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

SIMPLE SUMMARY: The extracellular matrix comprises an important collection of proteins that aids in the body’s response to pain. Evaluating the effect of electrical neuromodulation treatments on expression levels in neural tissues associated with neuropathic pain is important for improving such treatments. Here, we analyzed extracellular matrix proteins in spinal cords of a rodent model of neuropathic pain. We evaluated two spinal cord stimulation (SCS) therapies, one based on differential target multiplexed programming (DTMP) and another based on a conventional low-rate program (LR-SCS), for their ability to reverse the effects associated with the pain model. Of the 186 proteins identified as extracellular-matrix-related, DTMP reversed expression levels of 83% of them back to levels seen in uninjured animals, whereas LR-SCS reversed 67%. Protein phosphorylation is indicative of activation/deactivation of signaling pathways. Phosphorylation can occur at multiple locations on a protein and multiple times as well. There were 883 unique phosphorylated states found among 93 ECM-related proteins. Relative to the pain model, DTMP had a reversal effect on 76% versus 58% by LR-SCS on phosphorylated proteins. This study helps up to better understand pain pathways and also highlights a more robust reversal by DTMP relative to LR-SCS. 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.