Newswise — Neuropathy causes persistent pain due to nerve damage or certain illnesses, greatly reducing the quality of life for millions of individuals worldwide. The condition may arise from injuring the sciatic nerve in the lower back or spinal cord, as seen in diseases like rheumatoid arthritis and diabetes or after chemotherapy treatment. Existing treatments aim to alleviate symptoms using opioids, but their effectiveness is limited, and they have adverse effects.
The investigation of the process underlying neuropathy and the search for ways to prevent or manage it was undertaken by a team of researchers from Baylor College of Medicine and the University of Alabama at Birmingham. According to their report in the journal Neuron, the gene Tiam1 plays a central role in the mechanisms responsible for the development and perpetuation of neuropathic pain. In animal models of the disorder, the elimination of the Tiam1 gene or inhibition of its actions prevented or reversed chronic pain resulting from various causes. These findings introduce new avenues for developing innovative therapies to alleviate the suffering of individuals with neuropathy.
According to Dr. Kimberley F. Tolias, a professor in the departments of neuroscience and biochemistry and molecular biology at Baylor and the last and co-corresponding author of the study, neuropathic pain differs from the pain that serves as a warning signal of potential injury to the body. For instance, if one touches a hot stove, the pain sensation immediately prompts them to withdraw, protecting the body from severe burns. However, neuropathic pain is persistent, prolonged, and does not provide any benefit to the body.
Individuals with neuropathy often have a heightened sensitivity to pain, experiencing hypersensitivity or extreme sensitivity to various stimuli. As Dr. Tolias explains, "Even situations that typically do not cause pain can become painful, and those that are usually mildly painful can become excruciatingly painful for individuals with neuropathy."
Previous research has demonstrated that pain hypersensitivity in neuropathy is due to both structural and functional changes that occur in the spinal cord. Specifically, alterations in the synapses, which are the physical connections between neurons responsible for transmitting nerve signals, have been implicated. In individuals with neuropathy, there is a reduction in the ability to inhibit synapses, while they become more easily excited. Additionally, there is an increase in both the size and density of dendritic spines, which are key structures involved in forming synaptic connections. These changes explain why neuropathic pain is long-lasting. However, until now, the precise mechanisms that control the initiation and persistence of these changes in neuropathic pain were not fully understood.
Dr. Tolias explains that the team's research has revealed that the gene Tiam1, which is involved in the regulation of normal synapse development, also has a key role in the establishment of both the structural and functional changes in synapses that underlie neuropathy.
Using multiple animal models, the research team demonstrated that Tiam1 is responsible for driving the initiation, transition, and maintenance of neuropathic pain in response to various forms of nerve injury. The team also found that eliminating the Tiam1 gene specifically in the spinal cord prevented the development of neuropathic pain without affecting the animals' ability to feel "warning" pain.
Crucially, the research team found that treating animals with neuropathic pain using antisense oligonucleotides (ASOs) that inhibited Tiam1 activity resulted in the elimination of both the structural and functional changes in the spinal cord, as well as neuropathic pain. ASOs are small pieces of modified DNA that are frequently used to reduce the amount of a specific protein in the body, in this case, Tiam1, by disrupting the protein production process. Notably, ASOs are already being used in clinical applications for treating other diseases.
Dr. Lingyong Li, the first and co-corresponding author of the study, expressed excitement about the findings, stating that Tiam1 is a central mechanism underlying neuropathic pain triggered by various injuries or diseases. Dr. Li believes that regulating the activity of Tiam1 could provide an effective strategy for treating neuropathic pain in the clinic based on the study's results.
The study also involved contributions from Qin Ru, Yungang Lu, Xing Fang, Guanxing Chen, Ali Bin Saifullah, and Changqun Yao. These researchers are affiliated with various institutions, including Baylor College of Medicine, University of Alabama at Birmingham, Jianghan University in China, and the University of Texas MD Anderson Cancer Center.
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