Tiam1 Identified as Key Factor in Neuropathic Pain Development

Researchers at Baylor College of Medicine and the University of Alabama at Birmingham have found that the gene Tiam1 is at the core of the mechanisms leading to the development and maintenance of neuropathic pain. Eliminating the Tiam1 gene or blocking its actions prevented or reversed chronic pain caused by a variety of triggers in animal models.

“Neuropathy is a different type of pain than the pain that acts as a warning system that something has or may injure the body,” said Kimberley F. Tolias, co-corresponding author of the study published in Neuron. “Neuropathy, on the other hand, is ongoing, long-lasting and not helpful to the body.” Patients with neuropathy 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. Functionally, the ability to inhibit synapses is reduced while they are more easily excited. Structurally, there is an increase in size and density of 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,” explained Tolias.

The researchers 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.

Moreover, treating animals with 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 discovered that Tiam1 is at the core of a mechanism that underlies neuropathic pain triggered by different types of injuries or diseases,” added Dr. Lingyong Li, first and co-corresponding author of the study. “Altogether, our results suggest that regulating Tiam1’s activity could provide an effective strategy to treat neuropathic pain in the clinic.”