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Environmental Factor, August 2012

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New approach to alleviate chronic pain in diabetic patients

By Brant Hamel

Bruce Hammock, Ph.D.

Hammock directs the Superfund Research and Training Program,  NIH Training Program in Biotechnology, and NIEHS Combined Analytical Laboratory at UC Davis, where he has performed extensive research into applications of metabolomics methodologies. (Photo courtesy of UC Davis)

A new study funded by the NIEHS Superfund Research Program describes a novel mechanism for treating the chronic neuropathic pain associated with diabetes. More than 23 million Americans suffer from diabetes, and their consistently high glucose levels damage nerves leading to chronic pain and other issues.

Current pain treatments, such as analgesics, suffer from lack of efficacy for neuropathic pain or, in the case of narcotics, dangerous side effects, such as addiction. The current study, published in the July 10 issue of the Proceedings of the National Academy of Sciences, found that inhibition of soluble epoxide hydrolase (sEH) results in the increase of natural fatty acids, with anti-inflammatory effects that reduce sensations of pain in an animal model of type I diabetes.

Leading the research team was veteran NIEHS grantee Bruce Hammock, Ph.D., a distinguished professor of entomology at the University of California (UC), Davis and a member of the UC Davis Comprehensive Cancer Center. Among his many honors was his election to the National Academy of Sciences in 1999.

“Our data indicate that this drug candidate is more effective for neuropathic pain caused by diabetes than any of the prescription drugs now on the market,” Hammock was quoted as saying in a press release about the findings.

Blocking inflammation and pain by regulating fatty acid metabolism

Previous work by Hammock has led to the creation of multiple start-up companies, including one focused on the anti-inflammatory effects of sEH inhibitors to control blood pressure (see story). His current work focuses on another property of this class of compounds — the ability to increase epoxygenated fatty acids in the body that appear to selectively block pain sensations in a rat model of diabetes.

Hammock’s approach to treating the neuropathic pain associated with diabetes was to inhibit sEH, the enzyme that degrades epoxygenated fatty acids. This led to an increase in epoxygenated fatty acids that reduced pain through as yet unknown mechanisms. Multiple inhibitors were tested and one compound, 1-(1-methylsulfonyl-piperidin-4-yl)-3-(4-trifluoromethoxy-phenyl)-urea (TUPS), was found to be more efficacious than a ten-fold higher dose of the widely prescribed therapeutic gabapentin.

TUPS has been engineered to have more drug-like characteristics than previous generations of inhibitors, including increased solubility and bioavailabilty. In tests of its efficacy, the compound was able to reduce pain over a prolonged 4-day period, compared to daily doses needed for current treatments.

In addition, as the drug works to increase the level of a natural biological pain modulator, there may be decreased side effects compared to current treatments. The TUPS treatments did not affect the glycemic status or insulin response of the animals and appeared to selectively decrease pain sensations. There also did not appear to be any side effects related to sensorimotor functions of the rats, as is commonly seen with narcotic drugs.

“Although it is not clear if sEH inhibitors will be efficacious in human patients, our findings in rodent models suggest that inhibition of sEH may become a viable strategy to prevent and alleviate neuropathic pain in diabetes patients,” the team concluded.

The study’s findings have their roots in much earlier work by the UC Davis Superfund Research Program on insect control through regulating insect larvae. Hammock’s laboratory pioneered the use of transition-state theory to inhibit enzymes with small molecules and recombinant viruses as green pesticides, as well as the use of immunochemistry for pesticide analysis.

Citation: Inceoglu B, Wagner KM, Yang J, Bettaieb A, Schebb NH, Hwang SH, Morisseau C, Haj FG, Hammock BD. 2012. Acute augmentation of epoxygenated fatty acid levels rapidly reduces pain-related behavior in a rat model of type I diabetes. Proc Natl Acad Sci 109(28):11390-11395.

(Brant Hamel, Ph.D., is an Intramural Research Training Award fellow in the NIEHS Molecular Endocrinology Group of the Laboratory of Signal Transduction.)

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