Neuropathic Pain: The Underlying Mechanism and a Potential Therapeutic Target Are Revealed in Mice

Neuropathic pain — abnormal hypersensitivity to stimuli — is associated with impaired quality of life and is often poorly managed.

In a paper published in the journal Neuron, researchers report that a mechanism involving the enzyme Tiam1 in dorsal horn excitatory neurons of the spinal cord both initiates and maintains neuropathic pain. 

Moreover, they show that targeting spinal Tiam1 with anti-sense oligonucleotides injected into the cerebrospinal fluid effectively alleviated neuropathic pain hypersensitivity.

It was known that one feature of neuropathic pain is maladaptive changes in neurons of the spinal dorsal horn — increases in the size and density of dendritic spines, the primary postsynaptic sites of excitatory synapses. 

However, the mechanisms driving this synaptic plasticity were unclear. Dendrites are tree-like appendages attached to the body of a neuron that receive communications from other neurons. The spinal dorsal horn is one of the three gray columns of the spinal cord.

In related work, Li and Tolias last year found that chronic pain in a mouse model leads to an activated Tiam1 in anterior cingulate cortex pyramidal neurons of the brain, resulting in an increased number of spines on the neural dendrites. 

This higher spine density increased the number of connections, and the strength of those connections, between neurons, a change known as synaptic plasticity. Those increases caused hypersensitivity and were associated with chronic pain-related depression in the mouse model.

The current neuropathic pain study by Li and Tolias used mouse models of neuropathic pain caused by nerve injury, chemotherapy or diabetes. The researchers showed that Tiam1 is activated in the spinal dorsal horn of mice subjected to neuropathic pain and that global knockout of Tiam1 in mice prevented the development of neuropathic pain. Global knockout causes no other apparent abnormalities in the mice.

After showing where Tiam1 acts in neuropathic pain, Li, Tolias and colleagues showed what Tiam1 does. Tiam1 is known to modulate the activity of other proteins that help build or unbuild the cytoskeletons of cells, and the building of cytoskeleton actin filaments is part of dendritic spine creation. 

Tiam1 functions to activate the small GTPase Rac1 enzyme that promotes actin polymerization. 

The researchers showed that the development of Tiam1-mediated neuropathic pain was dependent on Tiam1-Rac1 signaling. They found that neuropathic pain was prevented or reversed at each time point. Thus, Tiam1-Rac1 signaling is essential for the initiation, transition and maintenance of neuropathic pain.

Tiam1 is an essential player in the pathogenesis of neuropathic pain that coordinates actin cytoskeletal dynamics, dendritic spine morphogenesis and synaptic receptor function in spinal dorsal horn excitatory neurons in response to nerve damage, Li and Tolias say.

Sources:

Lingyong Li, Qin Ru, Yungang Lu, Xing Fang, Guanxing Chen, Ali Bin Saifullah, Changqun Yao, Kimberley F. Tolias. Tiam1 coordinates synaptic structural and functional plasticity underpinning the pathophysiology of neuropathic pain. Neuron, 2023; DOI: 10.1016/j.neuron.2023.04.010

University of Alabama at Birmingham. (2023, May 4). Neuropathic pain: The underlying mechanism and a potential therapeutic target are revealed in mice. ScienceDaily. Retrieved May 12, 2023 from www.sciencedaily.com/releases/2023/05/230504111839.htm

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