Key Driver of Neuropathic Pain Identified by Baylor College of Medicine Scientists Interview with:
Kimberley Tolias, Ph.D.
Department of Neuroscience
Biochemistry & Molecular Biology
Baylor College of Medicine
Houston, TX 77030 What is the background for this study?

Response: Neuropathic pain is a chronic pain condition that affects millions of people worldwide, significantly impairing their quality of life.  Symptoms of neuropathic pain include spontaneous shooting or burning pain, pain from activities that don’t normally cause pain (allodynia), and heightened pain sensitivity (hyperalgesia).  Current treatment options for neuropathic pain, such as opioids, focus on symptom suppression and are generally ineffective and often cause unwanted side effect.  In order to develop safer, more effective chronic pain treatments, we need to better understand the processes that lead to neuropathic pain.

Neuropathic pain is caused by nerve damage from a variety of insults (e.g., injury, disease, infection, chemotherapy drugs), which trigger structural and functional changes in the neurons and synaptic connections that transmit pain signals.  These activity-dependent alterations in somatosensory neural circuits are thought to be responsible for the persistent symptoms associated with chronic pain, but how they are induced and maintained following nerve injury or disease remains unclear.  To address this problem, our research team, including lead and co-corresponding author Dr. Lingyong Li (now at University of Alabama at Birmingham), investigated the mechanisms that underlie neuropathic pain, with the goal of identifying strategies to prevent or control it. What are the main findings?

Response: In our study recently published in the journal Neuron, we identified the enzyme Tiam1 as a key driver of the maladaptive synaptic plasticity responsible for the development and maintenance of neuropathic pain, and we showed that abolishing Tiam1 activity can alleviate neuropathic pain symptoms.  Tiam1 is known to regulate synaptic growth during brain development by shaping the neuronal cytoskeleton, but its role in neuropathic pain had not been investigated.  Using animal models of neuropathic pain caused by nerve injury, chemotherapy, or diabetes, we showed that Tiam1 was activated in the spinal cord of mice experiencing neuropathic pain, and that complete elimination of Tiam1 expression in mice prevented the development of all forms of neuropathic pain tested.  Furthermore, we determined that expression of Tiam1 in excitatory neurons in the dorsal horn of the spinal cord was required for the development of neuropathic pain, whereas its expression in other neurons (e.g., dorsal root ganglion neurons, excitatory forebrain neurons, or inhibitory neurons) was not important.

After determining where Tiam1 acts in neuropathic pain, we investigated its role in the process.  Tiam1 is known to activate the small GTPase protein Rac1, which helps build and strengthen neuronal synaptic connections by remodeling the underlying cytoskeleton. We found that in response to nerve damage, Tiam1 induced Rac1-dependent synaptic structural and functional plasticity in spinal dorsal horn neurons that promoted the development of neuropathic pain.  To further explore the role of Tiam1-Rac1 signaling in neuropathic pain, we used a small molecule inhibitor to block Tiam1-mediated Rac1 activation at three different time points – immediately after nerve injury, four days after injury when neuropathic pain hypersensitivity appeared, or three weeks after nerve injury when chronic pain was fully established.  We found that neuropathic pain was prevented or reversed at each time point, suggesting that Tiam1-Rac1 signaling is essential for the development and maintenance of neuropathic pain.

Since Tiam1 showed potential as a therapeutic target for treating neuropathic pain, we also explored the possibility of reducing neuropathic pain sensitivity in a rat model of chronic pain by injecting antisense oligonucleotides (ASOs) into their cerebrospinal fluid.  ASOs are short, synthetic, single-stranded oligodeoxynucleotides designed to reduce the expression of targeted genes, which have been used in clinical trials to treat other diseases.  We found that injecting an ASO against Tiam1 that decreased Tiam1 expression significantly reduced neuropathic pain hypersensitivity in rats one week after injection, and the effect lasted another two weeks.

In summary, our results revealed Tiam1 as an essential player in the pathogenesis of neuropathic pain that mediates synaptic structural and functional remodeling in spinal dorsal horn excitatory neurons in response to nerve damage.  By showing that blocking Tiam1 function alleviates neuropathic pain in a variety of animal models, our work identified Tiam1 as a potentially promising therapeutic target to treat neuropathic pain effectively. What should readers take away from your report?

Response: The goal of our study was to better understand how neuropathic pain works and how we might be able to treat it.  We found that Tiam1 mediates the pathological synaptic remodeling in spinal excitatory neurons that drives the development and maintenance of neuropathic pain triggered by injury or disease. Moreover, our results suggest that inhibiting Tiam1’s activity could provide an effective strategy to treat neuropathic pain in the clinic. What recommendations do you have for future research as a result of this study?

Response: Future research is needed to further characterize the roles Tiam1-Rac1 signaling plays in the development and maintenance of different types of chronic pain, and to determine how this pathway can be effectively targeted to treat chronic pain in a clinical setting.  This is especially important given that we have also recently identified a role for Tiam1 in chronic pain-associated mood disorders.  Chronic pain often leads to depression and anxiety, intensifying patient suffering and worsening their prognosis.  In related work published last year in the Journal of Clinical Investigations, we reported that chronic pain ultimately triggers Tiam1 activation in the anterior cingulate cortex (ACC) region of the brain, resulting in structural and functional remodeling of ACC neuron synapses that drives chronic pain-induced depressive-like behaviors in mice.  Moreover, we showed that low-dose ketamine, a promising treatment for chronic pain and depression, induces sustained antidepressant-like effects in mouse models of chronic pain by blocking Tiam1-mediated maladaptive synaptic plasticity in ACC neurons. Thus, developing better methods to effectively target Tiam1 signaling could be used in the future to treat both chronic pain and chronic pain-induced depression.

Disclosures: This research was supported by grants from the Department of Defense W81XWH-20-10790 (L.L.), the National Institutes of Health NS124141 (L.L. and K.F.T.), the Mission Connect – TIRR Foundation (L.L. and K.F.T.), and the National Institutes of Health NS062829 (K.F.T.).


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 May 04; DOI:  PMID 37146610

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Last Updated on May 11, 2023 by