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tions may indicate complicated interactions between
peripheral nociception and central processes.
Nerve growth factor (NGF) and brain-derived
neurotrophic factor (BDNF) are proteins involved in
sensitization processes reasonably associated with
hyperalgesia (1, 7), an important characteristic of
FM. They are neurotrophins (NTs), which regulate
the growth and apoptosis of neurones in the develop-
ing nervous system and repairing injured neurones.
NGF and BDNF are mostly synthesized in the dorsal
root ganglia of the spinal cord (7).There are 4 NTs
in humans: NGF, BDNF, neurotrophin 3 (NT-3), and
neurotrophin 4 (NT-4). NTs bind with high affinity
to their specific tyrosine receptor kinase (Trk); NGF
binds to TrkA, BDNF and NT4 to TrkB, and NT3 to
TrkC. All NTs can also bind with lower affinity to the
neurotrophin receptor p75 (7).
NGF is a key molecule for the sensitization of pri-
mary nociceptors associated with tissue inflammation
and it is increased in inflamed tissue (8). Preclinical
data have revealed that neutralization of endogenous
NGF prevents inflammatory hyperalgesia (8). The
NGF-TrkA complexes are retrogradely transported by
sensory fibres to the cell bodies, resulting in several
genomic actions that increase the sensitivity of pain
fibres. In addition to increased ion channel functions,
NGF causes the release of substance P and CGRP at
both peripheral and central levels and may contribute to
sensitization (8). In addition, increased muscle and sys-
temic and cerebrospinal fluid (CSF) levels of substance
P have been found in FM (9–11). Higher concentrations
of both NGF and BDNF have been reported in CSF
of patients with FM (12, 13). However, to the best of
our knowledge, no studies have reported circulating
levels of NGF in FM.
BDNF regulates neuronal growth, recovery, develop-
ment, and central and peripheral plasticity, as well as
pre- and post-synaptic mechanisms (14, 15). A possible
negative role of BDNF is the development and mainte-
nance of central sensitization in chronic pain conditions
(16). There are only a few studies of circulating BDNF
in FM and they are not in agreement. Higher plasma
levels of BDNF in FM have been reported (17), but
another study found no difference (18). Serum studies
are also conflicting (19, 20). Despite a possible role in
sensitization mechanisms, only one study has investi-
gated the relationship between circulating BDNF levels
and pain sensitivity in FM; a high BDNF level was as-
sociated with low pressure pain thresholds (PPT) (21).
Several symptoms of FM, such as hyperalgesia, anx-
iety, pain, and cognitive dysfunction, can be induced
by cytokines (22, 23). Binding of NGF to TrkA and
p75 can activate transcription factors, such as nuclear
factor NF-κB and production of tumour necrosis
www.medicaljournals.se/jrm
factor alpha (TNF-α), and interleukins IL-1β, IL-2,
IL-6, IL-8, and IL-12 (24). Elevated levels of IL-8 in
blood and in CSF have been reported in FM (25–27),
but less consistent alterations have been reported in
other cytokines, such as IL-6, IL-1β, and IL-2 (28,
29). More complex alterations in plasma patterns of
inflammatory substances have been reported recently
in FM/widespread pain (27, 30).
Exercise is an often-used intervention in FM (31).
However, the effects of exercise on NGF and BDNF and
their relationships to improvements in clinical outcomes
are sparsely investigated. Increased levels of BDNF
were found after an exercise intervention in patients with
osteoarthritis (32). In FM, changes in fatigue after an
exercise intervention correlated negatively with changes
in NGF (33). No alterations in plasma levels of BDNF
were found after whole-body vibration in FM (18).
To summarize, it is unclear whether BDNF and NGF
levels in blood are altered in FM, whether these levels
are associated with important clinical characteristics,
whether physical exercise affects BDNF or NGF levels,
and, if so, whether these changes are related to clinical
outcomes. These knowledge gaps motivated this study,
which compares patients with FM and healthy controls
with regard to plasma levels of NGF and BDNF, and
investigates the effect of a 15-week programme of
progressive resistance exercise therapy on these NTs.
Within these aims, this study investigated correlations
between these NTs, cytokine levels, chemokine levels,
clinical presentations, and outcomes.
METHODS
Study design
This is a sub-study of a randomized controlled multi-centre
study (34).
Recruitment process
Recruitment and intervention of the multi-centre study started in
2010 and ended in 2013. It was executed in 3 cities: Linköping,
Stockholm and Gothenburg. A more detailed description can be
found in previous publications (34).
Inclusion criteria for women with FM were being of working
age (20–65 years) and a diagnosis according to American Col-
lege of Rheumatology criteria from 1990. Exclusion criteria
were high blood pressure (>160/90 mmHg), osteoarthritis in
knee or hip, severe somatic or psychiatric disorders, causes
of pain other than FM, high use of alcohol, and inability to
understand or speak Swedish. Subjects were not allowed to
participate in a rehabilitation programme within the past year or
practice resistance exercise or relaxation therapy twice a week or
more. Consuming analgesics, non-steroidal anti-inflammatory
drugs (NSAID), or hypnotic drugs were not allowed for 48 h
before examination (34).
Subjects with FM were recruited through local newspaper
advertisements. As a result, 402 women with FM expressed