Putting a hurt on neuropathic pain

UC Davis researchers identify carboline compound that could lead to drugs to prevent neuropathic pain syndromes

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Editor's note: Due to a typo in materials sent to us from UC Davis, the print version of this story (April 2015 issue) mistakenly said "nitrous oxide" when it should have said "nitric oxide." We apologize for the error, and we have corrected it in the online version of the story below.
SACRAMENTO, Calif.—A team of University of California, Davis (UC Davis) investigators has discovered a new carboline compound which has potent action against the production of nitric oxide, 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 (8-Gly carb) may provide an important avenue of research for developing drugs to prevent the severe pain that sometimes remains long after an injury or infection has healed.
“We have discovered a new compound that is 43 times more potent in inhibiting nitric oxide production than the current reference compound known to have this action,” said Dr. Fredric Gorin, professor and chair of the UC Davis department of neurology and co-principal investigator for the study. “A compound like 8-Gly carb that selectively targets nitric oxide production and does not block cytokine expression makes a promising candidate for drug development aimed at preventing a neuropathic pain syndrome without interfering with recovery.”
Neuropathic pain is distinguished by frequently severe pain that sometimes develops with nerve damage from such conditions as shingles, injuries, amputation, autoimmune inflammation and cancer. Months or even years after the initial trauma, the areas with damage can remain extremely painful, a condition possibly caused by the brain misinterpreting nerve signals from the affected area. The pain can be completely spontaneous, or triggered by something like a light touch or a temperature change. Traditional pain treatment is usually ineffective, both with non-steroidal anti-inflammatory drugs and even opioids such as morphine.
The neuropathic pain condition is thought to develop from immune cells called microglia, a type of macrophage which resides in the spinal cord and provides an important defense against injury and infection. After trauma to a peripheral spinal nerve, microglia release a number of chemicals, among them cytokines, which are important for recovery, and nitric oxide, which is believed to be a key factor in initiating and continuing the inflammation associated with neuropathic pain. Suppressing the production of nitric oxide at the time of a nerve injury may be important to prevent the development of chronic neuropathic pain. 8-Gly carb belongs to a class of drug 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 a precursor—tumor necrosis factor α—in the nitric oxide production pathway as well, resulting in the reduction of the expression of the cytokine interleukin-1β.
According to the authors of the UC Davis study, “8-Gly carb was significantly more potent than the nitric oxide synthases inhibitor NG-nitro-L-arginine methyl ester in inhibiting constitutive and inducible nitric oxide formation. These data demonstrate that relative to other carbolines and pharmacologic inhibitors of nitric oxides, 8-Gly carb exhibits a unique pharmacological profile by inhibiting constitutive and inducible nitric oxide formation independent of NF-κB activation and cytokine expression. Thus, this novel carboline derivative holds promise as a parent compound, leading to therapeutic agents that prevent the development of neuropathic pain without interfering with cytokine expression required for neural recovery following peripheral nerve injury.”
The exact mechanism of nitric oxide reduction by the new compound is poorly understood and will be a focus of future research. Said Gorin, “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 isn’t UC Davis’ only recent neuropathic pain research. In 2013, Drs. Barth Wilsey, Thomas D. Marcotte and colleagues published findings on a double-blind, placebo-controlled study assessing the analgesic potency of vaporized cannabis in subjects experiencing neuropathic pain in spite of traditional treatment. The study found that vaporized cannabis has analgesic efficacy, even at low doses, and may present an effective option for patients with treatment-resistant neuropathic pain. The study was published in the Journal of Pain.
The more recent neuropathic pain research by Gorin and colleagues resulted from a partnership between the UC Davis School of Medicine and School of Veterinary Medicine, as well as with the University of Louisville in Kentucky. Dr. Pamela Lein, professor in the Department of Molecular Biosciences of the UC Davis Veterinary School of Medicine, is co-principal investigator and study author. Other study authors include Dr. Ana Cristina Grodzki and Nagarekha Pasupuleti of UC Davis and Drs. Bhaskar Poola and Michael Nantz of the University of Louisville. The neuropathic pain study was funded by the UC Davis MIND Institute and the National Institute of Environmental Health Sciences and UC Davis Research Investments in the Sciences and Engineering Program. The study findings were published in The Journal of Pharmacology and Experimental Therapeutics.

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