A new compound discovered by a team of UC Davis investigators has potent actions against production of a chemical which is implicated in the development of chronic pain following a peripheral nerve injury in the spinal cord.
The compound, a molecule named 6-chloro-8-(glycinyl)-amino-β-carbolin, or 8-Gly carb, provides an important new avenue of research for developing drugs to prevent the severe pain that sometimes remains long after an injury or infection has healed.
The findings are published in The Journal of Pharmacology and Experimental Therapeutics.
“We have discovered a new compound that is more than 40 times more potent in inhibiting nitric oxide production than the currently used reference compound,” said Fredric Gorin, professor and chair of the UC Davis Department of Neurology and co-principal investigator for the study. “That makes 8-Gly carb a potentially very fruitful focus for new drug development against neuropathic pain syndromes.”
Neuropathic pain is a disorder characterized by often severe pain that sometimes develops following nerve damage resulting from conditions such as shingles, nerve injury, amputation, autoimmune inflammation and cancer. Months or even years after the initial trauma, the area can remain extremely painful, a condition believed to result from the brain misinterpreting nerve signals from the area. The pain can be completely spontaneous or triggered by something normally as innocuous as a light touch or temperature change. Traditional pain treatment with non-steroidal anti-inflammatory drugs and even opioids such as morphine is usually ineffective.
Neuropathic pain is thought to be initiated by the inflammatory response of immune cells called macrophages and microglia. The latter are a type of macrophage that resides in the spinal cord and provides an important defense against injury and infection. Following a trauma to a peripheral nerve, these inflammatory cell types release a host of chemicals, among them cytokines that are important for recovery, and nitric oxide, which is believed to be a key factor in initiating and sustaining inflammation associated with the establishment of neuropathic pain. Inhibiting the production of nitric oxide at the time of a nerve injury may be an important mechanism to prevent the later development of a chronic neuropathic pain syndrome, Gorin said.
The class of drug to which 8-Gly carb belongs is known as β-carbolines, a large group of natural and synthetic organic compounds, some of which are known to reduce nitric oxide production. Previously characterized β-carbolines block the cytokines tumor necrosis factor α and interleukin -1B, which are required for recovery. However, these experiments show that 8-Gly carb does not reduce levels of tumor necrosis factor α or IL-1B. The exact mechanism by which this new compound inhibits macrophage production of nitric oxide is not yet understood and will be a focus of future research, according to Gorin.
“A compound like 8-Gly carb that selectively targets nitric oxide production and does not block cytokine expression could make it a promising prototype for drug development aimed at preventing a neuropathic pain syndrome without interfering with recovery,” Gorin said. “We look forward to extending this research by developing and testing this compound and related ones in the laboratory and eventually in clinical trials.”
This research has resulted from a fruitful collaboration between the UC Davis Schools of Medicine and Veterinary Medicine, as well as with the University of Louisville, Kentucky. Pamela Lein, professor and co-chair in the Department of Molecular Biosciences of the UC Davis School of Veterinary Medicine, is co-principal investigator of this study.
Other authors include Ana Cristina Grodzki, Nagarekha Pasupuleti of UC Davis and Bhaskar Poola and Michael Nantz of the University of Louisville, Kentucky.
The study was funded by the UC Davis MIND Institute and the National Institute of Environmental Health Sciences (R01-ES017592) and UC Davis Research Investments in the Sciences and Engineering (RISE) Program (R01-NS060880).