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

Research OverviewLingyong 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.