ABSTRACT
Introduction: Little is still known about the underlying mechanisms that drive and maintain neuropathic pain (NeuP). Recently, lipids have been implicated as endogenous proalgesic ligands affecting onset and maintenance of pain; however, in the case of NeuP, the relationship is largely unexplored. Objectives: The aim of this study was to investigate the lipoprotein profile in patients with chronic peripheral NeuP compared with healthy controls. Methods: The concentrations of 112 lipoprotein fractions in plasma from patients with NeuP (n = 16) and healthy controls (n = 13) were analyzed using proton nuclear magnetic resonance spectroscopy. A multiplex immunoassay based on an electrochemiluminescent detection method was used to measure the concentration of 71 cytokines in plasma from patients with NeuP (n = 10) and healthy controls (n = 11). Multivariate data analysis was used to identify patterns of protein intercorrelations and proteins significant for group discrimination. Results: We found 23 lipoproteins that were significantly upregulated in patients with NeuP compared with healthy controls. When the influence of cytokines was included in a regression model, 30 proteins (8 cytokines and 22 lipoprotein fractions) were significantly upregulated or downregulated in patients with NeuP. Both conditions presented lipoprotein profiles consistent with inflammation. Body mass index did not affect lipoprotein profiles in either group. No relationship between age and lipoprotein pattern was found in NeuP, but a significant relationship was found in healthy controls. Conclusion: Patients with NeuP presented a lipoprotein profile consistent with systemic low-grade inflammation, like that seen in autoimmune, cardiometabolic, and neuroprogressive diseases. These preliminary results emphasize the importance of chronic low-grade inflammation in NeuP.
ABSTRACT
BACKGROUND: Neuropathic pain (NeuP) is a complex, debilitating condition of the somatosensory system, where dysregulation between pro- and anti-inflammatory cytokines and chemokines are believed to play a pivotal role. As of date, there is no ubiquitously accepted diagnostic test for NeuP and current therapeutic interventions are lacking in efficacy. The aim of this study was to investigate the ability of three biofluids - saliva, plasma, and cerebrospinal fluid (CSF), to discriminate an inflammatory profile at a central, systemic, and peripheral level in NeuP patients compared to healthy controls. METHODS: The concentrations of 71 cytokines, chemokines and growth factors in saliva, plasma, and CSF samples from 13 patients with peripheral NeuP and 13 healthy controls were analyzed using a multiplex-immunoassay based on an electrochemiluminescent detection method. The NeuP patients were recruited from a clinical trial of intrathecal bolus injection of ziconotide (ClinicalTrials.gov identifier NCT01373983). Multivariate data analysis (principal component analysis and orthogonal partial least square regression) was used to identify proteins significant for group discrimination and protein correlation to pain intensity. Proteins with variable influence of projection (VIP) value higher than 1 (combined with the jack-knifed confidence intervals in the coefficients plot not including zero) were considered significant. RESULTS: We found 17 cytokines/chemokines that were significantly up- or down-regulated in NeuP patients compared to healthy controls. Of these 17 proteins, 8 were from saliva, 7 from plasma, and 2 from CSF samples. The correlation analysis showed that the most important proteins that correlated to pain intensity were found in plasma (VIP > 1). CONCLUSIONS: Investigation of the inflammatory profile of NeuP showed that most of the significant proteins for group separation were found in the less invasive biofluids of saliva and plasma. Within the NeuP patient group it was also seen that proteins in plasma had the highest correlation to pain intensity. These preliminary results indicate a potential for further biomarker research in the more easily accessible biofluids of saliva and plasma for chronic peripheral neuropathic pain where a combination of YKL-40 and MIP-1α in saliva might be of special interest for future studies that also include other non-neuropathic pain states.
