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A micrograph of an injured nerve, showing a decrease in myelinated fibers (pink) and an increase in fibrous scar tissue (yellow).

Big pain, small molecule

Neuropathic pain is a condition in which damaged, dysfunctional or poorly repaired nerves transmit incorrect signals, resulting in an often chronic, crippling range of afflictions that affect millions of people worldwide.

There are no effective treatments. Indeed, the fundamental mechanisms of neuropathic pain remain largely unexplained. 

However, in a paper published in the January 22 issue of Nature Chemical Biology, scientists at The Scripps Research Institute, the University of California, San Diego School of Pharmacy and Pharmaceutical Sciences, Washington University in St. Louis and elsewhere have identified a small molecule that may provide a key to eventually, effectively treating neuropathic pain.

The small molecule is called dimethylsphingosine (DMS), a little-known byproduct of cellular reactions involved in producing and sheathing nerve fibers with myelin. Myelin is a fatty substance that acts as insulation around nerve fibers, helping to contain and concentrate passage of their signals.

“We think this is a big step forward in understanding and treating neuropathic pain,” said lead author Gary J. Patti, a research associate at Scripps Research during the study, and now an assistant professor of genetics, chemistry, and medicine at Washington University in St. Louis.

Patti and colleagues identified DMS using a relatively new approach called metabolomics, which measures and contrasts the products of cellular metabolism, such as sugars and amino acids, in much the same way that genomics focuses on genes and their expression or proteomics looks at differences in the levels and activities of proteins.

“These are the molecules that are actually being transformed during cellular activity, and tracking them provides more direct information on what’s happening at a biochemical level,” said Patti.

In test rats with spinal cord injuries and neuropathic pain, the researchers found that DMS levels were abnormally high in select tissues. Injections of the molecule appeared to produce pain as well.

“Once Dr. Patti had identified DMS in the metabolomics screen, we were able to directly test the effect of dosing DMS to produce neuropathic pain in rats, and to characterize the mechanism of the reactive response that DMS produces in astrocytes, neuron-supporting cells found in the spinal cord,” said Marianne Manchester, PhD, a professor in the Skaggs School of Pharmacy and Pharmaceutical Sciences at UC San Diego and a study co-author.

“These results highlight the power of combining metabolomics and in vivo studies to identify new biochemical pathways that can be directly validated and tested for therapeutic benefit.”

DMS appears to cause pain in part by stimulating the release of pro-inflammatory molecules from astrocytes. The scientists are now investigating exactly how DMS works and, more importantly, whether specific inhibitors of the small molecule might successfully ease or prevent neuropathic pain.

“We’re very excited about this therapeutic metabolomics approach,” said Gary Siuzdak, a senior investigator in the study, professor of chemistry and molecular biology and director of the Scripps Research Center for Metabolomics. “In fact, we’re already involved in several other projects in which metabolites are giving us a direct indication of disease biochemistry and potential treatments.”