Systemic gene expression profiles according to pain types in individuals with chronic spinal cord injury

Abstract

Pain affects most individuals with traumatic spinal cord injury (SCI). Major pain types after SCI are neuropathic or nociceptive, often experienced concurrently. Pain after SCI may be refractory to treatments and negatively affects quality of life. Previously, we analyzed whole blood gene expression in individuals with chronic SCI compared to able-bodied (AB) individuals. Most participants with SCI reported pain (N = 19/28). Here, we examined gene expression of participants with SCI by pain status. Compared to AB, participants with SCI with pain had 468 differentially expressed (DE) genes; participants without pain had 564 DE genes (FDR < 0.05). Among DE genes distinct to participants with SCI with pain, Gene Ontology Biological Process (GOBP) analysis showed upregulated genes were enriched in categories related to T cell activation or inflammation; downregulated genes were enriched in categories related to protein proteolysis and catabolism. Although most participants with pain reported multiple pain types concurrently, we performed a preliminary comparison of gene expression by worst pain problem type. Compared to AB, participants with SCI who ranked neuropathic (N = 9) as worst had one distinct DE gene (TMEM156); participants who ranked nociceptive (N = 10) as worst had 61 distinct DE genes (FDR < 0.05). In the nociceptive group, the GOBP category with the lowest P-value identified among upregulated genes was “positive regulation of T cell activation”; among downregulated genes it was “receptor tyrosine kinase binding”. An exploratory comparison of pain groups by principal components analysis also showed that the nociceptive group was enriched in T-cell related genes. A correlation analysis identified genes significantly correlated with pain intensity in the neuropathic or nociceptive groups (N = 145, 65, respectively, Pearson’s correlation r > 0.8). While this pilot study highlights challenges of identifying gene expression profiles that correlate with specific types of pain in individuals with SCI, it suggests that T-cell signaling should be further investigated in this context.

Systematic analysis of critical genes and pathways identified a signature of neuropathic pain after spinal cord injury

“…Furthermore, TLRs are key receptors in various acute and chronic diseases, which can activate the inflammatory cascade and manifest by amplifying the inflammatory response (Iannotta et al, 2021). Reports have shown that SCI has a significant inducing effect on the TLR signalling pathway and induces pro‐inflammatory signals, such as NF‐κB, STAT signalling and lipopolysaccharide signalling (Morrison et al, 2021). Studies have shown that the TLR4 pathway is related to the induction of tactile allodynia, which is the main symptom associated with peripheral NP (T. Liu et al, 2012).…”

Long March Toward Safe and Effective Analgesia by Enhancing Gene Expression of Kcc2: First Steps Taken

“…The pain relief was profound, long-lasting, and with protracted onset, consistent with the drug having an impact on gene regulation. Derailed gene regulation underlies transition from acute to chronic pain (Okamoto et al, 2001;Wang et al, 2002;Hozumi et al, 2021;Morrison et al, 2021).…”

Coexistence of chronic hyperalgesia and multilevel neuroinflammatory responses after experimental SCI: a systematic approach to profiling neuropathic pain

“…Per established protocols [ 14 , 22 ], the paired sections were quickly washed, hydrated, and perforated using phosphate-buffered saline (PBS) with 0.03% Triton X-100 (PBST; Sigma-Aldrich) before blocking non-specific binding sites with 4% (vol/vol) normal donkey serum (Jackson ImmunoResearch Laboratories, West Grove, PA) in PBST for 1 h at room temperature. Different primary antibody solutions were added for incubations at 4 °C overnight, followed by quick PBST washing and reactions (1 h) with the corresponding secondary antibodies (Table 1 ) at room temperature.…”

“…These data suggested that local and systemic inflammation may act as pathogenic factors to induce the evolvement of NP, pain-triggered complications, and other neural disorders p.i. (e.g., affective components of pain, distal motor neuron/neuromuscular junction abnormalities, and axon demyelination) [ 15 – 22 ]. However, to date, little has been done to systematically investigate NIF in the central nervous system (CNS) using clinically relevant SCI models.…”