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
Posted by
Robert Karl Stonjek
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