Neuropathic pain (abnormal hypersensitivity to stimuli) is associated with impaired quality of life and is often poorly treated. Estimates suggest that between 3 and 17 percent of adults suffer from neuropathic pain, including a quarter of people with diabetes and a third of people with HIV.
In an article published in the magazine Neuron, the researchers report that a mechanism involving the enzyme Tiam1 in excitatory neurons in the dorsal horn of the spinal cord initiates and maintains neuropathic pain. Furthermore, they show that targeting of spinal Tiam1 with antisense oligonucleotides injected into the cerebrospinal fluid effectively alleviated neuropathic pain hypersensitivity.
“Therefore, our study has uncovered a pathophysiological mechanism that initiates, transitions, and maintains neuropathic pain, and we have identified a promising therapeutic target to treat neuropathic pain with lasting consequences,” said Lingyong Li, Ph.D., associate professor. . in the Department of Anesthesiology and Perioperative Medicine at the University of Alabama at Birmingham. “Understanding the pathophysiological mechanisms underlying neuropathic pain is critical to developing new therapeutic strategies to treat chronic pain effectively.”
Li and Kimberley Tolias, Ph.D., a professor at Baylor College of Medicine in Houston, Texas, were co-directors of the research.
It was known that a hallmark of neuropathic pain is maladaptive changes in spinal cord dorsal horn neurons: increases in the size and density of dendritic spines, the major postsynaptic sites of excitatory synapses. However, the mechanisms that drive 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 found last year that chronic pain in a mouse model leads to activated Tiam1 in pyramidal neurons of the brain’s anterior cingulate cortex, resulting in increased numbers of dendrite spines. neural. This increased 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 study of neuropathic pain 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 dorsal horn of the spinal cord of mice subjected to neuropathic pain and that global knockout of Tiam1 in mice prevented the development of neuropathic pain. Global deletion causes no other apparent abnormalities in the mice.
The UAB and Baylor researchers found that Tiam1 expression in spinal cord dorsal horn neurons, but not in dorsal root ganglion neurons or forebrain excitatory neurons, was essential for brain development. neuropathic pain. Furthermore, they found that the development of neuropathic pain was dependent on Tiam1 expression in excitatory neurons, not inhibitory neurons.
After showing where Tiam1 works in neuropathic pain, Li, Tolias and their colleagues showed what Tiam1 does. Tiam1 is known to modulate the activity of other proteins that help build or destroy the cytoskeletons of cells, and the construction of the actin filaments of the cytoskeleton is part of the creation of the dendritic spine. The researchers found that Tiam1 is required during the development of neuropathic pain to increase the density of dendritic spines in high-dynamic-range neurons of the spinal dorsal horn and to increase synaptic NMDA receptor activity of spinal cord dorsal horn neurons. the marrow.
Tiam1 works to activate the small enzyme GTPase Rac1 that promotes actin polymerization. The researchers demonstrated that Tiam1-mediated neuropathic pain development was dependent on Tiam1-Rac1 signalling. They then used a small molecule inhibitor to block Rac1 activation at three different time points: just after peripheral nerve injury, four days after nerve injury when neuropathic pain hypersensitivity gradually develops, or three weeks. after nerve injury when chronic neuropathic pain is fully established. They found that neuropathic pain was prevented or reversed at every point in time. Therefore, Tiam1-Rac1 signaling is essential for the initiation, transition, and maintenance of neuropathic pain.
Since Tiam1 appeared to be a promising therapeutic target for treating neuropathic pain, Li and Tolias also tested whether they could reduce neuropathic pain by injecting antisense oligonucleotides, or ASOs, short, synthetic, single-stranded oligodeoxynucleotides designed to alter Tiam1 expression by modulation of its mRNA processing or degradation, in the cerebrospinal fluid of the spine.
In a rat model, they found that injecting an ASO against Tiam1 decreased Tiam1 protein levels in the spinal dorsal horn by 50 percent and significantly reduced neuropathic pain hypersensitivity one week after injection, a reduction that lasted another two weeks.
Thus, Tiam1 is an essential player in the pathogenesis of neuropathic pain coordinating actin cytoskeleton dynamics, dendritic spine morphogenesis, and synaptic receptor function in spinal dorsal horn excitatory neurons in response to nerve damage, say Li and Tolias.
The two investigators are the corresponding authors of the study, “Tiam1 coordinates synaptic structural and functional plasticity underpinning the pathophysiology of neuropathic pain.”
Coauthors are Qin Ru, Yungang Lu, Xing Fang, and Ali Bin Saifullah, Baylor College of Medicine; Guanxing Chen, University of Texas MD Anderson Cancer Center, Houston, Texas; and Changqun Yao, UAB Department of Anesthesiology and Perioperative Medicine.
Support came from US Department of Defense grant W81XWH-20-10790, the Mission Connect/TIRR Foundation, and grants NS062829 and NS124141 from the National Institutes of Health.
At UAB, Anesthesiology and Perioperative Medicine is a department of the Marnix E. Heersink School of Medicine.
—————————————————-
Source link