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High Levels of Cerebrospinal Fluid Chemokines Point to the Presence of Neuroinflammation in Peripheral Neuropathic Pain: A Cross-Sectional Study of Two Cohorts of Patients Compared to Healthy Controls
Linköping University, Linköping, Sweden. (Pain and Rehabilitation Center, and Department of Medical and Health Sciences,)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Statistics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Animal models suggest that chemokines are important mediators in the pathophysiology of neuropathic pain. Indeed, these substances have been called “gliotransmitters”, a term that illustrates the close interplay between glial cells and neurons in the context of neuroinflammation and pain. However, evidence in humans is scarce. The aim of the study was to determine a comprehensive cerebrospinal fluid (CSF) inflammatory profile for neuropathic pain patients. Our hypothesis was that we would thereby find indications of a postulated on-going process of central neuroinflammation.  

CSF samples were collected from two cohorts of patients with neuropathic pain (n=11 and n=16, respectively) and healthy controls (n=11). The samples were analyzed with a multiplex proximity extension assay in which 92 inflammation-related proteins were measured simultaneously (Proseek® Multiplex Inflammation I, Olink Bioscience, Uppsala, Sweden). Univariate testing with control of false discovery rate, as well as orthogonal partial least squares – discriminant analysis, were used for statistical analyses.

CSF levels of chemokines CXCL6, CXCL10, CCL8, CCL11, CCL23, as well as protein LAPTGF-beta-1, were significantly higher in both neuropathic pain cohorts compared to healthy controls, pointing to neuroinflammation in patients. These 6 proteins were also major results in a recent similar study in fibromyalgia patients. The findings need to be confirmed in larger cohorts, and the question of causality remains to be settled. Since it has been suggested that prevalent co-morbidities to chronic pain (e.g., depression, anxiety, poor sleep, and tiredness) also are associated with inflammation, it will be important to determine whether inflammation is a common mediator.

Keyword [en]
biomarker; cerebrospinal fluid; chemokines; cytokines; human; inflammation; neuroinflammation; neuropathic pain; protein profile; proximity extension assay (PEA), chronic pain
National Category
Anesthesiology and Intensive Care Clinical Laboratory Medicine Biomedical Laboratory Science/Technology Neurosciences Medical Laboratory and Measurements Technologies
Research subject
Anaesthesiology and Intensive Care; Biomedical Laboratory Science; Chemistry with specialization in Analytical Chemistry; Medical Science; Medical Biochemistry; Molecular Medicine
Identifiers
URN: urn:nbn:se:uu:diva-326161OAI: oai:DiVA.org:uu-326161DiVA: diva2:1119210
Projects
Uppsala Berzelii Technology Centre for NeurodiagnosticsAFA Insurance (140341)Swedish Research Council (grant no. K2015-99x-21874-05-4)the Swedish Research Council (grant no. P29797-1).Swedish Governmental Agency for Innovation Systems (Vinnova)County Council of Östergötland (LIO-35923, SC-2013-00395-36)
Funder
AFA Insurance, 140341VINNOVA, P29797-1Swedish Research Council, P29797-1Swedish Research Council, K2015-99x-21874-05-4
Available from: 2017-07-03 Created: 2017-07-03 Last updated: 2017-07-03
In thesis
1. Biomarkers for Better Understanding of the Pathophysiology and Treatment of Chronic Pain: Investigations of Human Biofluids
Open this publication in new window or tab >>Biomarkers for Better Understanding of the Pathophysiology and Treatment of Chronic Pain: Investigations of Human Biofluids
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Chronic pain affects 20 % of the global population, causes suffering, is difficult to treat, and constitutes a large economic burden for society. So far, the characterization of molecular mechanisms of chronic pain-like behaviors in animal models has not translated into effective treatments.

In this thesis, consisting of five studies, pain patient biofluids were analyzed with modern proteomic methods to identify biomarker candidates that can be used to improve our understanding of the pathophysiology chronic pain and lead to more effective treatments.

Paper I is a proof of concept study, where a multiplex solid phase-proximity ligation assay (SP-PLA) was applied to cerebrospinal fluid (CSF) for the first time. CSF reference protein levels and four biomarker candidates for ALS were presented. The investigated proteins were not altered by spinal cord stimulation (SCS) treatment for neuropathic pain. In Paper II, patient CSF was explored by dimethyl and label-free mass spectrometric (MS) proteomic methods. Twelve proteins, known for their roles in neuroprotection, nociceptive signaling, immune regulation, and synaptic plasticity, were identified to be associated with SCS treatment of neuropathic pain. In Paper III, proximity extension assay (PEA) was used to analyze levels of 92 proteins in serum from patients one year after painful disc herniation. Patients with residual pain had significantly higher serum levels of 41 inflammatory proteins. In Paper IV, levels of 55 proteins were analyzed by a 100-plex antibody suspension bead array (ASBA) in CSF samples from two neuropathic pain patient cohorts, one cohort of fibromyalgia patients and two control cohorts. CSF protein profiles consisting of levels of apolipoprotein C1, ectonucleotide pyrophosphatase/phosphodiesterase family member 2, angiotensinogen, prostaglandin-H2 D-isomerase, neurexin-1, superoxide dismutases 1 and 3 were found to be associated with neuropathic pain and fibromyalgia. In Paper V, higher CSF levels of five chemokines and LAPTGF-beta-1were detected in two patient cohorts with neuropathic pain compared with healthy controls.

In conclusion, we demonstrate that combining MS proteomic and multiplex antibody-based methods for analysis of patient biofluid samples is a viable approach for discovery of biomarker candidates for the pathophysiology and treatment of chronic pain. Several biomarker candidates possibly reflecting systemic inflammation, lipid metabolism, and neuroinflammation in different pain conditions were identified for further investigation.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. 89 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1342
Keyword
chronic pain, neuropathic pain, lumbar radicular pain, amyotrophic lateral sclerosis, radiculopathy, fibromyalgia, pathophysiology, spinal cord stimulation, mechanism of action, disc herniation, cerebrospinal fluid, plasma, biomarker, human, protein, chemokines, cytokines, inflammation, neuroinflammation, mass spectrometry, proximity ligation assay, proximity extension assay, antibody suspension bead array, protein profiling, molecular medicine, personalized medicine
National Category
Anesthesiology and Intensive Care Clinical Laboratory Medicine Biomedical Laboratory Science/Technology Analytical Chemistry
Research subject
Anaesthesiology and Intensive Care; Biomedical Laboratory Science; Chemistry with specialization in Analytical Chemistry; Medical Science; Molecular Medicine
Identifiers
urn:nbn:se:uu:diva-326180 (URN)978-91-513-0006-1 (ISBN)
Public defence
2017-09-15, Enghoffsalen, Ingång 50, bv, Akademiska sjukhuset, Uppsala, 09:00 (Swedish)
Opponent
Supervisors
Projects
Uppsala Berzelii Technology Centre for Neurodiagnostics
Funder
Swedish Research CouncilVINNOVA
Available from: 2017-08-24 Created: 2017-07-03 Last updated: 2017-09-08

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