Scientists have a new understanding of what causes neuropathic pain to persist, a finding that could lead to development of new drugs to fight pain. Millions of people suffer from neuropathic pain, a chronic pain triggered by nerve damage. Why that pain persists has long been a mystery and current treatments are often ineffective.
A team led by scientists at the Scripps Research Institute has discovered that dimethylsphingosine (DMS), a byproduct of cellular membranes in the nervous system, is produced at abnormally high levels in rats with neuropathic pain. DMS also appears to cause pain when injected into the rats. The finding suggests that inhibiting the molecule could be an important target for drug developers.
“We think that this is a big step forward in understanding and treating neuropathic pain,” said 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 is a lead author of a report on the study, which appears online in the journal Nature Chemical Biology.
The DMS finding was unexpected. While studying neuropathic pain in the legs of lab rats, scientists collected blood plasma and tissue from the injured nerves, as well as tissue from the rats’ spinal cords. Then they compared the tissues to those found in rats not suffering from neuropathic pain. To their surprise, scientists found major abnormalities in metabolite levels in tissue from the spinal cord, but not in the blood plasma or nerves of the injured rats’ legs. Metabolites contain sugars, vitamins and amino acids that serve as the building blocks of cells.
The researchers then set up a test to see which of the abnormal metabolites in the spinal cord could evoke signs of pain signaling. One metabolite stood out: DMS.
“This is the first characterization and quantitation of DMS as a naturally occurring compound,” Patti noted. When the scientists injected DMS into healthy rats, at a dose similar to that found in the nerve-injured rats, it induced pain.
DMS appears to cause pain by stimulating the release of inflammatory molecules. Researchers are now trying to learn more about how DMS induces pain and are testing inhibitors of DMS production. That may lead to a new class of drugs to treat and prevent neuropathic pain.
“We’re very excited about this therapeutic metabolomics approach,” said Gary Siuzdak, a 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.”