Published online 26 April 2010 | Nature | doi:10.1038/news.2010.202

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Mammals could have opiate factories.

Mice can synthesize morphine from various intermediate chemicals. N. Grobe & N. Weir

Mammals may possess the biochemical machinery to produce morphine — a painkiller found in the opium poppy, according to a new study.

Meinhart Zenk of the Donald Danforth Plant Science Center in St Louis, Missouri, and colleagues detected traces of morphine in the urine of mice after injecting chemical precursors of the drug. They report their findings today in the Proceedings of the National Academy of Sciences1.

Like other opioids, morphine is a potent, potentially addictive pain reliever. Scientists have speculated for decades that animals naturally synthesize morphine because specialized receptors in the brain respond to the drug. Trace amounts of morphine had been found in human urine and cells2. But studies using living animals yielded inconclusive results because of possible contamination from external sources of morphine in their food or in the environment.

"This paper seems to be one of the most definitive I've seen," says Chris Evans, a neurobiologist and expert on opioid drugs at the University of California, Los Angeles. "They've convincingly shown that there's a pathway there which could possibly produce morphine."

Mouse morphine

Alkaloids are ring-shaped chemical compounds that contain nitrogen. The presence of an alkaloid called tetrahydropapaveroline (THP) in brain tissue and urine has led to speculation that it may be a precursor to morphine made naturally inside the body.

The mouse pathway for making morphine is likely to have evolved independently from that of the opium poppy. A. Kohlberg, Leibniz Institute of Plant Biochemistry

The research team injected mice daily with THP and other potential morphine precursors for four days and evaluated the metabolites of these compounds in the urine. By labelling the precursors with deuterium (heavy hydrogen) to replace hydrogen atoms, they were able to distinguish the injected compounds from other sources of morphine, and thus eliminate the possibility of contamination. After isolating alkaloids from the urine samples the team analyzed their chemical make-up using highly sensitive mass spectrometry.

Zenk and his colleagues identified several intermediate biochemical steps between THP and morphine. After injecting THP, they found a four-ringed metabolite of THP called salutaridine in the urine. Salutaridine is an intermediate on the morphine-synthesis pathway in the opium poppy. Injecting salutaridine yielded a five-ringed opiate called thebaine, and injecting thebaine generated three similarly structured opiates: codeine, oripavine and morphine.

Trace evidence

Although the latter stages of morphine production are conserved between plants and mammals, the early stages differ: the first alkaloid intermediate in mammals, preceding salutaridine, has an extra hydroxyl (OH) group compared to that in plants. "It may seem trivial to you, but in biochemistry, hydroxylation more or less determines whether a baby is male or female," Zenk says. These differences suggest that the morphine pathways in mammals and plants evolved independently, he says.

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The researchers did not find any traces of morphine in blood or tissue. As a result, this study does not prove that mammals make morphine naturally, or that the compound would serve any specific purpose, such as pain relief or addiction, Evans says. "The question is whether there are significant quantities to have any effect on the endogenous receptors, which I think is unlikely."

Aside from detecting morphine in relevant organs, such as the brain and spinal cord, future studies should identify enzymes that are involved in transforming THP to morphine. Then scientists could interfere with the genes coding for the enzymes to determine their functional roles, Evans says. "To show that endogenous morphine naturally exists and has functional significance in mammals, I think there's still a lot to be done."

Zenk's team plans on using more sensitive techniques to look for traces of morphine in tissues. He'd also like to identify enzymes in the pathway and analyze how the formation of morphine fluctuates in humans depending on their pain levels. "Because it's a fact that morphine is found, we have to consider that there must be a function for it," Zenk says.