Targeting GSK-3B signaling to prevent spinal cord injury pain Grant uri icon

abstract

  • Approximately 12,000 spinal cord injuries (SCI) occur each year and up to 230,000 persons currently live with SCI in the US. Of these, 55% develop neuropathic pain within the first 6 months and up to 90% have neuropathic pain including dysesthesia, paresthesia, and allodynia 5 years post-injury that persists throughout their lifetimes, contributing to a decreased quality of life. Most importantly, these pain syndromes are typically refractory to standard pain therapies, underscoring the need for insight into the cellular mechanisms behind the development of post-SCI pain Preliminary data suggests that injury to the cord results in damage to and sprouting of peripheral sensory afferents at the level of injury, correlating with the presence of at-level sensory abnormalities. SCI also resulted in inactivation of glycogen synthase kinase-3? (GSK-3?), a key intracellular regulator of neuronal survival and sprouting. We hypothesize that post-SCI pain may result from aberrant sprouting of primary afferent fibers after injury in response to altered GSK-3? activity and that modulation of GSK-3 ? activity can prevent both the sprouting and onset of at- and below-level pain syndromes. The aims of this project are (1) to correlate GSK-3 ? activity with DRG morphology, at-level pain, and below-level pain after SCI and (2) to determine the effect of inhibition and activation of GSK-3? on these same parameters after SCI. The excitotoxic model of SCI will be used to produce pathological and behavioral changes in the rat consistent with those observed after human SCI including post-SCI pain syndromes. A timeline of GSK-3? expression in the cord and DRG as well as changes in DRG morphology at the level of injury and at the level of the sciatic nerve entry into the cord will be constructed and these changes correlated to the onset of both at- and below-level pain. Pharmacologic inhibitors and activators of GSK-3? will then be used after injury and the impact on pathological and behavioral changes will be studied. The goal of the proposed studies is to investigate GSK-3? as a potential molecular mechanism by which SCI promotes sensory abnormalities related to sprouting of nociceptive afferents both at and below the level of injury. Successful completion will provide information on a molecular target that is unstudied in the context of pain, but one that has potential to be translated to a specific pharmaceutical intervention.

date/time interval

  • January 2015 - December 2017