Human cells produce morphine

Results of biosynthesis studies may improve understanding of pain, immunity, and behavior

Charles Choi(
Sep 20, 2004

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.