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Ship : Costa Concordia

On the night of Friday, January 13 2012, the luxury cruise ship Costa Concordia ran aground off Isola del Giglio, Italy. Of the more than 4,200 aboard, 13 have been confirmed dead, 64 injured, 20 remain missing, and hopes of finding any more survivors are fading quickly.

 

Untargeted metabolic profiling implicates a new suite of metabolites that may be involved in nerve damage-induced pain.

By Jeffrey M. Perkel |

A rendition of the bioinformatics analysis superimposed between two neurons. Combined with the METLIN metabolite database, the analysis ultimately revealed DMS as a naturally occurring metabolite and as an active molecule in chronic pain.Gary Siuzdak and Gary Patti

An analysis of the metabolic profile of a rat model of chronic pain has identified novel dysregulated metabolites that may underlie the condition, according to a study published today (January 22) in Nature Chemical Biology. If the results hold up in humans, one of these metabolites, which has not previously been associated with neuropathic pain, could potentially serve as both a molecular indicator of and therapeutic target for the condition, for which few treatment options exist.

The findings are “a great example of how metabolomics is leading to novel insights into, in this case pain, and how that’s mediated,” said Lloyd Sumner, a metabolomics researcher at the Samuel Roberts Noble Foundation who was not involved in the research.

In the United States, more than 30 percent of adults suffer from chronic pain of one form or another. Neuropathic pain is a form of chronic pain induced by previous nerve damage, like the phantom pain felt by those who have lost limbs. “Neuropathic pain is the worst,” because it’s the hardest to treat, said Gary Patti, an assistant professor at Washington University in St. Louis and lead author of the study. “It is a disease with an unmet medical need.”

While a research associate at the Scripps Research Institute in La Jolla, California, Patti and his then-research advisor, Gary Siuzdak, senior director of the Center for Metabolomics and Mass Spectrometry and professor of Chemistry and Molecular Biology at Scripps, used an animal model of the condition, in which rats are subjected to tibial nerve transection (TNT)—that is, the tibial nerve in one leg is severed and allowed to heal. Three weeks later, these animals apparently continue to experience pain, though the wound itself has healed.

Rather than studying the genes involved, or the proteins they encode, the researchers identified instead potential metabolic players in this response. Metabolites, after all, are the ultimate molecular arbiters of biological function, the molecules upon which proteins often act.

The team used an approach called untargeted metabolomics to profile the metabolites at the site of injury, the neural cell body of the damaged nerve, the dorsal horn (where the damaged nerve connects to the spinal cord), , and in the blood. It was essentially a molecular fishing expedition—collecting boatloads of data that can point to molecules that may be involved.

“We are seeing many more metabolites than can be accounted for by the canonical pathways in biochemistry textbooks,” Patti said. “The untargeted approach allows us to explore that space.”

In total, the team observed some 733 mass spectrometric peaks whose levels varied at least 2-fold between control and TNT animals. The vast majority of them were localized not at the site of injury, but at the dorsal horn of the spinal cord. In particular, the researchers noticed differential expression of several members of the sphingomyelin-ceramide pathway, a lipid metabolic pathway linked to, among other things, myelin formation and programmed cell death. “That screamed at us that this pathway was important,” Siuzdak said.

The team then tested these different molecules directly to see whether they could induce a pain response on their own. Indeed, one such metabolite, called N,N-dimethylsphingosine (DMS),  induced symptoms akin to neuropathic pain when injected directly into the animals at comparable concentrations to those found in TNT rats a few weeks after injury. The authors also determined that DMS may function by activating astrocytes, inducing them to release cytokines such as IL-1beta and MCP-1, both of which are associated with inflammation and pain.

If validated in humans, DMS could potentially serve as a biomarker of for neuropathic pain, Sumner said. Furthermore, “by defining specific molecules involved in the pain response, [the finding] also provides a pathway for mediating the pain management,” he added. “If they can mediate how those molecules are made and modify that with inhibitors or other medications, then the opportunity for pain management is substantial.”

Indeed, Siuzdak calls his approach “therapeutic metabolomics.” “You survey the pathways, find molecules that are dysregulated, and then find enzymes that produce those molecules. We are currently trying to figure out explicitly what enzyme produces DMS, because that’s a much more specific target.”

(See this month’s feature article on other efforts to manage chronic pain.)

G.J. Patti et al., “Metabolomics implicates altered sphingolipids in chronic pain of neuropathic origin,” Nature Chemical Biology, DOI: 10.1038/nchembio, 2012.

Source: TheScientist

http://the-scientist.com/2012/01/22/metabolite/

Posted by

Robert Karl Stonjek

Scanning the Psychedelic Brain

Brain scans reveal the surprising secret of magic mushrooms’ hallucinogenic effect.

By Ruth Williams | 

Psilocybin cubensis mushroomFlickr, Kristie Gianopulos

The geometric visuals and vivid imaginings experienced by those tripping on mushrooms are not, as scientists had suspected, the result of increased brain activity, according to a report out today (23 January) in Proceedings of the National Academy of Sciences. Instead, under the influence of psilocybin—the psychedelic component of magic mushrooms—brain activity and connectivity decrease. The reduced connectivity might be what frees people’s minds from normal constraints, the researchers propose.
“It was often thought to be the case that these classic hallucinogens must increase brain function—you know, they expand awareness, expand consciousness—but in fact what we see is decreased activity,” said Roland Griffiths of Johns Hopkins Bayview Medical Center, who was not involved in the study.
“I have to say this was totally unexpected,” said David Nutt of Imperial College London, who led the study.  But, he added, “when you get exactly the opposite result to what you predict, you know it is right, because there is no bias.”
Although humans have used magic mushrooms for centuries if not millennia, very little is known about how they work. Soon after psychedelics gained widespread popularity in the 1950s and 60s, “the drugs were criminalized and the research into their beneficial uses was suppressed,” explained Rick Doblin of the Multidisciplinary Association for Psychedelic Studies, which partly funded the study.
Because of psilocybin’s illegality, organizing and performing the new study was a regulatory ordeal, said Nutt. “You have to go through lots of hoops and get special licenses. You’ve got to have special cupboards and fridges to hold it… it’s a real rigmarole.”
There was also the ethical concern that the volunteers might experience a so-called bad trip. Although psilocybin is generally associated with feelings of euphoria and human connectedness, it can sometimes cause anxiety. Should this have happened, Nutt explained, the person would have been kept safe, calmed down, and if necessary, given Valium. To lessen the chance of a bad experience, all 30 volunteers were chosen on the basis that they had taken hallucinogens at least once before and so would know what to expect.
It was worth all the effort, said Nutt. Psychedelics offer not only insight into the biology of human perception and cognition, but may also be of therapeutic use. And, as it happened, he added, “they all had a good experience—some had very good experiences, some had experiences they said were very meaningful and altered the way they thought about life.”
Nutt and his team administered psilocybin to the volunteers by a slow—one minute long—injection while their brains were scanned by functional magnetic resonance imaging (fMRI). “We wanted to know exactly what happens when you make that transition from the normal state to the psychedelic state,” he explained.
The first 15 volunteers had their brains scanned by arterial spin labeling (ASL), an fMRI technique that examines blood flow. After seeing widespread decreases in flow, the researchers were so surprised they scanned a further 15 volunteers by blood-oxygen level dependent (BOLD) fMRI, which more directly measures metabolism. Both gave strikingly similar results.
Brain blood flow and activity were particularly decreased in the medial prefrontal cortex—a region involved in emotions, learning, memory, and executive function—and the posterior cingulate cortex, the function of which is less clear.
The team also used the fMRI data to look at functional connectivity between these two regions over time, and found that their deactivation was linked. “Assessing circuitry in terms of connectivity is a more sophisticated and informative approach to understanding function, so I think that is the real strength of their work,” said Mark Geyer of the University of San Diego, California, who did not participate in the study.
The two regions are connected by the default mode network (DMN), which integrates brain functions including sensations, memories, and ambitions. “It’s kind of who you are and how you see the world,” said Nutt. The DMN might also act as a cognitive constraining mechanism—to filter and make sense of information. Reduced DMN activity, therefore, might enable an unconstrained mode of cognition, such as that experienced on a magic mushroom trip.
Interestingly, DMN activity is hyperactive in people with depression, suggesting that psilocybin may be effective as a depression treatment.

Taking a hallucinogen to deal with depression might not appeal to everyone. But for those willing to give it a try, the hope is that the need for all medication might be reduced or even eradicated. “Psilocybin would only be given a few times under supervision of a therapist…with the hope that at the end of the process you are no longer dependent on a daily medication,” explained Doblin. “It would be like opening a door and showing them that there is another way of being,” said Nutt.

R.L. Carhart-Harris et al., “Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin,” Proceedings of the National Academy of Sciences, doi/10.1073/pnas.1119598109, 2012.
Source: TheScientist
http://the-scientist.com/2012/01/23/scanning-the-psychedelic-brain/
Posted by
Robert Karl Stonjek