Mechanisms Underlying Neuropathic Pain Revealed

summary: The enzyme Tiam1 in dorsal horn excitatory neurons of the spinal cord is involved in the initiation and maintenance of neuropathic pain. Targeting her Tiam1 in the spinal cord with antisense oligonucleotides injected into the cerebrospinal fluid effectively relieves pain hypersensitivity.

Neuropathic pain is often poorly managed and has a significant negative impact on quality of life. This study highlights the importance of understanding the underlying mechanisms of neuropathic pain in developing effective therapies.

Important facts:

1. A mechanism involving the enzyme Tiam1 in dorsal horn excitatory neurons of the spinal cord initiates and sustains neuropathic pain.
2. Targeting Tiam1 in the spinal cord with antisense oligonucleotides injected into the cerebrospinal fluid effectively alleviated neuropathic pain hypersensitivity in a mouse model.
3. Poorly managed neuropathic pain affects approximately 3% to 17% of adults and is associated with a poor quality of life.

sauce: University of Alabama

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

Estimates suggest that 3% to 17% of adults suffer from neuropathic pain, including one-quarter of people with diabetes and one-third of people with HIV.

In a paper published in the journal neuronresearchers report that a mechanism involving the enzyme Tiam1 in dorsal horn excitatory neurons of the spinal cord is involved in both initiation and maintenance of neuropathic pain.

Furthermore, they show that targeting Tiam1 in the spinal cord with antisense oligonucleotides injected into the cerebrospinal fluid effectively attenuates neuropathic pain hypersensitivity.

“Thus, our study reveals the pathophysiologic mechanisms that initiate, migrate, and sustain neuropathic pain, and provide promising therapeutic targets for treating neuropathic pain with long-term consequences.” We identified it,” said Associate Professor Lingyong Li, PhD. Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham.

“Understanding the pathophysiological mechanisms underlying neuropathic pain is critical for developing new therapeutic strategies to effectively treat chronic pain.”

Lee and Dr. Kimberly Trias, a professor at Baylor College of Medicine in Houston, Texas, were co-leaders of the study.

One of the hallmarks of neuropathic pain is known to be maladaptive changes in neurons in the dorsal horn of the spinal cord, which alter the size and density of dendritic spines, the major post-synaptic site of excitatory synapses. Increased has.

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

In a related study, Li and Tolias last year found that chronic pain in a mouse model led to activation of Tiam1 in anterior cingulate cortical pyramidal neurons of the brain, increasing the number of neurodendritic spines. bottom.

This higher spine density increased the number of connections between neurons and the strength of those connections, a change known as synaptic plasticity. It was associated with depression related to

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

UAB and Baylor researchers found that Tiam1 expression in spinal cord dorsal horn neurons, but not dorsal root ganglion neurons or excitatory forebrain neurons, is essential for the development of neuropathic pain. Furthermore, we found that the development of neuropathic pain depended on his Tiam1 expression in excitatory, but not inhibitory, neurons.

After showing where Tiam1 acts in neuropathic pain, Li, Tolias and colleagues showed what Tiam1 does. Tiam1 is known to regulate the activity of other proteins that help build or disassemble the cell’s cytoskeleton, and the assembly of cytoskeletal actin filaments is part of the creation of dendritic spines. .

The researchers found that Tiam1 increases the density of dendritic spines in wide dynamic range neurons from the dorsal horn of the spinal cord and increases synaptic NMDA receptor activity in the dorsal horn of the spinal cord during the onset of neuropathic pain. have found that it is necessary for

Tiam1 functions to activate the small GTPase Rac1 enzyme that promotes actin polymerization. The researchers showed that Tiam1-mediated neuropathic pain generation is dependent on her Tiam1-Rac1 signaling.

We then used small-molecule inhibitors to block Rac1 activation at three different time points. Immediately after peripheral nerve injury, 4 days after nerve injury with gradual onset of neuropathic pain hypersensitivity, and 3 weeks after nerve injury for chronic neuropathic pain. pain fully established.

They found that neuropathic pain was prevented or reversed at each time point. Thus, Tiam1-Rac1 signaling is essential for neuropathic pain initiation, transition, and maintenance.

As Tiam1 appears to be a promising therapeutic target for treating neuropathic pain, Li and Tolias also tested whether neuropathic pain could be reduced by injecting antisense oligonucleotides (ASOs). Did. Processing or decomposition – into the cerebrospinal fluid of the spine.

In a rat model, injection of ASO against Tiam1 reduced Tiam1 protein levels in the dorsal horn of the spinal cord by 50% and significantly reduced neuropathic pain hypersensitivity 1 week after injection, which persisted for an additional 2 weeks. .

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

The two researchers are co-authors of the study “Tiam1 modulates synaptic structural and functional plasticity that underpins the pathophysiology of neuropathic pain.”

Co-authors are Qin Ru, Yungang Lu, Xing Fang, and Ali Bin Saifullah of Baylor College of Medicine. Guanxing Chen, University of Texas MD Anderson Cancer Center, Houston, TX. and Changqun Yao, UAB Department of Anesthesiology and Perioperative Medicine.

Funding: Support was from US Department of Defense grant W81XWH-20-10790, Mission Connect/TIRR Foundation, and National Institutes of Health grants NS062829 and NS124141.

About this pain research news

author: Jeffrey Hansen
sauce: University of Alabama
contact: Jeffrey Hansen – University of Alabama
image: Image credited to Neuroscience News

Original research: open access.
“Tiam1 modulates synaptic structural and functional plasticity that underpins the pathophysiology of neuropathic pain” By Lingyong Lee. neuron

overview

Tiam1 modulates synaptic structural and functional plasticity that underpins the pathophysiology of neuropathic pain

highlight

• Tiam1 in spinal cord excitatory neurons determines the development of neuropathic pain
• Tiam1 modulates synaptic structural and functional plasticity in neuropathic pain
• Tiam1-Rac1 signaling initiates, passes through, and sustains neuropathic pain
• ASOs targeting spinal Tiam1 alleviate neuropathic pain sensitivity

summary

Neuropathic pain is a common debilitating chronic pain condition caused by injury or disease affecting the somatosensory nervous system. Understanding the pathophysiological mechanisms underlying neuropathic pain is critical for developing new therapeutic strategies to effectively treat chronic pain.

Tiam1 is a Rac1 guanine nucleotide exchange factor (GEF) that promotes dendritic and synaptic growth during hippocampal development by inducing actin cytoskeletal remodeling.

Here, using multiple neuropathic pain animal models, we show that Tiam1 coordinates the structural and functional plasticity of synapses in the dorsal horn of the spinal cord via actin cytoskeleton reorganization and synaptic NMDAR stabilization, demonstrating that these We show that action is essential for the initiation, transition, and maintenance of neuropathic pain. Furthermore, an antisense oligonucleotide (ASO) targeting spinal Tiam1 persistently reduces neuropathic pain sensitivity.

Our findings suggest that Tiam1-regulated synaptic functional and structural plasticity underlies the pathophysiology of neuropathic pain, and that Tiam1-mediated intervention of maladaptive synaptic plasticity may contribute to long-term neuropathic pain management. suggests that it will produce positive results.