatograms showed the tyramine
exclusively labeled the cyclohexane ring of morphine, a pattern that
exactly follows that of the poppy plant, the researchers explained.
"Although much time and effort has been spent in the past to avoid
contamination," said Thomas Bilfinger of the State University of New
York at Stony Brook, who did not participate in this study, "a low-level
exogenous source such as food could not be completely excluded, and so
it is nice to see that unequivocally morphine is present in human cells
at a nanomolar range."
In the poppy, S-reticuline is converted to R-reticuline, which in turn
is transformed into morphine with R configuration at carbon atom C-9.
The reticuline discovered in the human cell lines was S-reticuline, and
when neuroblastoma cells were supplied with carbon-13-labeled
S-reticuline, the resultant morphine was also R configured. This
suggests human cells carry out the same stereochemistry conversion as in
plants, Zenk said. His group plans to identify the genes and enzymes
behind the human morphine biosynthesis pathway.
"The chance-through convergent evolution-of making the same
intermediates and using enzymes that must be similar because they're
catalyzing stereospecific reactions-that's pretty remote. This
biosynthetic pathway probably existed before animals and plants
diverged," Stefano said.
Gregory Fricchione, associate chief of psychiatry of Massachusetts
General Hospital in Boston who was not involved in this study, noted
morphine is a product of the dopamine pathway, which in turn is central
to the brain's reward and motivation circuitry. Addictive behavior,
social attachment behavior, and pain mechanisms are examples of reward
and motivation functions that endogenous morphine may impact.
"If endogenous morphine proves to be physiologically active, then we can
suspect it of playing a role in the functions dopamine is playing a role
in, a very exciting prospect for neuropsychiatry and its disorders,"
Fricchione told The Scientist.
Links for this article
C. Poeaknapo et al., "Endogenous formation of morphine in human cells,"
PNAS, 101:14091-6, September 28, 2004. http://www.pnas.org
Meinhart H. Zenk
http://www4.nationalacademies.org/nas/naspub.nsf/(urllinks)/NAS
-58N433?opendocument
George B. Stefano
http://www.sunynri.org/members.htm#George%20B.%20Stefano,%20Ph.D
P. Cadet et al., "Molecular identification and functional expression of
mu3, a novel alternatively spliced variant of the human mu opiate
receptor gene," J Immunol, 170: 5118-23, May 15, 2003.
Thomas Bilfinger
http://www.rfsuny.org/Science_Engineering_Medicine_Honorees/Bil
finger.htm
Gregory Lewis Fricchione
http://www.mgh.harvard.edu/doctor/Medical_Professional_Detail.a
sp?MPR=7332&ON=21586
C2004, The Scientist Inc. in association with BioMed Central.
__________________________________
Do you Yahoo!?
Yahoo! Mail - 50x more storage than other providers!
http://promotions.yahoo.com/new_mail
---------------------------------------------
Nonpartisan ME/CFS Petition: http://www.petitiononline.com/CFS2004/
Send posts to mailto:[log in to unmask]
Join or leave the list at http://www.co-cure.org/sub.htm
Select list topic options at http://www.co-cure.org/topics.htm
Co-Cure Archives: http://listserv.nodak.edu/archives/co-cure.html
---------------------------------------------
To unsubscribe, send an email to: [log in to unmask]
To contact the List owner: [log in to unmask]
Yahoo! Groups Links
<*> To visit your group on the web, go to:
http://groups.yahoo.com/group/CFS-FM_INFO/
<*> To unsubscribe from this group, send an email to:
[log in to unmask]
<*> Your use of Yahoo! Groups is subject to:
http://docs.yahoo.com/info/terms/
|
