Eliminating or Blocking the Tiam1 Gene Prevents, Reverses Chronic Neuropathic Pain

Neuropathy is a type of chronic pain triggered by nerve injury or certain diseases. It affects millions of people worldwide, significantly deteriorating their quality of life. Neuropathy, for example, might emerge from hurting the sciatic nerve on the lower back or the spinal cord, in diseases like rheumatoid arthritis and diabetes or after chemotherapy drugs. Current therapies attempt to suppress the symptoms with pain medications like opioids, but their efficacy is low, and they carry undesirable side effects.

A group led by researchers at Baylor College of Medicine and University of Alabama at Birmingham took on the challenge of investigating the process that leads to neuropathy with the goal of identifying strategies to prevent or control it. They report in the journal Neuron that the gene Tiam1 is at the core of mechanisms leading to the development and maintenance of neuropathic pain. In animal models of the condition, eliminating the Tiam1 gene or blocking its actions prevented or reversed chronic pain caused by a variety of triggers. The findings open new possibilities for novel therapies to provide much needed relief to patients with this condition.

Neuropathy is a different type of pain than the pain that acts as a warning system that something has or may injure the body. For instance, if you touch a hot stove, the pain will make you pull away immediately, protecting the body from a serious burn. Neuropathy, on the other hand, is on-going, long-lasting and not helpful to the body."

Dr. Kimberley F. Tolias, last and co-corresponding author, professor in the departments of neuroscience and biochemistry and molecular biology at Baylor

Neuropathy patients experience hypersensitivity or extreme sensitivity to pain. "Situations that are not normally painful, become painful, and those that are a bit painful become very painful," Tolias said.

Previous studies have shown that pain hypersensitivity emerges from structural and functional changes that occur in the spinal cord. Some of these changes involve alterations in the synapses, the physical connections between neurons, cells that transmit nerve signals. Functionally, the ability to inhibit synapses is reduced while they are more easily excited. Structurally, there is an increase in size and density of the dendritic spines, primary structures involved in establishing synaptic connections. These changes account for the long-term nature of neuropathic pain. However, although the physical and functional changes in the spinal cord are clear, the mechanisms controlling their implementation and persistence in neuropathic pain remained a mystery.

"In this study we discovered that the gene Tiam1, which is known to regulate normal synapse development, also plays a central role in establishing the structural and functional changes in synapses that lead to neuropathy," Tolias said.

The team showed in multiple animal models that in response to various forms of nerve injury, Tiam1 drove the initiation, transition and maintenance of neuropathic pain and that eliminating the gene in the spinal cord prevented the development of neuropathic pain without eliminating the animals' ability to feel 'warning' pain.

Importantly, treating animals having the condition with antisense oligonucleotides (ASO) that inhibited Tiam1 activity eliminated the structural and functional changes in the spinal cord as well as neuropathic pain. ASOs are small stretches of modified DNA that are commonly used to reduce the amount of a specific protein in the body (Tiam1 in this case) by interfering with the process that produces the protein. ASOs are already in clinical use to treat other diseases.

"We are excited about these findings," said first and co-corresponding author Dr. Lingyong Li, associate professor of anesthesiology and perioperative medicine at the University of Alabama. "We discovered that Tiam1 is at the core of a mechanism that underlies neuropathic pain triggered by different types of injuries or diseases. Altogether, our results suggest that regulating Tiam1's activity could provide an effective strategy to treat neuropathic pain in the clinic."

Other contributors to this work include Qin Ru, Yungang Lu, Xing Fang, Guanxing Chen, Ali Bin Saifullah and Changqun Yao. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, University of Alabama at Birmingham, Jianghan University – China and the University of Texas MD Anderson Cancer Center.

This work was supported by grants from the Department of Defense W81XWH-20-10790, the National Institutes of Health grant NS124141 and NS062829 and the Mission Connect/TIRR Foundation.