Unilateral L4-dorsal root ganglion stimulation evokes pain relief in chronic neuropathic postsurgical knee pain and changes of inflammatory markers: part II whole transcriptome profiling

Abstract

Background In our recent clinical trial, increased peripheral concentrations of pro-inflammatory molecular mediators were determined in complex regional pain syndrome (CRPS) patients. After 3 months adjunctive unilateral, selective L4 dorsal root ganglion stimulation (L4-DRG STIM ), significantly decreased serum IL-10 and increased saliva oxytocin levels were assessed along with an improved pain and functional state. The current study extended molecular profiling towards gene expression analysis of genes known to be involved in the gonadotropin releasing hormone receptor and neuroinflammatory (cytokines/chemokines) signaling pathways. Methods Blood samples were collected from 12 CRPS patients for whole-transcriptome profiling in order to assay 18,845 inflammation-associated genes from frozen blood at baseline and after 3 months L4-DRG STIM using PANTHER™ pathway enrichment analysis tool. Results Pathway enrichment analyses tools (GOrilla™ and PANTHER™) showed predominant involvement of inflammation mediated by chemokines/cytokines and gonadotropin releasing hormone receptor pathways. Further, screening of differentially regulated genes showed changes in innate immune response related genes. Transcriptomic analysis showed that 21 genes (predominantly immunoinflammatory) were significantly changed after L4-DRG STIM . Seven genes including TLR1 , FFAR2 , IL1RAP , ILRN , C5 , PKB and IL18 were down regulated and fourteen genes including CXCL2, CCL11, IL36G, CRP, SCGB1A1, IL - 17F, TNFRSF4, PLA2G2A, CREB3L3, ADAMTS12, IL1F10, NOX1, CHIA and BDKRB1 were upregulated. Conclusions In our sub-group analysis of L4-DRG STIM treated CRPS patients, we found either upregulated or downregulated genes involved in immunoinflammatory circuits relevant for the pathophysiology of CRPS indicating a possible relation. However, large biobank-based approaches are recommended to establish genetic phenotyping as a quantitative outcome measure in CRPS patients. Trial registration The study protocol was registered at the 15.11.2016 on German Register for Clinical Trials (DRKS ID 00011267). https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00011267

Quantitative sensory phenotyping in chronic neuropathic pain patients treated with unilateral L4-dorsal root ganglion stimulation

“…In addition, 3 months of adjunctive L4-DRG STIM was found to alter levels of peripheral circulating mediators of inflammation in blood and saliva in favor of an anti-inflammatory state [4,5]. Additional transcriptome analysis of the L4-DRG STIM treated CRPS patients revealed a distinct upregulated-downregulated pattern of genes associated with inflammatory circuits pivotal for the development of CRPS (cytokine activity, glucose hemostasis, innate immune response, metabolic processing, sensory perception of pain, chronic inflammatory signaling, cell chemotaxis and neural synaptic transmission, cell chemotaxis, cell-cell signaling, vasodilatation, immune cell proliferation, cartilage development, cytokine synthesis, lipid metabolic function, angiogenesis, blood pressure and response to mechanical stimuli) [5]. Despite molecular inflammatory phenotyping, other outcome measures such as functional/structural neuroimaging or electrophysiological assessment by electroencephalography/laser evoked potential (EEG/LEP) means have been explored in the past as potential objective responsiveness parameters for spinal modulation therapy [4][5][6][7][8].…”

“…Most recently, we confirmed these reported findings in a cohort of complex regional pain syndrome (CRPS) patients treated with unilateral L4-DRG STIM complying with the diagnostic criteria of CRPS. In addition, 3 months of adjunctive L4-DRG STIM was found to alter levels of peripheral circulating mediators of inflammation in blood and saliva in favor of an anti-inflammatory state [ 4 , 5 ]. Additional transcriptome analysis of the L4-DRG STIM treated CRPS patients revealed a distinct upregulated—downregulated pattern of genes associated with inflammatory circuits pivotal for the development of CRPS (cytokine activity, glucose hemostasis, innate immune response, metabolic processing, sensory perception of pain, chronic inflammatory signaling, cell chemotaxis and neural synaptic transmission, cell chemotaxis, cell–cell signaling, vasodilatation, immune cell proliferation, cartilage development, cytokine synthesis, lipid metabolic function, angiogenesis, blood pressure and response to mechanical stimuli) [ 5 ].…”

Beyond Revision Surgery: Work‐Up and Interventional Treatments for the Painful Total Knee Arthroplasty

“…In addition, the transcription of 21 different genes was changed after DRG stimulation was initiated, indicating the potential relationship between pain control and this treatment modality. 48,49…”

Leptin and Associated Mediators of Immunometabolic Signaling: Novel Molecular Outcome Measures for Neurostimulation to Treat Chronic Pain

“…To date, there exist a few randomized-controlled and uncontrolled observational neurostimulation human studies, which have quantified peripheral circulating markers of inflammation related to metabolic homeostasis in chronic pain patients [4,5,6,7,75,76,77,78,79] (Table 1).…”

“…In an extended subgroup assay, the gene expression profile revealed several significantly up- and down-regulated genes. Despite their function for inflammatory host response and neural nociceptive excitability and traffic, some of the genes assessed from the CRPS patients like free fatty acid receptor 2 (FFAR2); interleukin receptor 1 antagonist (ILRN), interleukin 17-F (IL-17F); phospholipase A2, group IIA (PLA2G2); and NADPH oxidase (NOX1) have been associated with metabolic function such as glucose hemostasis, response to starvation, insulin resistance, lipid catabolic function, angiogenesis, blood pressure, and metabolic functions [79]. With regards to CRPS, caution is needed due to the protean nature of CRPS over time and varying phenotypes.…”