title: The Development of Translational Biomarkers as a Tool for Improving the Understanding, Diagnosis and Treatment of Chronic Neuropathic Pain.
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.
authors.affiliation: Centre for Biomarker Research and Department of Pharmacy, School of Applied Sciences, University of Huddersfield, Huddersfield, HD1 3DH, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Buckley
authors.affiliation: Pharmacology and Therapeutics, National University of Ireland, Galway, Ireland.|Centre for Pain Research and Galway Neuroscience Centre, National University of Ireland, Galway, Ireland.
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Jennings
authors.affiliation: Pharmacology and Therapeutics, National University of Ireland, Galway, Ireland.|Centre for Pain Research and Galway Neuroscience Centre, National University of Ireland, Galway, Ireland.|Physiology, School of Medicine, National University of Ireland, Galway, Ireland.
authors.forename: Nikita N
authors.initials: NN
authors.lastname: Burke
authors.affiliation: Centre for Pain Research and Galway Neuroscience Centre, National University of Ireland, Galway, Ireland.|Physiology, School of Medicine, National University of Ireland, Galway, Ireland.
authors.forename: Michelle
authors.initials: M
authors.lastname: Roche
authors.affiliation: University Hospital Galway, Galway, Ireland.
authors.forename: Veronica
authors.initials: V
authors.lastname: McInerney
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Wren
authors.affiliation: Pharmacology and Therapeutics, National University of Ireland, Galway, Ireland.|Centre for Pain Research and Galway Neuroscience Centre, National University of Ireland, Galway, Ireland.
authors.forename: David P
authors.initials: DP
authors.lastname: Finn
authors.affiliation: Centre for Biomarker Research and Department of Pharmacy, School of Applied Sciences, University of Huddersfield, Huddersfield, HD1 3DH, UK. p.c.mchugh@hud.ac.uk.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: McHugh
mesh_terms: D000818:Animals; D059350:Chronic Pain / Q000175:diagnosis* / Q000235:genetics* / Q000628:therapy; D005819:Genetic Markers / Q000235:genetics*; D006801:Humans; D017116:Low Back Pain / Q000175:diagnosis / Q000235:genetics / Q000628:therapy; D008297:Male; D009437:Neuralgia / Q000175:diagnosis* / Q000235:genetics* / Q000628:therapy; D020671:Posterior Horn Cells / Q000378:metabolism / Q000473:pathology; D014176:Protein Biosynthesis / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D005819:Genetic Markers; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1
keywords: Back pain; Biomarker; Dorsal horn; Inflammatory pain; Neuropathic pain; Plasma