EPV035 - PROTEOMICS AND PHOSPHOPROTEOMICS OF DIFFERENTIAL TARGET MULTIPLEXED PROGRAMING FOR SPINAL CORD STIMULATION IN AN ANIMAL MODEL OF NEUROPATHIC PAIN (ID 222)
- David L. Cedeno, United States of America
- David L. Cedeno, United States of America
- Ricardo Vallejo, United States of America
- Dana M. Tilley, United States of America
- Courtney A. Kelley, United States of America
- William J. Smith, United States of America
- Alejandro Vallejo, United States of America
- Samuel M. Thomas, United States of America
Abstract
Introduction
Neuropathic chronic pain is governed by over and under expression of proteins that starts at the onset of injury and continue throughout. Our group studies the molecular mechanisms involved in the electrical modulation of chronic pain using spinal cord stimulation (SCS) algorithms that differentially target neurons and glial cells. This differential target multiplexed programming (DTMP) has proven more effective than standard approaches in clinical trials and pre-clinical work. Proteomics analysis complement the understanding of the effects of DTMP already obtained in previous work by accounting its effect on protein expression in pain-related biological process. Phosphoproteomic analyses will ascertain if targets of proteins involved in the regulation and signaling within pain-related pathways were affected by DTMP.
Methods/Materials
Procedures were approved by the IACUC at Illinois Wesleyan University. Twenty-four male Sprague-Dawley rats were implanted with a 4-contact lead and subjected to the spared-nerve injury (SNI) model of neuropathic pain. Animals were assigned to either No-SCS or DTMP. A set of 10 rats was kept as a naïve group. Standard assessments were used to measure mechanical and thermal hypersensitivity. Rats underwent continuous stimulation for 48-h. No-SCS and naïve animals were assessed in parallel to DTMP animals. After 48-h, animals were sacrificed and the spinal cord sub-adjacent to the lead was extracted and preserved until proteomics testing.
Results
DTMP significantly decreased mechanical and thermal hypersensitivity relative to No-SCS. A total of 7194 proteins and 12847 phosphoproteins were identified. The SNI model significantly change the expression of 234 proteins and 2076 phosphoproteins relative to naïve. DTMP modulated the expression of about 50% of these proteins towards pre-injury. These proteins are involved in actin binding, cell adhesion in the extracellular matrix, calcium binding, cell development, enzymatic action, G-protein regulation, signaling, phosphorylation and dephosphorylation, lipid binding, transmembrane transport, and protein regulation, which are central to neuroglial interactions.
Discussion
DTMP modulates the activity of protein kinases, such as PKCE and GRK2, which play crucial roles in inflammation and nociception within neural tissue following the SNI. The effect on the pathways involved demonstrate their ability to modulate some regulators involved in the perception of pain. Seven phosphorylated targets of PKCE and GRK2 were also modulated by DTMP, indicating the role of DTMP on regulation of signaling cascades in pain processing.
Conclusions
DTMP is an effective method for pain relief. Its mode of action involves modulation of genes and proteins associated with neuroglial interactions that affect key biological processes involved in pain pathways.
References
1. Ji RR, Berta T, Nedergaard M. Glia and pain: Is chronic pain a gliopathy? Pain. 2013; 154: S10–S28.
