Synaptic Plasticity Mechanisms Underlying Neuropathic Pain Following Spinal Cord Injury
Abstract
Neuropathic pain is a debilitating consequence of spinal cord injury (SCI) that is an area of unmet clinical need, because it is frequently intractable to conventional treatments. Mechanisms underlying SCI pain remain poorly understood, hampering novel therapeutic development. Research is needed to elucidate the fundamental mechanisms that determine the development of neuropathic pain following SCI in order to identify new potential therapeutic targets to alleviate neuropathic pain. Accumulating evidence suggests that SCI-induced functional and structural plasticity in the spinal dorsal horn neurons serves as the neural substrate of neuropathic pain. Functionally, diminished synaptic inhibition and increased synaptic excitation in the spinal cord dorsal horn are key mechanisms underlying neuropathic pain following SCI. In addition, excitatory synapses of spinal dorsal horn neurons undergo structural changes (i.e., increases in the size and density of dendritic spines) following SCI that may contribute to the long-term nature of neuropathic pain. However, it remains unclear how SCI orchestrates structural and functional plasticity in the development of neuropathic pain and whether these mechanisms can be targeted for the alleviation of neuropathic pain. Our proposal addresses the major knowledge gaps regarding neuropathic pain following SCI: We will determine the role that Tiam1 plays in linking SCI-induced synaptic receptor activation to structural and functional plasticity in the spinal dorsal horn neurons, which determines the development of neuropathic pain. The contribution of this proposed research is significant, because it will uncover a previously unknown mechanism that determines the development of neuropathic pain following SCI and will identify a promising therapeutic target that could alleviate neuropathic pain hypersensitivity. Notably, maladaptive synaptic structural and functional plasticity in the spinal cord is thought to drive all types of chronic pain. Thus, targeting Tiam1 may be beneficial for treating chronic pain triggered by different etiologies, including peripheral nerve injury, trauma, amputation, viral infection, inflammation, tumor growth, exposure to neurotoxin, autoimmune disease, vascular disease, and metabolic disorders.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110742
Entities
People
- Lingyong Li
Organizations
- Baylor College of Medicine
- United States Army