Lingyong Li, Ph.D.Lingyong Li, Ph.D., associate professor in the Department of Anesthesiology and Perioperative Medicine, is the latest winner of the Heersink School of Medicine’s Featured Discovery. This initiative celebrates important research from Heersink faculty members.

Li’s study, “TIAM1-mediated synaptic plasticity underlies comorbid depression-like and ketamine antidepressant-like actions in chronic pain," was recently published in The Journal of Clinical Investigation.

Li and his team worked to research the cause of chronic pain-induced depression and develop a treatment option.

“Chronic pain is often comorbid with mood disorders, like depression and anxiety, which intensify patients’ suffering and are clinically difficult to treat,” said Li. “Our study uncovered the molecular mechanisms underlying chronic pain-induced depression and developed the off-label prescription of Esketamine in the treatment of patients suffering from chronic pain-induced depression.”

Read more from UAB News about the team’s work.

The Heersink School of Medicine communications staff sat down with Dr. Lingyong Li to gain insight into this study, UAB, and the science community.

Q: What compelled you to pursue this research?

My research focuses on synaptic and neural circuit mechanisms underlying chronic pain, chronic pain-induced mood disorders, opioid analgesic tolerance and tolerance, and their translational studies. I met a lot of chronic pain patients with depression and knew their suffering. Patients would state things like, “The chronic pain is very depressive, and I feel like I have only gotten half of the equation to a healthier mental and physical condition. The physical pain is taxing my system, and I feel as though I must reach out and seek more help.” Another patient stated, “These chronic pains keep me in a hopeless agitated depressive cycle which I need to be free from.” As a pain scientist, I thought I had the responsibility to do something to relieve patients’ suffering.

Q: What was your most unexpected finding?

Clinical and preclinical studies have established that anterior cingulate cortex (ACC) hyperactivity is essential for driving chronic pain-induced depressive symptoms, but the cause of ACC hyperactivity remains unknown. Here, we identified a protein called Tiam1, which mediated the increased number of connections and strength of connections between neurons and neurons that caused ACC hyperactivity and underlined chronic pain-induced depressive symptoms. Our study also showed that ketamine’s sustained antidepressant-like effects in chronic pain are mediated, at least in part, by ketamine’s blocking the Tiam1-dependent numbers and strengths of neuron-neuron connections in the mouse ACC neurons.

|Q: How do you feel your research will impact the science community?

Our work demonstrates the critical role Tiam1 plays in the pathophysiology of chronic pain-induced mood dysregulation and the sustained antidepressant-like effects of ketamine, revealing it as a potential therapeutic target for the treatment of comorbid mood disorders in chronic pain.

Q: What is your research’s relevance to human disease?

What makes our research relevant is the use of an FDA-approved nasal spray called Esketamine, which is derived from ketamine, to treat resistant depression in 2019. Based on the findings that ketamine’s sustained antidepressant-like effects in chronic pain are mediated, at least in part, by ketamine’s blocking the Tiam1-dependent numbers and strengths of neuron-neuron connections in the mouse ACC neurons, Esketamine nasal spray has the potential use to treat patients suffering from chronic pain-induced depression clinically.

Q: When did you know you had an important discovery?

When we found that the protein Tiam1 was activated in the chronic pain mice displaying depression-like behaviors, we realized Tiam1 might play an important role in developing chronic pain-induced depression. The Tiam1 functions were further confirmed by conditional deletion of the protein Tiam1 from brain excitatory neurons or pharmacologically inhibiting Tiam1 signaling pathway that prevents depression-like behaviors in chronic pain mice.

Q: What do you find makes the science community here unique?

The UAB Heersink School of Medicine consistently ranks among the nation's very best academic medical centers for research, education, and clinical care. In 2022, the Heersink School of Medicine received $266 million in annual total research support and ranked 26th among all U.S. universities for NIH research funding. Numerous investigators with complementary expertise and scientific interests have laboratories in the UAB Heersink School of Medicine. The intellectual environment of the Department of Anesthesiology and Perioperative Medicine is rich with other extramurally funded investigators who are doing work that is complementary to what is proposed here.