Tiam1-Mediated Synaptic Structural and Functional Plasticity Underlying Transition to Chronic Pain
Abstract
Chronic pain is a major health issue in our society that clearly impacts quality of life. Approximately 30% to 40% of the U.S. population suffers from chronic pain, and its total annual cost has been estimated to be 560–635 billion dollars. Unfortunately, the current treatments are inadequate and there has been limited progress in the development of novel therapies, which has contributed to the alarming epidemic of opioid overdose deaths and addictions. Therapeutic strategies for chronic pain historically have focused on targeting key proteins that are dysregulated in the established chronic pain state rather than on preventing the transition from acute to chronic pain. Research is needed to elucidate the mechanisms that mediate the conversion of pain from an acute episode to a chronic condition in order to identify new potential therapeutic targets to alleviate chronic pain. Accumulating evidence suggests that chronic pain is not simply a temporal continuum of acute pain, but rather entails distinct pathophysiological mechanisms. For instance, the development of chronic pain involves the generation of imbalances between synaptic excitation and inhibition in spinal cord dorsal horn neurons, which contributes to pain hypersensitivity. In addition, excitatory synapses of spinal dorsal horn neurons undergo structural changes (i.e., increases in the size and density of dendritic spines) that may contribute to the long-term nature of chronic pain. However, it remains unclear how nociceptive activity orchestrates structural and functional plasticity in the transition to chronic pain and whether these mechanisms can be targeted for the prevention of chronic pain. Our proposal addresses these two major knowledge gaps regarding the chronification of pain: (1) we will determine the role that Tiam1-Rac1 signaling plays in linking nociceptive activity-induced synaptic receptor activation to structural and functional plasticity in the spinal dorsal horn neurons during the transition from acute to chronic pain and (2) we will develop a novel antisense oligonucleotides (ASO) strategy targeting Tiam1 to inhibit maladaptive synaptic plasticity in the spinal cord to prevent the transition to chronic pain. The contribution of this proposed research is significant because it will uncover a previously unknown mechanism that promotes the transition from acute to chronic pain and will develop a novel, targeted, non-addictive therapeutic strategy that could be translated into the clinic to prevent the development of chronic pain. Notably, maladaptive synaptic structural and functional plasticity in the spinal cord is thought to drive all types of chronic pain. Thus, targeting Tiam1-Rac1 signaling may be beneficially for treating chronic pain triggered by different etiologies, including neural 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
- Mar 10, 2021
- Source ID
- W81XWH2010790
Entities
People
- Lingyong Li
Organizations
- Baylor College of Medicine
- United States Army