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The Li Lab is led by Lingyong Li, Ph.D. 

Research OverviewLi HeadshotLingyong Li, Ph.D.

Our research focuses on the synaptic and neural circuit mechanisms underlying chronic pain, chronic pain-induced mood disorders, opioid analgesic tolerance and addiction, and their translational studies to develop effective therapeutic treatments for chronic pain. To investigate these areas of interest, we utilize a wide range of approaches- including genetic and viral manipulations, Patch-seq, electrophysiology, and in vivo imaging.

Synaptic mechanisms of chronic pain and chronic pain-induced mood disorders

Chronic pain, triggered by tissue or nerve injury, is a significant cause of human suffering worldwide, with limited options for effective treatment. The heterogeneity of chronic pain conditions, and the complexity and diversity of underlying pathophysiological mechanisms, make it challenging to identify tractable targets with broad implications for therapy. We use mouse genetics, electrophysiology, confocal imaging, and behavioral testing to study whether and how the conserved synaptic mechanism underlies different types of chronic pain triggered by peripheral nerve injury, inflammation, chemotherapy, diabetes, and spinal cord injury and to illustrate the synaptic plasticity mechanisms underlying chronic pain-induced mood disorders, such as depression and anxiety.

Synaptic mechanisms of opioid analgesic tolerance and addiction

Opioid action at µ opioid receptors (MORs) expressed by nociceptors not only depress synaptic transmission acutely in the superficial dorsal horn but can increase excitatory plasticity after opioid withdrawal, which initiates downstream events in pain pathways and in turn leads to tolerance and opioid-induced hyperalgesia (OIH). However, the downstream events that result in tolerance and OIH remain unclear. We are using genetics, viral manipulations, electrophysiology, confocal imaging, biochemistry, and behavior to illustrate how synaptic structural and functional plasticity contributes to opioid analgesic tolerance and addiction.

Decoding cell types and circuit mechanisms of chronic pain and its modulation by opioids

Chronic pain is one of the most underestimated healthcare problems in the world today. In past decades, remarkable progress has been made in understanding molecular mediators that govern activity across pain pathways. However, we still know little about how pain information is transmitted and processed in the central nervous system, starting at the spinal dorsal horn. Neurons in the spinal dorsal horn are composed of a vast majority of excitatory and inhibitory interneurons. Pain information is not just simply transmitted via specific sensory neurons. Instead, there is complex coordination among different types of neurons. Understanding how the somatosensory system works to process and convey pain information has long been considered one of the great challenges for the pain field. We are using Patch-seq, which combines patch-clamp recording, morphological recovery, and single-cell RNA sequencing, in vivo imaging, opto/chemogenetics, etc., to illustrate how the specific cell types and circuits are coordinated in the spinal dorsal horn to code and relay pain information and its modulation by opioids.

Translational studies to develop effective therapeutic treatments for chronic pain

Our current research identified Tiam1 as a promising therapeutic target in chronic pain management. Inhibiting Tiam1 signaling not only prevents the initiation and transition of chronic pain but also reverses established chronic pain. Furthermore, inhibiting Tiam1 signaling can alleviate chronic pain-induced mood disorders and reduce opioid analgesic tolerance in chronic pain management. Antisense oligonucleotides (ASOs) are an emerging area of drug development, and FDA has approved several ASOs-based drugs recently. This translational study plans to develop novel therapeutic approaches for chronic pain management, such as lumbar puncture injection of ASOs targeting Tiam1.

  • Recent Publications

    For a full list of publications prior to 2022, see PubMed.  

    Selected Publications (#denotes equal contributions, *denotes corresponding authors) 

    1. Yao C, Fang X, Ru Q, Li W, Li J, Mehsein Z, Tolias KF, and Li L. (2024) Tiam1-mediated maladaptive plasticity underlying morphine tolerance and hyperalgesia. Brain (In press) (https://doi.org/10.1093/brain/awae106). ScienceNews Release on April 09, 2024

    2. Li L* (lead contact), Ru Q, Lu Y, Fang X, Chen G, Saifullah AB, Yao C, and Tolias KF. (2023) Tiam1 coordinates synaptic structural and functional plasticity underpinning the pathophysiology of neuropathic pain. Neuron 111: 2038-2050. ScienceDaily Release on May 4, 2023. See also the Neuron’s Preview of our article (111: 1993-1995, 2023)

    3. Ru Q, Magnusson J, and Li L. (2023) Characterization of synaptic structural plasticity in mouse spinal dorsal horn neurons. STAR Protocols 4(4): 102752.

    4. Ru Q, Lu Y, Saifullah AB, Blanco FA, Yao C, Cata JP, Li DP, Tolias KF, and Li L. (2022) Tiam1-mediated synaptic plasticity underlies comorbid depression-like and ketamine antidepressant-like actions in chronic pain. Journal of Clinical Investigation 132(24): e158545. ScienceNews Release on January 30, 2023

    5. Li L, Chen SR, Zhou M, Wang L, Li DP, Chen H, Lee G, Jayaraman V, and Pan HL. (2021) α2δ-1 switches the phenotype of synaptic AMPA receptors by physically disrupting heteromeric subunit assembly. Cell Reports 36: 109396 (1-17).

    6. Chen J#, Li L# (co-first), Chen SR, Chen H, Xie JD, Sirrieh RE, Maclean DM, Zhang Y, Jayaraman V, and Pan HL. (2018) The α2δ-1-NMDA receptor complex is critically involved in neuropathic pain development and gabapentin therapeutic actions. Cell Reports 22: 2307-2321.F1000 Prime Recommended Article

    7. Li L, Chen SR, Chen H, Wen L, Hittelman WN, Xie JD, and Pan HL. (2016) Chloride homeostasis critically regulates synaptic NMDA receptor activity in neuropathic pain. Cell Reports 15: 1376–1383. ScienceDaily Release on May 5, 2016

    8. Li L, Homan KT, Vishnivetskiy SA, Manglik A, Tesmer JGJ, Gurevich VV, and Gurevich EV. (2015) G protein-coupled receptor kinases of the GRK4 subfamily phosphorylate inactive GPCRs. Journal of Biological Chemistry 290(17): 10775-10790.

  • Active Grants and Other Support

    Current R-01s
    R01NS12414 (PI: Li)
    08/2022-07/2027 NIH / NINDS
    The conserved mechanisms underlying different types of chronic pain

    R01DA056673 (PI: Li)
    08/2022-07/2027 NIH / NIDA
    Targeting Tiam1-mediated synaptic plasticity for the relief of opioid tolerance  

    R21NS128600 (Pi: Li)
    07/2022-06/2024 NIH / NINDS
    Multi-modal cell type atlases of somatosensory spinal cord neurons

    R21NS130325 (PI: Li)
    09/2022-08/2024 NIH / NINDS
    Alternative polyadenylation (APA) mechanisms of comorbid mood disorders in chronic pain

    Other Support
    W81XWH-20-10790 (PI:Li)
    DoD Chronic Pain Management Research Program
    Synaptic structural and functional plasticity underlying transition to chronic pain

    W81XWH-21-10742 (PI: Li)
    DoD Spinal Cord Injury Research Program
    Synaptic plasticity mechanisms underlying neuropathic pain following spinal cord injury  

    UAB Start-Up (PI:Li)