Activation of Neuroinflammation via mTOR Pathway is Disparately Regulated by Differential Target Multiplexed and Traditional Low-Rate Spinal Cord Stimulation in a Neuropathic Pain Model

• Published in: Journal of pain research Vol. 15; pp. 2857 - 2866
• Main Authors: Tilley, Dana M, Vallejo, Ricardo, Vetri, Francesco, Platt, David C, Cedeno, David L
• Format: Journal Article
• Language: English
• Published: Dove Medical Press Limited 30.09.2022; Dove; Dove Medical Press
• Subjects: Analysis; central sensitization; Chronic pain; inflammation; Mass spectrometry; nerve injury; Original Research; Phosphoproteins; phosphoproteomic analysis; proteomic analysis
• ISSN: 1178-7090; 1178-7090
• DOI: 10.2147/JPR.S378490

Introduction: Spinal cord stimulation (SCS) has been used for decades to treat neuropathic pain conditions with limited understanding of its mechanisms of action. The mTOR pathway is a well-known co-factor in chronic pain and has not been previously linked to SCS therapy. Proteomic and phosphorylation analyses allow capturing a broad view of tissue response to an injury model and subsequent therapies such as SCS. Here, we evaluated the effect of differential target multiplexed SCS programming (DTMP) and traditional low-rate spinal cord stimulation (LR-SCS) on the mTOR pathway using proteomic and phosphoproteomic analyses. Methods: The spared nerve injury (SNI) model of neuropathic pain in animals was established followed by continuous treatment with either DTMP or LR-SCS for 48 hours. Control groups included sham-stimulated (No-SCS) and uninjured animals (No-SNI). Proteins were extracted from spinal cord tissue removed post-stimulation and subjected to liquid chromatography/tandem mass spectrometry to assess changes in protein expression and states of phosphorylation. Bioinformatics tools and literature were used to identify mTOR-related proteins in the various groups. Results: Over 7000 proteins were identified and filtered to find 1451 and 705 proteins significantly affected by DTMP and LR-SCS (p < 0.05), respectively, relative to No-SCS. Literature and bioinformatic tools yielded 192 mTOR-related proteins that were cross-referenced to the list of DTMP and LR-SCS affected proteins. Of these proteins, 49 were found in the proteomic dataset. Eight of these proteins showed a significant response to the pain model, 25 were significantly modulated by DTMP, and 8 by LR-SCS. Phosphoproteomic analyses yielded 119 mTOR-related phosphoproteins affected by the injury model with a 66% reversal following DTMP versus a 58% reversal by LR-SCS. Conclusion: Proteomic and phosphoproteomic analyses support the hypothesis that DTMP, and to a lesser extent LR-SCS, reverse injury induced changes of the mTOR pathway while treating neuropathic pain. Keywords: proteomic analysis, phosphoproteomic analysis, nerve injury, central sensitization, inflammation