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Table 3 Evidence for the response of cytokines and neurotrophic factors to spinal cord stimulation (SCS) paradigms

From: Spinal cord stimulation in chronic pain: evidence and theory for mechanisms of action

  Tissue Sampled and Measured Change with SCS
Neuromediator WDR/NS Firing Nociceptive Effect P-SCS B-SCS HF-SCS DRG-S
Measured Centrally:
 BDNF Increased Algesia DRG:  ↔ (Tilley et al., 2017)    
 C3 Increased Algesia SC:      ↑ (Stephens et al., 2018)    
 c-Fos Increased Algesia SC:      ↑ (Tilley et al., 2016)    
 IL-1β Increased Algesia SC:      ↑ (Stephens et al., 2018; Vallejo et al., 2016)
DM:    ↑ (Tilley et al., 2019)
DRG:    ↑ (Tilley et al., 2017)
   
 IL-6 Increased Algesia DRG:     ↓ (Tilley et al., 2017)    
 TNF-a Increased Algesia SC:        ↑ (Tilley et al., 2016)    
 VEGF Increased Algesia CSF:       ↓ (McCarthy et al., 2013)    
 CXCL16 Decreased Analgesia SC:        ↑ (Vallejo et al., 2016)
DRG:     ↑ (Vallejo et al., 2016)
   
 GDNF Decreased Analgesia CSF:      ↑ (McCarthy & McCrory, 2014a)    
 IL-1α Decreased Analgesia SC:        ↑ (Vallejo et al., 2016)    
 IL-10 Decreased Analgesia DM:      ↑ (Tilley et al., 2019)    
 NpY Decreased Analgesia DRG:   ↔ (Tilley et al., 2017)    
 VIP Decreased Analgesia DRG:   ↔ (Tilley et al., 2017)    
Measured Peripherally
 CXCL10 Increased Algesia IF:        ↓ (Kriek et al., 2018)    
 IFN-γ Increased Algesia IF:       ↓(Kriek et al., 2018)
Plasma: ↔(Kamieniak et al., 2019a)
   
 IL-1β Increased Algesia Plasma: ↔(Kamieniak et al., 2019a)    
 IL-2 Increased Algesia IF:       ↓(Kriek et al., 2018)    
 IL-6 Increased Algesia IF:        ↔(Kriek et al., 2018)
Plasma:  ↔(Kamieniak et al., 2019a)
   
 IL-12 Increased Algesia IF:           ↓(Kriek et al., 2018)    
 IL-15 Increased Algesia IF:           ↓ (Kriek et al., 2018)    
 TNF-a Increased Algesia IF:          ↔(Kriek et al., 2018)
Plasma:    ↔(Kamieniak et al., 2019a)
   
 VEGF Increased Algesia IF:           ↓ (Kriek et al., 2018)    
 IL-4 Decreased Analgesia IF:           ↓(Kriek et al., 2018)    
 IL-5 Decreased Analgesia IF:           ↓(Kriek et al., 2018)    
 IL-10 Decreased Analgesia IF:           ↓(Kriek et al., 2018)
Plasma:    ↔(Kamieniak et al., 2019a)
Plasma: ↑(Kinfe et al., 2017)   
 TGF-β Decreased Analgesia Plasma:    ↔(Kamieniak et al., 2019a)    
  1. Measured centrally or peripherally, changes in neuromediator concentration and gene expression have been observed with P-SCS, sampled from multiple tissues. As glia are intimately associated with neurons and nociceptive signal propagation, small changes in local and systemic neuromediators can affect glial activation, recruitment and propagation of the inflammatory cascade. While evidence suggests that P-SCS exerts antinociceptive efficacy partially through modulation of glia, inflammation and gene expression, little is known about the mechanisms of other stimulation modalities including B-SCS, HF-SCS and DRG-S. More work is necessary to elucidate the analgesic mechanisms of theses stimulation paradigms. Up’ and ‘down’ arrows represent increases or decreases, respectively, in concentration and expression. ‘Sideways’ arrows represent no significant difference. Acronyms: BDNF (Brain-Derived Neurotrophic Factor), C3 (Complement Component 3), c-Fos (proto-oncogene), IL-1α (Interleukin 1 Alpha), IL-1β (Interleukin 1 Beta), IL-2 (Interleukin 2), IL-6 (Interleukin 6), IL-10 (Interleukin 10), IL-12 (Interleukin 12), IL-15 (Interleukin 15), TNF-α (Tumor Necrosis Factor Alpha), VEGF (Vascular Endothelial Growth Factor), CXCL16 (Chemokine C-X-C Motif Ligand 16), GDNF (Glial Cell Line-Derived Neurotrophic Factor), NpY (Neuropeptide Y), VIP (Vasoactive Intestinal Peptide), IFN-γ (Interferon Gamma), TGF-β (Transforming Growth Factor Beta), DRG (Dorsal Root Ganglion), SC (Spinal Cord), DM (Dura Mater), CSF (Cerebrospinal Fluid), IF (Interstitial Fluid)