Abstract
Chronic neuropathic pain (CNP) is one of the most significant unmet clinical needs in modern medicine. Alongside the lack of effective treatments, there is a great deficit in the availability of objective diagnostic methods to reliably facilitate an accurate diagnosis. We therefore aimed to determine the feasibility of a simple diagnostic test by analysing differentially expressed genes in the blood of patients diagnosed with CNP of the lower back and compared to healthy human controls. Refinement of microarray expression data was performed using correlation analysis with 3900 human 2-colour microarray experiments. Selected genes were analysed in the dorsal horn of Sprague–Dawley rats after L5 spinal nerve ligation (SNL), using qRT-PCR and ddPCR, to determine possible associations with pathophysiological mechanisms underpinning CNP and whether they represent translational biomarkers of CNP. We found that of the 15 potential biomarkers identified, tissue inhibitor of matrix metalloproteinase-1 (TIMP1) gene expression was upregulated in chronic neuropathic lower back pain (CNBP) (p = 0.0049) which positively correlated (R = 0.68, p = ≤0.05) with increased plasma TIMP1 levels in this group (p = 0.0433). Moreover, plasma TIMP1 was also significantly upregulated in CNBP than chronic inflammatory lower back pain (p = 0.0272). In the SNL model, upregulation of the Timp1 gene was also observed (p = 0.0058) alongside a strong trend for the upregulation of melanocortin 1 receptor (p = 0.0847). Our data therefore highlights several genes that warrant further investigation, and of these, TIMP1 shows the greatest potential as an accessible and translational CNP biomarker.
Highlights
Chronic neuropathic pain (CNP) is a physically debilitating and pathologically complex disorder featuring maladaptive cellular responses and the subsequent development of ectopic discharge and neuronal hyperexcitability [1]
PAXgene Blood RNA Tubes (IVD; PreAnalytiX GmbH, Hombrechtikon, Switzerland) from 10 individuals with chronic neuropathic lower back pain (CNBP) lasting for more than 6 months were obtained through ProteoGenex tissue procurement services (Culver City, correlation analysis (CA)), alongside a further 10 agegender matched controls acquired through ProteoGenex tissue procurement services
tissue inhibitor of matrix metalloproteinase-1 (TIMP1), which was highlighted by our correlation analysis, dipeptidyl peptidase 3 (DPP3) and melanocortin 1 receptor (MC1R), all exhibited a strong basis of literature supporting the role of these genes in pain pathways [36,37,38,39]
Summary
Chronic neuropathic pain (CNP) is a physically debilitating and pathologically complex disorder featuring maladaptive cellular responses and the subsequent development of ectopic discharge and neuronal hyperexcitability [1]. The majority of gene expression studies have focused solely on animal models of neuropathic pain (NP) [13], ranging from chronic constriction injury (CCI) [14] and spinal nerve ligation (SNL) [15] to the spared nerve injury [16] and druginduced neuropathy [17] models Such studies have identified extensive groups of genes whose expression is altered after nerve injury [18] and have provided valuable insights into the mechanisms underpinning the development and maintenance of CNP. After our initial array analysis in human samples, we investigated the expression of a subset of the candidate genes identified in the dorsal horn of sham and L5 SNL Sprague– Dawley rats This strategy prioritised the search for viable biomarkers in human blood whilst determining if these biomarkers are translational across species. Using the translational approach to biomarker discovery highlights whether these molecules may be perturbed in the mechanisms underpinning CNP and whether they may hold potential as disease phenotypic indicators and/or pharmacological targets in preclinical analgesic drug development
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