Evidence of central inflammation in fibromyalgia — Increased cerebrospinal fluid interleukin-8 levels
Introduction
Recently activation of glia cells has been implicated in the development and maintenance of chronic pain (Watkins and Maier, 2005). Interactions between activated glia and neurons are of importance for the development of central sensitization and hyperalgesia (Ren and Dubner, 2008, Milligan and Watkins, 2009). Therefore, it has been hypothesized that activation of glia could be involved in human chronic pain syndromes characterized by pain amplification, such as fibromyalgia (FM) (Staud, 2004, Gur and Oktayoglu, 2008).
The concept of FM as a pain amplification syndrome relies on the presence of generalized, multimodal allodynia and hyperalgesia (Kosek et al., 1996) and a dysfunction of endogenous pain inhibitory mechanisms (Kosek and Hansson, 1997, Lautenbacher and Rollman, 1997) in FM patients. Recent imaging studies show enhanced transmission and/or processing of nociceptive input and an inability to activate descending pain inhibitory mechanisms in FM patients (Gracely et al., 2002, Jensen et al., 2009). Furthermore, elevated concentrations of substances involved in nociceptive transmission and central sensitization, such as substance P (SP), glutamate, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), have been reported in the cerebrospinal fluid (CSF) of FM patients (Russell et al., 1998, Giovengo et al., 1999, Sarchielli et al., 2007). Notably, SP, glutamate and BDNF can activate glia cells through receptors localized on microglia and astrocytes (Milligan and Watkins, 2009). Following activation, glia cells release pro-inflammatory cytokines/chemokines such as tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1b) and interleukin-8 (IL-8) as well as BDNF, NGF, glutamate and SP (Sofroniew et al., 2001, Watkins and Maier, 2005, Milligan and Watkins, 2009). Thereby, the activation of glia cells can further increase pain amplification (Watkins and Maier, 2005) and could thus be implicated in the altered pain modulation in FM patients.
An alternative way to activate glia is through blood-borne, pro-inflammatory cytokines released by peripheral immune cells (Watkins and Maier, 2005) and transported across the blood–brain-barrier by a special transport mechanism (Gutierrez et al., 1993, Banks et al., 1995, Quan and Herkenham, 2002). Increased levels of pro-inflammatory cytokines (Gur et al., 2002, Bazzichi et al., 2007) and reduced concentrations of anti-inflammatory cytokines (Uceyler et al., 2006) have been reported in the blood of FM patients. Furthermore, elevated serum IL-8 concentrations were related to increased pain intensity in FM patients (Gur et al., 2002). However, markers for glial cell activation in the CNS, such as CSF levels of cytokines have, to our knowledge, never been studied in FM patients. The aim of this study was to assess two major pro-inflammatory substances in CSF of FM patients, i.e., IL-1b and IL-8, both recently reported to be elevated in CSF of patients with long-term nociceptive pain (knee osteoarthritis) (Lundborg et al., 2010). Our a priori hypothesis was that also patients with a dysfunctional pain syndrome, such as FM, have increased CSF IL-1b and IL-8 concentrations in agreement with the hypothesized glia cell activation in chronic pain.
Section snippets
FM patients
Fifteen FM patients (average age 46.2 years, range 25–60 years) participated. They were outpatients at the Department of Rehabilitation Medicine, Danderyds Hospital and fulfilled the classification criteria of the American College of Rheumatology 1990 for fibromyalgia (Wolfe et al., 1990). All patients had normal erythrocyte sedimentation rate, hematology count, liver enzymes, creatinine kinase, thyroid function, rheumatoid factor and antinuclear antibodies. No medications were taken on a regular
Subject characteristics
FM patients had an average duration of FM corresponding to 2.9 years (range 1–10 years) and an average duration of pain corresponding to 10.3 years (range 2–30 years). They rated ongoing pain intensity as 65.8 mm (range 42–87 mm), while all healthy controls were pain free (p < 0.001). PPTs were lower in FM patients compared to healthy controls (p < 0.001). Compared to healthy controls, FM patients had higher ratings of fatigue (p < 0.001), sleep disturbance (p < 0.001), depression (p < 0.001) and anxiety (p <
Discussion
FM patients had elevated CSF and serum IL-8 and the average CSF concentration of IL-8 was three times higher than the average serum IL-8 concentration. To our knowledge, this is the first report of intrathecal inflammatory mediators in FM patients. Our results indicate a central inflammatory response involving the pro-inflammatory chemokine IL-8. The findings tally previous reports of increased CSF IL-8 in patients with postherpetic neuralgia (Kikuchi et al., 1999, Kotani et al., 2004),
Acknowledgments
The study was supported by Swedish Research Council (K2009-53X-21070-01-3), Swedish Rheumatism Association, Karolinska Institute Foundations and Stockholm County Council. We thank Rosmarie Jonsson and Seija Johansson for excellent assistance in collecting patient samples and PhD Mohsen Khademi for contributing with technical knowhow. No financial support from commercial sources has been received for this study. There is no conflict of interest.
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