In addition to impairment of motor, autonomic, and sensory functions, severe pain is highly prevalent in patients after spinal cord injury (SCI) including active military personnel and veterans. This project aims to better understand the mechanisms and changes underlying the development of central neuropathic pain after SCI and test a novel strategy for controlling the pain. Because SCI causes an initial deprivation of afferent input to the somatosensory cortex and subsequent hyperexcitability, we hypothesize that this transition in cortical activity is driven by excessive homeostatic compensation to the initial loss of activity of SCI and that enhancing cortical activity will suppress this overcompensation and control pain. Our previous work has characterized the onset and maintenance of chronic central neuropathic pain in a mouse model of contusion injury. Our preliminary data also show that sensory cortical activity is initially decreased after a transient spinal cord ischemia followed by hyperactivity paralleling the onset of pain behavior. This hyperactivity and the associated pain behavior can be diminished by optogenetic stimulation of somatosensory cortex early after injury. In addition, we have shown that treadmill training can prevent the development and partially reverse pain-associated behavior in mice. We now aim to characterize in detail changes in somatosensory cortical activity after traumatic SCI in mice using patch-clamp recording and in vivo two-photon imaging of neuronal activity in transgenic mice. We also aim to determine whether modulating cortical activity by optogenetics, electrical stimulation or somatosensory training or a combination can modulate cortical hyperactivity after SCI and thereby ameliorate neuropathic pain. Based on the homeostatic plasticity hypothesis, this project will challenge the conventional assumption that hyperexcitability of neuronal circuits can only be modified by directly blocking excitation or increasing the activity of inhibitory circuits. Thereby, we will advance our understanding of the development and maintenance of chronic pain after SCI, identify cortical mechanisms underlying the development of chronic pain, and validate a novel activity-enhancing therapeutic strategy that can be translated into novel pharmacological and rehabilitative treatments that interfere with homeostatic plasticity for a comprehensive pain management in active military and veterans.

Public Health Relevance

Spinal cord injury (SCI) frequently results from vehicular accidents, blast injuries and sports-related activities, afflicting many active military personnel, but also increasingly older patients and veterans. Severe neuropathic pain is frequently observed in SCI patients and adequate methods to ameliorate pain are not available. Thus, novel means of pain treatment are urgently needed to return patients to active duty and to minimize long-term disability and psychological distress associated with chronic pain. This proposal aims to understand how chronic pain develops after SCI and investigates a new treatment strategy for better pain control. Specifically, we think that a loss of sensory input to certain brain areas (sensory cortex) after SCI causes plastic responses that lead to excessive brain sensitivity, abnormal activity and pain. We will therefore characterize these changes in the cortex of transgenic mice and stimulate brain activity directly or indirectly through rehabilitative training to restore the lost sensory input after SCI, to normalize brain activity and to control pain.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Spinal Cord Injury/Disorders & Neuropathic Pain (RRDA)
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VA San Diego Healthcare System
San Diego
United States
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