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. 2023 Mar 31;12(4):537.
doi: 10.3390/biology12040537.

Regulation of Expression of Extracellular Matrix Proteins by Differential Target Multiplexed Spinal Cord Stimulation (SCS) and Traditional Low-Rate SCS in a Rat Nerve Injury Model

Dana M Tilley  1 , Ricardo Vallejo  1   2 , Francesco Vetri  3 , David C Platt  1   2 , David L Cedeño  1   2
Affiliations

Regulation of Expression of Extracellular Matrix Proteins by Differential Target Multiplexed Spinal Cord Stimulation (SCS) and Traditional Low-Rate SCS in a Rat Nerve Injury Model

Dana M Tilley et al. Biology (Basel). .

Abstract

There is limited research on the association between the extracellular matrix (ECM) and chronic neuropathic pain. The objective of this study was twofold. Firstly, we aimed to assess changes in expression levels and the phosphorylation of ECM-related proteins due to the spared nerve injury (SNI) model of neuropathic pain. Secondly, two modalities of spinal cord stimulation (SCS) were compared for their ability to reverse the changes induced by the pain model back toward normal, non-injury levels. We identified 186 proteins as ECM-related and as having significant changes in protein expression among at least one of the four experimental groups. Of the two SCS treatments, the differential target multiplexed programming (DTMP) approach reversed expression levels of 83% of proteins affected by the pain model back to levels seen in uninjured animals, whereas a low-rate (LR-SCS) approach reversed 67%. There were 93 ECM-related proteins identified in the phosphoproteomic dataset, having a combined 883 phosphorylated isoforms. DTMP back-regulated 76% of phosphoproteins affected by the pain model back toward levels found in uninjured animals, whereas LR-SCS back-regulated 58%. This study expands our knowledge of ECM-related proteins responding to a neuropathic pain model as well as providing a better perspective on the mechanism of action of SCS therapy.

Keywords: differential target multiplexed programming (DTMP); extracellular matrix (ECM); matrisome; neuropathic pain; phosphorylation; proteomic; spared nerve injury (SNI); spinal cord stimulation (SCS).

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Conflict of interest statement

D.C. and R.V. are consultants and advisory board members of Medtronic and co-inventors of patents related to differential target multiplexed SCS. D.T. was a paid consultant for SGX Medical to work on the matter of this study. The other authors do not have conflict to disclose.

Figures

Figure 1
Figure 1
Fold-change (FC) heatmap of the ECM structural proteins (n = 48). Red (decrease) and blue (increase) represent significantly changed expression levels, and white stands for no significant change.
Figure 2
Figure 2
Fold-change (FC) heatmap of the ECM cell junction proteins (n = 112). Red (decrease) and blue (increase) represent significantly changed expression levels, and white stands for no significant change.
Figure 3
Figure 3
Fold-change (FC) heatmap of signaling proteins associated with the ECM (n = 102). Red (decrease) and blue (increase) represent significantly changed expression levels, and white stands for no significant change.
Figure 4
Figure 4
Heat maps with expression level fold changes (FC) of selected phosphoproteins isoforms associated with (A) structure of the ECM, (B) cell adhesion at the ECM. Only the isoforms with the largest expression change due to the pain model are shown for each phosphoprotein. Values in the table below the heat map indicate the number of isoforms identified, how many were affected by the pain model and how many of these were back-regulated (back-reg) by DTMP or LR SCS.
Figure 5
Figure 5
Heat map with expression level fold changes (FC) of selected phosphoproteins isoforms associated with cell junction at the ECM. Isoforms with the largest expression change due to the pain model are shown for each phosphoprotein. Values in the table below the heat map indicate the number of isoforms identified, how many were affected by the pain model and how many of these were back-regulated (back-reg) by DTMP or LR SCS.
Figure 6
Figure 6
Heat map with expression level fold changes (FC) of selected ECM phosphoproteins isoforms associated with the cell signaling. Isoforms with the largest expression change due to the pain model are shown for each phosphoprotein. Values in the table below the heat map indicate the number of isoforms identified, how many were affected by the pain model and how many of these were back-regulated (back-reg) by DTMP or LR SCS.
Figure 7
Figure 7
Venn diagram showing the overlap of different functions of the proteins of the matrisome identified in our dataset. Circle sizes are scaled based on the number of proteins and the number of shared proteins between the three groups.
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