Neuropathic pain (NP) affects approximately 4 million people in the United States with spinal cord injury (SCI) being a common cause. Matrix metalloproteinases (MMPs) play an integral role in mediating inflammatory responses, cellular signaling, cell migration, extracellular matrix degradation and tissue remodeling and repair. As such, they are major components in the pathogenesis of secondary injury within the central nervous system. Other gene regulatory pathways, specifically MAPK/extracellular signaling-regulated kinase (ERK) and Wnt/β-catenin, are also believed to participate in secondary injury likely intersect. The study aims to examine the MMP-2 signaling pathway associated with ERK and Wnt/β-catenin activity during contusion SCI (cSCI)-induced NP in a rat model. This is an experimental study investigating the implication of MMP-2 in SCI-induced NP and its association with the cellular and molecular changes in the interactions between extracellular signaling kinase and β-catenin. Adult Sprague-Dawley rats received cSCI injury by NYU impactor by dropping 10 g weight from a height of 12.5 mm. Locomotor functional recovery of injured rats was measured on post cSCI day 1, and weekly thereafter for 6 weeks using Basso, Beattie and Bresnahan scores. Thermal hyperalgesia (TH) testing was performed on days 21, 28, 35 and 42 post cSCI. The expression and/or activity of MMP-2, β-catenin and ERK were studied following harvest of spinal cord tissues between 3 and 6 weeks post cSCI. All experiments were funded by the department of Neurological Surgery at the University of Wisconsin, School of Medicine and Public Health having no conflict of interest. MMP-2 and β-catenin expression were elevated and gradually increased from days 21 to 42 compared to sham-operated rats and injured rats that did not exhibit TH. The expression of phosphorylated ERK (phospho-ERK) increased on day 21 but returned to baseline levels on day 42 whereas total ERK levels remained relatively unchanged and constant. Chronic NP is associated with changes in the expression of MMP-2, β-catenin and ERK. Our data suggest that the transient upregulation of phospho-ERK is involved in the initial upregulation of both β-catenin and MMP-2 following cSCI-induced NP states.

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Millions of people suffer from spinal cord injury (SCI) with little known effective clinical therapy. Neuropathic pain (NP) is often accompanied with SCI, making clinical treatment challenging. Even though the key mediators in the development of NP have been discovered, the pathogenesis is still unclear. Some of the key mediators in the sustenance of NP include the inflammatory processes, cannabinoid receptors, matrix metalloproteases, and their tissue inhibitors. Animal models have shown promising results with modulation of these mediators, yet the clinical models have been unsuccessful. One such study with matrix metalloproteases (MMPs) has yielded encouraging results. The relationship between MMPs and their tissue inhibitors (TIMPs) plays a significant role in the pathogenesis and recovery of SCI and the CNS. Key factors that lead to the functional consequences of MMP activity are cellular localization, tissue distribution, and temporal pattern of MMP expression. Studies concluding that MMPs can be seen as contributors of tissue damage and as contributors in the repair mechanisms have provided a need to reexamine their roles after acute and chronic neuropathic pain

Neuropathic pain (NP) is common among spinal cord injury (SCI) patients, and there remain clinical difficulties in treating NP due to the lack of understanding of underlying mechanisms. Extracellular proteins, such as matrix metalloproteinase and β-catenin, have been shown to be activated in the spinal cord regions following an injury, and may play a key role in contributing to NP states. While these extracellular proteins have been used as therapeutic targets in the spinal cord, there has also been evidence of up-regulation in the hypothalamus following a SCI. We hypothesize that the hypothalamus is involved in regulating NP following a SCI, and hence should be researched further to determine if it is a viable target for future therapeutic treatments.