On The Road to Attenuating Neuropathic Pain
Neuropathic pain is a chronic condition, often resulting from prior conditions such as diabetes, shingles, and traumatic injury due to hyper excitability of certain voltage-gated sodium channels. The condition affects approximately 18 percent of the population, in addition to being a considerable cost burden to the United States economy. And the symptoms can be harrowing, from a shooting and burning pain to tingling and numbness. While treatments do exist, they are accompanied by side effects. For example, non-selective sodium channel blockers are used to treat chronic pain, but they can affect several voltage-gated sodium channels, thus causing severe unintentional side effects. Omar Samad, Associate Research Scientist, and Stephen Waxman, Professor of Neurology, Neurobiology, and Pharmacology and Director of the Center for Neuroscience & Regeneration Research at Yale University, have managed to attenuate neuropathic pain caused by traumatic nerve injury in rats by targeting the Nav1.3 sodium channel. This novel gene knockdown technique shows promise for finding a method for effective and specific treatment.
Samad and colleagues chose to focus on the Nav1.3 sodium channel because their earlier studies indicated that its upregulation in nerve-injured rats is coupled with neuropathic pain. To treat pain at the source, the team utilized a peripheral Nav1.3 gene knockdown technique to gauge the therapeutic efficacy of targeting this channel. Using computational algorithms, Samad searched for a molecule that would block Nav1.3 expression, and then experimentally identified the two most promising “hits”. In order to simulate the conditions that often cause neuropathic pain, the experimenters used rats that had injured nerves. The two most promising molecules were then delivered directly into the dorsal root ganglion of these experimental rats, and then the rats were assessed for pain behavior.
This experimental approach showed very promising results. The lab’s data showed that these specific molecules were successful in attenuating the neuropathic pain caused by nerve injury in rats. This finding served as a confirmation of the Nav1.3 sodium channel’s role in neuropathic pain. Importantly, the method was found to be specific to the Nav1.3 sodium channel, leaving other channels unaffected and thus avoiding potential side effects.
Samad and colleagues have therefore shown that knocking down Nav1.3 has therapeutic benefits in their animal model. With the results of this research, pharmaceutical companies and research groups can now direct their attention to working with the Nav1.3 sodium channel in humans. With this approach, potential gene therapies can be developed for treating chronic pain. By focusing on this one sodium channel, medications for neuropathic pain will have the potential to be more effective and specific with fewer side effects and greater patient usage.
This research was conducted in Dr. Stephen Waxman’s laboratory. It was supported by the Department of Veteran Affairs and the Nancy Taylor Foundation for Chronic Diseases. Other authors involved in the study were Andrew M. Tan, Xiaoyang Cheng, Edmund Foster, and Sulayman D. Dib-Hajj.