High levels of cerebrospinal fluid chemokines point to the presence of neuroinflammation in peripheral neuropathic pain: a cross-sectional study of 2 cohorts of patients compared with healthy controls

Emmanuel Bäckryd, Anne-Li Lind, Måns Thulin, Anders Larsson, Björn Gerdle, Torsten Gordh, Emmanuel Bäckryd, Anne-Li Lind, Måns Thulin, Anders Larsson, Björn Gerdle, Torsten Gordh

Abstract

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 of patients with neuropathic pain. Our hypothesis was that we would thereby find indications of a postulated on-going process of central neuroinflammation. Samples of CSF were collected from 2 cohorts of patients with neuropathic pain (n = 11 and n = 16, respectively) and healthy control subjects (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. Levels of chemokines CXCL6, CXCL10, CCL8, CCL11, CCL23 in CSF, as well as protein LAPTGF-beta-1, were significantly higher in both neuropathic pain cohorts compared with healthy controls, pointing to neuroinflammation in patients. These 6 proteins were also major results in a recent similar study in patients with fibromyalgia. The findings need to be confirmed in larger cohorts, and the question of causality remains to be settled. Because it has been suggested that prevalent comorbidities to chronic pain (eg, depression, anxiety, poor sleep, and tiredness) also are associated with neuroinflammation, it will be important to determine whether neuroinflammation is a common mediator.

Conflict of interest statement

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Figures

Figure 1.
Figure 1.
Expression of the 11 most group-discriminating inflammation-related proteins in the cerebrospinal fluid of neuropathic pain patients (cohort 1a) versus healthy control subjects (cohort 1b). The protein levels (y-axis) are expressed as normalized protein expression, as described in the proximity extension assay subsection. Median values are represented by horizontal lines and the interquartile ranges by boxes. The ends of the whiskers depict the lowest and highest datum within 1.5 interquartile range of the lower or upper quartile, respectively. Points represent outliers.
Figure 2.
Figure 2.
Two-dimensional score plot of orthogonal partial least squares discriminant analysis comparing inflammation-related proteins in the cerebrospinal fluid of patients with neuropathic pain (cohort 1a) with healthy control subjects (cohort 1b). Class separation between neuropathic pain patients (n = 11, green dots marked “1”) and healthy controls (n = 11, blue dots marked “2”) occurs along the t[1] axis (interclass variation). The to[1] axis represents intraclass variation. The ellipse represents the Hotelling T2 95% confidence interval used when identifying strong outliers.

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