In examining the conditions under which neuropathic pain develops following spinal cord injury (SCI), we propose that the presence of noxious input plays an important role. Specifically, we suggest that nociceptive input accompanying SCI may determine if and when neuropathic pain develops. The studies described in this proposal will investigate the interaction between SCI and nociceptive input, derived from peripheral inflammation, to further our understanding of its consequence on pain hypersensitivity. Prior clinical and experimental studies have shown that there is a tremendous amount of variability in both the onset and incidence of chronic pain following SCI. Because current studies attempting to identify the mechanisms underlying SCI-induced pain hypersensitivity have not been successful, additional studies are warranted. Recently, we observed that noxious input given shortly after SCI significantly increases behavioral signs of neuropathic pain for at least 3 weeks following injury. We also found that the pro-inflammatory cytokine TNFalpha, which is implicated in inflammatory pain, is up-regulated by the stimulation and appears to play a role in pain hypersensitivity following SCI. These observations are consistent with our past work showing the negative effects of noxious stimulation on spinal cord plasticity in adult rats with a transection SCI. Consequently, we hypothesize that noxious input derived from peripheral inflammation or electrical stimulation enhances the development of chronic neuropathic pain through a spinal TNFalpha signaling pathway. This proposal, consisting of three aims, will introduce a novel approach to investigate the mechanisms underlying pain following SCI. We will combine behavioral, pharmacological and molecular techniques to study the interaction between SCI and peripherally-derived nociceptive input as a potential predictor of chronic pain. In the first aim, we will assess the effect of noxious input induced by peripheral inflammation on the induction and maintenance of pain hypersensitivity following SCI.
The second aim will assess the effects of noxious stimulation on the spatial and temporal expression of TNFalpha signaling genes.
In aim 3, we will explore the role TNFalpha signaling plays in the induction of enhanced pain behaviors following SCI, by administering a TNFR1 blocker. These studies will establish the feasibility of this novel approach of investigation and advance our understanding of the mechanisms producing pain. This work is innovative in that it combines clinically relevant models of peripheral sensitization and SCI to investigate the centrally mediated mechanisms underlying pain following SCI, a combination that has been under-studied in prior studies. It will allow us to more accurately associate nociceptive input to the development of pain hypersensitivity following SCI and also identify potential cellular targets, which play a critical ole in these mechanisms. If successful, this work could lead to new procedures to prevent the development of neuropathic pain after SCI.
The goal of this study is to establish peripheral noxious input as a pivotal factor in the development of chronic pain following spinal cord injury. We propose that nociceptive input from peripheral inflammation increases the incidence, onset and maintenance of pain hypersensitivity after SCI. By combining a moderate contusion SCI model with several experimental models of peripheral sensitization and inflammatory pain, we will investigate the interaction between SCI and nociceptive input and its consequence on the induction and maintenance of pain hypersensitivity.
| Grau, James W; Huie, J Russell; Lee, Kuan H et al. (2014) Metaplasticity and behavior: how training and inflammation affect plastic potential within the spinal cord and recovery after injury. Front Neural Circuits 8:100 |
| Garraway, Sandra M; Woller, Sarah A; Huie, J Russell et al. (2014) Peripheral noxious stimulation reduces withdrawal threshold to mechanical stimuli after spinal cord injury: role of tumor necrosis factor alpha and apoptosis. Pain 155:2344-59 |
