Background: The goal of our research is to identify a clinically applicable treatment strategy for intractable pain and spasticity after spinal cord injury (SCI). Over fifty percent of patients with SCI live a severely diminished quality of life due to neuropathic pain and spasticity that are ofte refractory to current medical treatments.There are approximately 42,000 US Veterans living with the physical and emotional burden of SCI while posing an economic burden to society at large. A variety of factors are known to contribute to chronic pain and spasticity after SCI. Dendritic spines are micron-sized structures located on neuronal branches in the brain and spinal cord. Because dendritic spines play an integral role in synaptic function and represent modifiable sites of synaptic contact, they provide the best visual clue into how neural networks form and retain function. Previous work has demonstrated that SCI-induced dendritic spine changes can produce long-lasting potentiation of nociceptive signals in the CNS, resulting in neuropathic pain, and contribute to the increased excitability of spinal reflex control associated with spasticity. Thus, targeting aberrant dendritic spine remodeling represents a potentially effective therapeutic approach for alleviating neuropathic pain and spasticity after SCI. Research Plan: Our main hypothesis is that dendritic spine remodeling after SCI contributes to the maintenance of hyperexcitability in spinal sensory and motor systems, leading to neuropathic pain and spasticity. To address this hypothesis, we will investigate whether dendritic spine remodeling after SCI contributes to the development and maintenance of neuropathic pain (Objective 1), and to dysfunction of the spinal motor reflex system (Objective 2). We will also determine the contribution of abnormal dendritic spine remodeling on spinal motor neurons to spinal reflex dysfunction and spasticity after SCI through the utilization of both a pharmacological approach (NSC23766) and a gene therapy approach (i.e., dominant-negative expression and Rac1 gene knockdown) (Objective 3). Finally, in a bridge-to-translation study (Objective 4), we will profile dendritic spine morphology in a non-human primate model of SCI. Significance: This project aims to directly benefit those with spinal cord injury. Of the >250,000 Americans with serious spinal cord injuries and disorders, about 42,000 are U.S. Veterans who are eligible for medical care and other benefits from the Department of Veterans Affairs. 50-80% of these individuals with SCI experience clinically significant pain and spasticity. Despite aggressive treatment, these complications are refractory to current medical treatments. Our proposed work will address the therapeutic potential targeting of abnormal dendritic spines in neuropathic pain and spasticity after SCI. Our findings will also provide the foundation for future translation of therapeutic treatment for pain and spasticity in patients with SCI.

Public Health Relevance

This project aims to directly benefit those with spinal cord injury (SCI). Of the >250,000 Americans with serious spinal cord injuries and disorders, about 42,000 are U.S. Veterans who are eligible for medical care and other benefits from the Department of Veterans Affairs. 50-80% of these individuals with SCI experience clinically significant pain and spasticity. Despite aggressive treatment, these complications are both refractory to current medical treatments. Knowledge of dendritic spine behavior in the spinal cord could elucidate mechanisms of spinal sensory-motor circuit dysfunction. Our proposed work will address the potential contribution of dysplastic dendritic spines in neuropathic pain and spasticity after SCI. Results from this study will help determine whether targeting aberrant dendritic spine remodeling mechanisms represents a potentially effective therapeutic approach for alleviating neuropathic pain and spasticity after SCI.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Veterans Administration (IK2)
Project #
1IK2RX001123-01A2
Application #
8672829
Study Section
Blank (RRD8)
Project Start
2014-04-01
Project End
2019-03-31
Budget Start
2014-04-01
Budget End
2019-03-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
VA Connecticut Healthcare System
Department
Type
DUNS #
039624291
City
West Haven
State
CT
Country
United States
Zip Code
06516