Brain Research Bulletin 179 (2022) 25–35

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Brain Research Bulletin

journal homepage: www.elsevier.com/locate/brainresbull

Muscle-brain communication in pain: The key role of myokines

Yuanyuan Wang a, 1, Zifeng Wu a, 1, Di Wang a, Chaoli Huang a, b, Jiali Xu a, Cunming Liu a, *,
Chun Yang a, *
a
Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
b
State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center, Nanjing University, Nanjing 210061, China

A R T I C L E I N F O A B S T R A C T

Keywords: Pain is the most common reason for a physician visit, which accounts for a considerable proportion of the global
Muscle burden of disease and greatly affects patients’ quality of life. Therefore, there is an urgent need to identify new
Myokines therapeutic targets involved in pain. Exercise-induced hypoalgesia (EIH) is a well known phenomenon observed
Exercise
worldwide. However, the available evidence demonstrates that the mechanisms of EIH remain unclear. One of
Hypoalgesia
the most accepted hypotheses has been the activation of several endogenous systems in the brain. Recently, the
Brain-derived neurotrophic factor
concept that the muscle acts as a secretory organ has attracted increasing attention. Proteins secreted by the
muscle are called myokines, playing a critical role in communicating with other organs, such as the brain. This
review will focus on several myokines and discuss their roles in EIH.

1. Introduction
“The greatest evil is physical pain,” stated St. Augustine of Hippo.
Pain is the most common reason for a physician visit (Dinakar and
Stillman, 2016). Often referred to as the 5th vital sign, pain is an un­
pleasant sensory and emotional experience associated with, or resem­
bling, actual or potential tissue damage (Wang and Thyagarajan, 2020).
Normally pain is a protective response for the nervous system to
recognize painful stimuli and avoid tissue damage through earlier and
faster-repeated exposure. However, when pain is prolonged, its alarming
effect disappears, but it also causes continuous damage and unbearable
pain to the organism (Woolf and Ma, 2007). Chronic pain should be seen
as a chronic disease just like other chronic diseases where expectations
of cure are limited (Suso-Ribera et al., 2018; Turk and Okifuji, 2002).
The prevalence of chronic pain is estimated at 10–20% of the adult
population, and the number of self-reported chronic pain is on the rise
(Geneen et al., 2017; Heiberg Agerbeck et al., 2021). Chronic pain takes
a huge toll, both economically and in terms of its impact on individuals’
lives; it has a significant impact on morbidity, mortality and disability
(Cieza et al., 2021). The most common treatments for chronic pain are
medications with first-line, second-line, and third-line treatment options
(Jensen et al., 2014; Vranken, 2012). However, most of the available
medications have shown poor efficacy. Additionally, long-term use of
the medications can be accompanied by severe side effects or, in the case
of opioids, the development of dependence or addiction. Multidisci­
plinary and multidimensional approaches demonstrate better outcomes
than medication alone, and non-pharmacological therapies are an
increasingly important component for chronic pain management (Cas­
telnuovo et al., 2016).
Current evidence suggests that physical activity and exercise provide
patients with multiple benefits, including improved strength, flexibility,
and endurance; reduced risk of cardiovascular and metabolic syndrome;
improved bone health; improved cognition and mood; and often, most
notably, improved pain control (Ambrose and Golightly, 2015; Bor­
isovskaya et al., 2020; Petersen and Pedersen, 2005; Sluka et al., 2018).
Improved pain control has been observed in chronic low back pain
(Zhang et al., 2021), arthritis (Metsios and Kitas, 2018), fibromyalgia
(Andrade et al., 2020), complex regional pain syndrome (Topcuoglu
et al., 2015), etc. The phenomenon of pain thresholds rising and pain
intensity declining after an exercise bout compared to pre-exercise is
called exercise-induced hypoalgesia (EIH) (Munneke et al., 2020). EIH
may be elicited through isometric, aerobic, and dynamic resistance ex­
ercise and is measured using a case-controlled pre-test/posttest design.
However, the reason for this improvement of pain extends far beyond
musculoskeletal health alone (Ambrose and Golightly, 2015).
Several studies have shown that exercise can improve pain even

* Correspondence to: Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road,
Nanjing 210029, China.
E-mail addresses: cunmingliu@njmu.edu.cn (C. Liu), chunyang@njmu.edu.cn (C. Yang).
1
These authors contributed equally to this work.

https://doi.org/10.1016/j.brainresbull.2021.11.017
Received 6 November 2021; Received in revised form 24 November 2021; Accepted 28 November 2021
Available online 4 December 2021
0361-9230/© 2021 Elsevier Inc. All rights reserved.
Y. Wang et al.
without improvements in strength, flexibility, or endurance (Booth
et al., 2017; Kroll, 2015). Exercising non-painful parts of the body can
have analgesic effects on other painful parts. Even exercise decreases the
perception of experimentally induced pain in healthy populations
(Daenen et al., 2015; Lannersten and Kosek, 2010; Naugle et al., 2012);
highlighting the onset of chronic pain and the mechanism of EIH tran­
scend a point of local pathology. Robust findings on exercise and brain
health indicate the presence of a muscle-brain endocrine loop, but it is
not fully understood which peripheral mechanisms cause these analgesic
effects of exercise (Pedersen, 2019). In one study, brain responses to
noxious thermal stimuli were measured using functional magnetic
resonance imaging before and after rest and exercise, suggesting that
exercise-stimulated brain regions involved in descending pain inhibition
in fibromyalgia and healthy pain-free controls (Ellingson et al., 2016).
Researches over the past two decades have uncovered novel roles of
skeletal muscle beyond its contractile function.Specifically, it has roles
as a secretory organ. Muscle cells are highly metabolically active, and
during exercise, skeletal muscle communicates with other organs by
producing and releasing so-called myokines. It has been established that
myokines mediate signaling within the muscle and muscle–organ
cross-talk to the adipose tissue, bone, liver, kidney, and pancreas (Chen
et al., 2021).
Of particular interest to the present review is the possible involve­
ment of the muscular secretome in modulating the beneficial effects of
exercise on the brain (Chen et al., 2021; Delezie and Handschin, 2018;
Ibeas et al., 2021; Pedersen, 2019), especially analgesic benefits. We
focus on the muscle-brain communication mediated by myokines in EIH.
2. Exercise-induced hypoalgesia
Exercise is “a sub-category of physical activity that is planned,
structured, repetitive, and aims to improve or maintain one or more
components of physical fitness” (WHO, 2015). Since the 1980s, health
care practitioners’ recommendations for treating pain have changed
from “rest” to minimizing or eliminating bed rest, and instead, staying
active (Waddell, 1987). Multiple studies have shown that exercise pro­
duces analgesic effects in both healthy subjects and chronic pain con­
ditions and extend these studies to examine the complex molecular
mechanisms involved in EIH (Da Silva Santos and Galdino, 2018).
Compared to less active individuals, physically active individuals show
greater conditioned pain modulation, a measure of central pain inhibi­
tion (Geva and Defrin, 2013; Naugle and Riley, 2014). Similarly, ath­
letes when compared to normally active adults indicate reduced pain
sensitivity (Tesarz et al., 2012). Physical inactivity is a risk factor for the
development of chronic pain, and physical activity may reduce this risk
(Sluka et al., 2018; Zhang et al., 2015). Regular physical activity can be
achieved through regular lifestyle activities or structured exercise. In
chronic pain, regular exercise is an effective treatment for most pain
conditions, and the effectiveness of exercise and physical therapy in
reducing disability and health care costs has long been recognized
(Hurley et al., 2012; Sluka et al., 2018).
EIH has been reported during and after different types of exercise,
such as aerobic, resistance, and isometric exercise (Jones et al., 2017;
Vaegter and Jones, 2020). This effect is most marked in aerobic and
isometric exercises with higher intensity and longer duration being
associated with greater analgesic effects (Da Silva Santos and Galdino,
2018). However, critical issues, optimal exercise parameters such as
type and intensity, remain poorly defined. As such, prescription of
specific exercise regimens remains difficult in some cases (Koltyn,
2002). Furthermore, not all types of pain conditions respond equally
well to EIH.
Some studies reported that aerobic exercise typically leads to wide­
spread EIH while resistance exercise may contribute to reduced pain
sensitivity close to the sites of muscle contraction and at remote sites of
the body, distant to the contracting muscle (Rice et al., 2019). A recent
meta-analysis (García-Correa et al., 2021) including twenty-seven
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Brain Research Bulletin 179 (2022) 25–35
studies showed that aerobic exercise was considered an option to treat
chronic pain, and there were significant improvements compared with
other treatment options in terms of pain measurements and aerobic
capacity. What is more, there is a negative relation between aerobic
capacity and pain for people with chronic pain, but not in healthy adults
(Jones et al., 2016). Aerobic exercise also has benefits for pain preven­
tion, including reducing the frequency of attacks and increasing the
quality of life in migraine patients (Varkey et al., 2011). Recent studies
have defined the benefits achieved according to the intensity of exercise.
Both moderate (50–60% of maximum heart rate [maxHR]) and vigorous
(60–80% of maxHR) aerobic exercise reduced pain intensity to heat
stimulus with a dose-response effect; there is a more reduction in pain
intensity after strenuous exercise (Naugle et al., 2014; Nelson et al.,
2007).
Resistance training that engages non-painful body parts can posi­
tively affect pain, providing an alternative exercise strategy for patients
experiencing painful episodes, especially for those with mobility diffi­
culties. However, the reduction in pain sensitivity after resistance ex­
ercise can be attributed to changes in pain threshold rather than pain
tolerance (Burrows et al., 2014). Dynamic and isometric resistance ex­
ercise induces EIH, with isometric loads as low as 10–30% of maximum
voluntary contraction capacity, provided the contraction duration is
sufficient—often held to exhaustion (maximum of 5 min) (Rice et al.,
2019). Interestingly, movement-based mind-body interventions such as
yoga, Tai Chi, and Qigong have also demonstrated benefits for chronic
pain with a lower intensity and are safe and well-tolerated in pop­
ulations of pain-sufferers (Anheyer et al., 2021; Marks, 2019; Urits et al.,
2021).
3. How do muscles communicate with the brain to modulate
pain via possible myokines?
In 1961, Goldstein raised the possibility that skeletal muscle cells
may release factors affecting metabolic processes during contraction
(Goldstein, 1961). Over the past decades, numerous studies demon­
strated that skeletal muscles could secret muscle-cell-derived effector
molecules, mediate “exercise effect” and exert endocrine or paracrine
effects. Pedersen and coworkers named these molecules “myokines”
(Pedersen et al., 2007). Now it is clear that myokines are secreted from
muscle cells during proliferation and differentiation or in response to
muscle contractions exerting autocrine, paracrine or endocrine effects
(Pedersen, 2019), which regulate muscle metabolism and other adja­
cent/remote organs such as adipose tissue, liver, gut, pancreas, bone,
vascular beds, and the brain (Pedersen, 2013; Yang and Luo, 2017). The
functional consequences of their release depend mainly on the amount
and volume of muscle mass exercised, intensity and frequency (Kim
et al., 2019; Sanchis-Gomar et al., 2019; Whitham and Febbraio, 2016).
Numerous exercise-induced myokines have been identified,
including brain-derived neurotrophic factor (BDNF), irisin, cathepsin B,
insulin-like growth factor-1 (IGF-1), and many more, have been linked
explicitly to the brain by modulating, for example, adult neurogenesis
and cognitive function (Whitham and Febbraio, 2016). This suggests
that these myokines at least partially mediate brain benefits in response
to regular exercise. It is known that the brain can vigorously inhibit pain
processing, which contributes to analgesia or hypoalgesia (Fig. 1).
Multiple brain sites and pathways are involved in modulating endoge­
nous analgesic mechanisms via descending inhibitory pain pathways
projecting from the cerebral cortex to the caudal medulla (Millan,
2002). The most well-characterized endogenous pain modulatory
pathway includes a circuitry linking the midbrain periaqueductal gray
(PAG), rostral ventromedial medulla (RVM), and the spinal cord (Ren
and Dubner, 2007). More research has recently found that some myo­
kines can act on these areas to produce a downstream modulation of
pain.
Y. Wang et al.
Fig. 1. The linkage between muscle-released myokines and brain in the pathophysiology and therapeutic mechanisms of pain. Myokines are produced and released
into circulation after exercise, and then cross the blood–brain barrier and activate descending pain modulatory system in different brain regions.
3.1. BDNF
BDNF, a secretory growth factor belonging to the family of neuro­
trophins, exerts many of their effects mainly by binding receptor tyro­
sine kinases of the Trk family. Of these, BDNF and its receptor TrkB are
most widely and abundantly expressed in the brain (Huang and Reich­
ardt, 2001; Pedersen, 2011). By binding to its cognate receptor TrkB,
BDNF triggers TrkB autophosphorylation, activating several signaling
pathways including PI3K/Akt, Ras/ERK, and PLCγ/CREB pathways
(Numakawa et al., 2010). Astrocytes and microglia primarily produce
BDNF in the brain. However, many studies show that BDNF is also
produced and secreted by human and rodent skeletal muscles and is
regulated by exercise (Ogborn and Gardiner, 2010).
Although the brain is supposed to be the source of 70–80% of the
circulating BDNF (Rasmussen et al., 2009), it is likely that reactive BDNF
product responds to exercise, both in human and animal skeletal muscle
models (Kim et al., 2019; Mackay et al., 2017; Matthews et al., 2009).
The increase of BDNF is correlated with the exercise volume, such as
intensity, duration, and frequency (De Assis et al., 2018; Di Liegro et al.,
2019). BDNF freely crosses the blood-brain barrier (BBB) (Pan et al.,
1998); therefore, if exercise contributes to an increase in the skeletal
muscle-derived BDNF, exercise-induced improvement of brain function
may be partially explained by the beneficial effects muscle-released
BDNF. Exciting studies in mice have shown that the myokine
cathepsin B (Moon et al., 2016) and irisin (Wrann et al., 2013) released
from muscle to blood during exercise cross the BBB and directly provoke
an increase in brain BDNF. BDNF plays a fundamental role in neuro­
plasticity, neurogenesis, neuronal survival, synaptogenesis, cognition,
and energy homeostasis (Di Liegro et al., 2019; Tyler et al., 2002).
Notably, this factor is emerging as an essential modulator of nociception.
Early studies demonstrated that a rat midbrain infusion of BDNF caused
a decreased response to thermal and chemical (formalin) stimuli,
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Brain Research Bulletin 179 (2022) 25–35
accompanied by enhanced serotonergic activity in the brain and spinal
cord of rats (Siuciak et al., 1994, 1998, 1995). Injection of BDNF into the
bilateral infralimbic cortices to activate neuronal activities could
accelerate long-term pain recovery and alleviate inflammatory pain
(Yue et al., 2017). In addition, the analgesic effect produced by BDNF
was reversed by naloxone preadministration (Siuciak et al., 1994; Nawa
et al., 1994; Sauer et al., 1994; Siuciak et al., 1995).
Furthermore, when BDNF was injected into the PAG, the dorsal
raphe and spinal cord showed increased β-endorphin levels (Siuciak
et al., 1995). Therefore, this suggests that an exercise-induced increase
in BDNF concentrations may contribute to increased concentrations of
endogenous opioids. The role of endogenous opioids in producing
analgesic effects is one of the most widely studied central mechanisms of
EIH. This hypothesis was confirmed by the following observations: in
spinal nerve ligation models, exercise increased the contents of
β-endorphin and met-enkephalin in the PAG and RVM (Stagg et al.,
2011; Holden et al., 2005), which may be mediated by BDNF. Both the
PAG and RVM are the two principal areas of the brainstem responsible
for the descending modulation of pain, which work synergistically to
produce the most effective analgesia.
Some studies found increased expression levels of cannabinoid CB1
receptor in the brain and concentration of endocannabinoid in plasma
after acute aerobic and resistance exercise, which were prevented by
cannabinoid receptor antagonists (Galdino et al., 2014a, 2014b; Rice
et al., 2019). The endocannabinoid system is comprised of two G
protein-coupled membrane receptors (cannabinoid CB1 and CB2 re­
ceptors), which have been found in the PAG, RVM (Pertwee, 2001).
Notably, the levels of circulating endocannabinoids are positively
related to BDNF concentration (Hillard, 2018). It is reported that BDNF
induces endocannabinoid release and regulates glutamate release in the
somatosensory cortex (Yeh et al., 2017).
The serotonergic system has been extensively studied for its role in
Y. Wang et al.
chronic pain. Not surprisingly, exercise has been demonstrated to exert
analgesic effects via modulating the serotonergic system. Bobinski et al.
(2015) showed that low-intensity treadmill running in sciatic nerve
crushed mice increases serotonin (5-HT) concentrations and expression
of its receptors (5HT-1B, 2A, 2C), and decreases the expression of the
serotonin transporter in the brainstem with a corresponding reduction in
mechanical hyperalgesia. Animals pretreated with r-chlor­
ophenylalanine, an inhibitor of 5-HT synthesis, blocked brainstem in­
creases of 5-HT and prevented the analgesic effect of treadmill exercise
in animals with neuropathic pain (Lesnak and Sluka, 2020). Experi­
mental evidence from rodent models, both pharmacologically treated
and genetically modified, have demonstrated functional reciprocity
between 5-HT and BDNF (Deltheil et al., 2008; Homberg et al., 2014);
BDNF enhances serotonin signaling, which in turn increases the level of
BDNF (Martinowich and Lu, 2008).
Moreover, it was also reported that serotonergic mechanisms may be
involved in the antinociceptive effect of BDNF (Siuciak et al., 1994).
Pietrelli et al. (2018) demonstrated that aerobic exercise upregulates the
BDNF-serotonin systems and improves cognitive function in rats. We
speculate that BDNF-serotonin systems may also contribute to pain
modulation, but more studies remain to verify.
BDNF also has several positive effects on dopamine availability in the
brain, including increased dopamine release, turnover, transporter up­
take capacity, and spontaneous electrical activity of dopaminergic
midbrain neurons (Peciña et al., 2014). Generally speaking, dopamine is
essential for allowing the proper functioning of descending anti­
nociception (Lapirot et al., 2011). Aerobic exercise increases evoked
dopamine release in the brain (Sacheli et al., 2019), but weather BDNF
induces the increase during exercise remains unclear. Furthermore,
BDNF reduced microglial activation in several brain disease models
(Mee-Inta et al., 2019). Indeed, it has been demonstrated that exogenous
BDNF alone can upregulate different anti-inflammatory microglial
markers and downregulate pro-inflammatory markers (Cappoli et al.,
2020). Many studies have shown that exercise can modulate the anal­
gesic effects of glial cells, but whether BDNF mediates this has not been
reported. However, microinjections of low doses of BDNF into the RVM
reproduced the hyperalgesic conditions (Guo et al., 2006), which is
related to enhancing N-methyl-D-aspartate receptors (NMDAR) activity
(Ren and Dubner, 2007). While administrating high doses of BDNF (in
the nmol range) into the cerebral ventricle (Cirulli et al., 2000), PAG
(Siuciak et al., 1994, 1995), RVM (Guo et al., 2006) produced analgesia
or hypoalgesia. Therefore, the effect of BDNF on pain behavior is
dose-dependent. We speculate that it is related to the large increase in
BDNF after exercise.
Current studies showed that women with a higher magnitude of in­
hibition in regulating pain were positively associated with higher levels
of BDNF (Stefani et al., 2012). Muscle-generated BDNF may be
sex-specific, as at least in response to fasting, it was observed in female
but not male mice (Yang et al., 2019). Although the molecular mecha­
nism underlying the sex-specific response to BDNF remains unclear, sex
hormones, particularly estrogens, have been demonstrated to regulate
BDNF expression and cross-talk with the TrkB cascade in the nervous
system (Carbone and Handa, 2013; Kight and McCarthy, 2017).
Furthermore, estrogens activates CREB activity and expression (Zhou
et al., 2005). Accordingly, several studies report more robust EIH in
women after both isometric (Gajsar et al., 2017; Lemley et al., 2016) and
aerobic exercise (Sternberg et al., 2001; Vaegter et al., 2014).
However, the source of the exercise-induced increase in circulating
BDNF is largely unclear. Furthermore, whether BDNF is a mediator of
exercise-induced pain improvement in the brain remains to be
elucidated.
3.2. Irisin
Irisin, a relatively new myokine, is secreted by myocytes during ex­
ercise, which plays a role in creating the beneficial effects of exercise on
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metabolism. Irisin is released by the cleavage of the membrane-bound
precursor protein fibronectin type III domain-containing protein 5
(FNDC5), a transmembrane precursor protein expressed in muscle under
the control of peroxisome proliferator-activated receptor γ coactivator
1α (PGC-1α) (Lourenco et al., 2019). In response to exercise, irisin
regulation depends on the specific training protocol (duration, intensity,
type of exercise), age, gender, training status, and muscle mass
(Schnyder and Handschin, 2015). It is well known that irisin promotes
the formation of brown adipose tissue phenotype on white adipose tissue
by increasing the density of mitochondria and the production of
uncoupling proteins, thereby increasing energy consumption (Boström
et al., 2012).
Interestingly, irisin is formed primarily during the contraction of the
skeletal muscle. However, it is also present in the brain, including Pur­
kinje cells, paraventricular nucleus, and cerebrospinal fluid (Jin et al.,
2018; Martinez Munoz et al., 2018). Dameni et al. (2018) found that
acute intrathecal administration of irisin increases the pain threshold
and decreases the expression of γamino butyric acid (GABA) receptors in
peripheral neuropathic pain model. Moreover, Dun et al. (2013) showed
that in cerebellar Purkinje cells, nearly all irisin-immunoreactive cells
were glutamate decarboxylase (GAD) positive. GAD is an enzyme that
catalyzes the decarboxylation of glutamate (i.e., an excitatory neuro­
transmitter), converting it to GABA (i.e., an inhibitory neurotransmitter)
in the nervous system (Meldrum, 2000). Thus, one mechanism of
chronic pain is dysregulation between the primary inhibitory (GABA)
and excitatory (glutamate) neurotransmitters of the central nervous
system (Peek et al., 2020). Therefore, irisin may act directly on the brain
to modulate the GABAergic system to exert analgesic effects, but the
evidence is still insufficient, and further studies are needed to confirm
this.
On the other hand, irisin can enter the central nervous system
through the BBB and induce BDNF expression (Ruan et al., 2018; Zsuga
et al., 2016). In addition, forced expression of FNDC5 in primary cortical
neurons increases BDNF expression, whereas RNAi-mediated knock­
down of FNDC5 reduces BDNF expression. Importantly, peripheral de­
livery of FNDC5 to the liver via adenoviral vectors, result in elevated
blood irisin and expression of BDNF in the hippocampus (Islam et al.,
2017).
In a middle cerebral artery occlusion mouse model, irisin treatment
inhibited activation of Iba-1+ microglia, infiltration of MPO-1+ mono­
cytes, and expression of TNF-α and IL-6 mRNA in the brain (Li et al.,
2017). Irisin also inhibits nuclear factor kappa B (NF-κB) activation in
cultured astrocytes, thereby reducing downstream cyclooxygenase-2
(COX-2) expression and releasing IL-6 and IL-1β (Wang et al., 2018).
Glial cells play a role in nociception genesis, especially chronic condi­
tions (Chen et al., 2012; Eto et al., 2018; Watkins and Maier, 2003). This
cell population mainly consists of astrocytes and microglia (Jung et al.,
2010). When activated, they release pro-inflammatory cytokines that
contribute to the transmission of nociceptive information (Kim et al.,
2016; Watkins et al., 2003). In the PAG, microinjection of microglial or
astrocytic inhibitors (minocycline or fluorocitrate) suppressed pain hy­
persensitivity (Ni et al., 2016), implicating glial-mediated descending
pain inhibition. Microglia also plays an active role in brain regions
important for the emotional and memory-related aspects of chronic pain
(Inoue and Tsuda, 2018). Growing evidence suggests that exercise in­
hibits the excessive activation of microglia and astrocytes in the brain
(Mee-Inta et al., 2019; Wang et al., 2021; He et al., 2017). So
exercise-induced glial inhibition may be via, in some part, irisin.
Although clinical studies showed a transient increase of irisin level
following acute exercise, most studies showed contradictory results
regarding how regular exercise training impacts irisin level. Regular
exercise also helps to lower the pain threshold. Moreover, the evidence
that irisin mediates EIH is insufficient. Even irisin directly contributes to
analgesia of the brain.
Y. Wang et al.
3.3. Cytokines
3.3.1. IL-6
Contracting muscles also release cytokines, such as interleukin 6 (IL-
6), IL-10, and IL-4. As interleukin passage across the BBB has been re­
ported (Banks et al., 1995), these molecules are putatively able to act on
the brain. In response to exercise, IL-6 is typically the first cytokine that
appears in the circulation during exercise, which is the most obvious and
the earliest reported that of the other cytokines; the basal plasma IL-6
concentration may increase up to 100-fold after exercise (Pedersen
and Fischer, 2007). Although several studies have demonstrated that
skeletal muscle is not the only source of exercise-induced IL-6, con­
tracted skeletal muscles may account for most of the IL-6 in circulation
(Pedersen, 2011). The magnitude of the increase in IL-6 levels is related
to the type, duration, intensity, and amount of muscle involved in the
exercise but is not affected by muscle damage (Fischer, 2006; Görgens
et al., 2015). Exercise-induced IL-6 can pass the BBB and participate in
the regulation of brain activity (Ibeas et al., 2021). However, IL-6 is a
double-edged sword presenting pro or anti-inflammatory effects. The
pro-inflammatory effects of IL-6 depend on trans-signaling, in which
IL-6 binds to a soluble form of the IL-6 receptor, whereas the
contraction-induced activation of IL-6 in muscle cells is independent of
NF-κB activation (Pedersen and Febbraio, 2008). The higher sensitivity
of IL-6 response to exercise benefits from its anti-inflammatory effects,
which was demonstrated by inhibition of lipopolysaccharide-induced
TNF-α production and by stimulation of anti-inflammatory cytokines
IL-1Ra(IL-1 receptor antagonist) and IL-10 by IL-6 (Steensberg et al.,
2003; Starkie et al., 2003).
Injection of IL-6 in a rat hind paw induced dose-dependent me­
chanical hyperalgesia in both hind paws (Cunha et al., 1992), and local
pretreatment with anti-IL-6 antibodies reduced this hyperalgesia,
whereas using anti-IL-6 antibodies alone did not affect nociception
(Cunha et al., 1992; Członkowski et al., 1993). In addition, intra­
cerebroventricular injection of nonpyrogenic amounts of IL-6 induce
hyperalgesia by prostaglandin-dependent actions (Hori et al., 1998).
However, in inflamed tissue, the administration of IL-6 was analgesic,
and this effect was reversed by naloxone (Członkowski et al., 1993). In
addition, studies showed that intrathecal administration of IL-6 sup­
pressed neuropathic pain symptoms (Mika et al., 2013).
Bianchi et al. suggested that IL-6 is necessary for the correct devel­
opment of neuronal mechanisms involved in response to both endoge­
nous and exogenous opioids: IL-6 knockout mice had larger
hypothalamic levels of β-endorphin, decreased opioid receptors in the
midbrain, and a reduced analgesic response to restraint stress or the
administration of morphine (Bianchi et al., 1999). This suggests that IL-6
has two sides in pain regulation, just as IL-6 has both pro-inflammatory
and anti-inflammatory properties, but the exact mechanism, especially
the analgesic mechanism, is not clear.
Ma et al. (2015) found that IL-6 exerts neuroprotection by inhibiting
the NMDAR subunits NR2B and NR2C via the intermediation of Janus
kinase/calcineurin ( JAK/CaN) signaling. Mice overexpressing the NR2B
subunit in the anterior cingulate and insular cortices strongly enhances
persistent pain and allodynia (Zhuo, 2002). Forebrain-targeted NR2B
overexpression, however, does significantly enhance paw licking
behavior related to prolonged noxious stimulation (peripheral formalin
injection) and mechanical allodynia (Wei et al., 2001). NR2C knockout
mice exhibit no significant differences compared to their wild-type
counterpart in pain sensitivity (Hillman et al., 2011). Therefore, we
speculate that elevated myokine IL-6 during exercise may be one of the
mechanisms of analgesia by modulating brain NMDAR and, in partic­
ular, inhibiting the NR2B subunit. Zhang et al. (2001) reported that
peripheral IL-6 administration evoked release of 5-HT in the rat stria­
tum, local injection of 1 ng of IL-6 into the striatum increased the evoked
release of 5-HT measured by amperometry in the same area. Also,
amperometric measurements showed that intraperitoneal injection of
IL-6 enhanced the 5-HT-like signal obtained from the striatum after
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Brain Research Bulletin 179 (2022) 25–35
electrical stimulation of the dorsal raphe nucleus (Zhang et al., 2001).
However, the myokine IL-6 regulates the analgesic mechanism of
NMDAR and the serotonergic system, and further research is needed.
3.3.2. IL-10
IL-10 is one of an essential anti-inflammatory and immunosuppres­
sive cytokines produced mainly by leukocytes (Saraiva and O’Garra,
2010; Saraiva et al., 2009). Keratinocytes and epithelial cells are also
reported to release IL-10 in response to tissue damage, infectious insult,
and the presence of tumor cells (Itakura et al., 2011). Nevertheless, IL-10
concentration was significantly elevated post-exercise (Sessions et al.,
2016; Timmerman et al., 2015). Exercise increases IL-10 by producing
IL-6 and produces a large number of fatigue metabolites during exercise
(such as protons, lactate, ATP) locally and in plasma (Pedersen et al.,
2007). These fatigue metabolites activate macrophages locally to release
IL-10 and promote phenotypic switching to an M2 phenotype in
response to exercise (Leung et al., 2016). Neurotrophins such as nerve
growth factor (NGF) and BDNF upregulated by exercise also stimulate
dendritic cells to release IL10 (Noga et al., 2007). Recently, some studies
revealed that IL-10 is also a myokine derived from a contraction of
cultured myotubes (Chen et al., 2019; Perrin et al., 2015; Santos et al.,
2020).
Growing evidence showed that endogenous IL-10 plays a role in
normal nociception since IL-10− /− mice or mice treated with an IL-10
neutralizing antibody had increased thermal pain thresholds (Borghi
et al., 2015; Tu et al., 2003). Systemic or contralateral intramuscular
injections of recombinant IL-10 inhibit acidic saline-induced muscle
hyperalgesia bilaterally or in the muscle IL-10 was administered in mice
(Kanaan et al., 1998; Plunkett et al., 2001). Interestingly, sustained
IL-10 treatment did not induce antinociceptive tolerance in chronic pain
states (Dengler et al., 2014; Wu et al., 2018). Multiple pieces of research
reported that IL-10 is an essential mediator in the EIH (Khan et al., 2021;
Leung et al., 2016), but the exact mechanism is not entirely understood.
To date, it is generally believed that IL-10 produced antinociception
mainly via inhibiting pro-inflammatory cytokines and reduction in the
recruitment and activation of immune cells at the injury site and the
central nervous system (Austin and Moalem-Taylor, 2010; Cianciulli
et al., 2015; Porro et al., 2020).
It has been reported that spinal IL-10 produced mechanical anti­
allodynic effects through microglial β-endorphin expression (Wu et al.,
2018). IL-10 or IL-10R is widely expressed in the brain, such as micro­
glia, astrocytes, oligodendrocytes, and neurons (Peferoen et al., 2014).
Thus, IL-10 may act as a downstream inhibitor of pain in the brain.
Ropelle et al. (2010) found that exercise increased the hypothalamic
levels of IL-10 and that this was mediated by IL-6. IL-10 treatment was
reported to ameliorate hyperphagia and upregulate the expression of the
β-endorphin precursor gene proopiomelanocortin expression in the hy­
pothalamus arcuate nucleus (Nakata et al., 2016). Importantly,
peripherally administered IL-10 could directly act on the hypothalamus
arcuate nucleus neurons (Faouzi et al., 2007). Microinjecting IL-10 into
the ventrolateral orbital cortex (VLO) region dose-dependently
decreased neuropathic pain (Shao et al., 2015). VLO, as a higher cen­
ter, is involved in an endogenous analgesic system consisting of a spi­
nal/medulla cord- thalamic nucleus submedius-VLO-PAG-spinal
/medulla cord loop (Tang et al., 2009). Furthermore, VLO is mediated
not only in the acute pain (Huo et al., 2008; Zhang et al., 1997), but also
in the persistent inflammatory pain (Dang et al., 2011; Huo et al., 2010)
and chronic neuropathic pain (Dang et al., 2010; Xu et al., 2013; Zhu
et al., 2013); which involves GABAergic modulation. L-10 is also able to
prevent microglia and astrocytes hyperactivation in the brain (Bala­
singam and Yong, 1996; Ledeboer et al., 2002; Shemer et al., 2020).
3.3.3. IL-4
IL-4 is a cytokine that functions as a potent regulator of immunity
secreted primarily by mast cells, Th2 cells, eosinophils, and basophils
(Gadani et al., 2012). Interestingly, contracting muscles also release IL-4
Y. Wang et al.
during exercise (Pedersen and Febbraio, 2012; Rosa Neto et al., 2011).
Further, exercised IL-4− /− and anti-IL-4 antibody-treated mice showed
reduced EIH, and IL-4− /− mice do not produce the phenotypic switch in
sciatic nerve macrophages (Bobinski et al., 2018), suggesting that the
increase in IL-4 is a part of the mechanism through which exercise
protects and reverses the development of hyperalgesia.
In the periphery, IL-4 diminishes pain not only by polarizing
microglia to M2 phenotype, as well as inducing expression of the anti-
inflammatory cytokines (such as IL4, IL10, IL13, TGF–β) and suppres­
sion of pro-inflammatory cytokines (such as IL-1β, IL-6, and TNF)
(Bobinski et al., 2018; Orihuela et al., 2016), but also by inducing
macrophages continuously produced opioids peptides (Met-enkephalin,
β-endorphin, and dynorphin A 1–17) at injured nerves (Celik et al.,
2020; Labuz et al., 2021). It is unknown whether IL-4 can induce
endogenous opioids production by the residual macrophages of the
brain parenchyma-microglia. Nevertheless, several cells in the brain
have IL-4 receptors, including oligodendrocytes and microglia (Zanno
et al., 2019). In vivo, IL-4 can elicit astrocytic expression of BDNF
(Derecki et al., 2010) and regulate astrocyte activation in vitro (Xiong
et al., 2011). Furthermore, IL-4 has been shown to polarize microglia
toward M2 in vivo (Tanaka et al., 2015). Indeed, IL-4 regulates
inflammation in the brain and down-regulates hippocampal
pro-inflammatory cytokines IL-1β concentration (Lynch et al., 2007).
Although it is not clear whether IL-4 crosses the BBB freely, it stimulates
the expression of vascular endothelial growth factors in endothelial
cells, enhancing vascular permeability (Michalak et al., 2019). Whether
myokine IL-4 acts on the brain to produce analgesia needs further study.
In summary, whether all of these cytokines are released from muscle
fibers or resident immune cells is still unknown. Moreover, the role of
cytokines in cross-talk between muscle and brain remains to be shown.
3.4. IGF-1
Insulin-like growth factor-1 (IGF-1) is a neurotrophic factor playing
an important role in neurotrophy, neurogenesis, and metabolic and in
other maintaining neuronal functions in the nervous system (Anderson
et al., 2002) through binding with its high affinity to the IGF-1 receptor
(IGF-1R) or its lower affinity to the insulin receptor (IR) (Forshee, 2006).
Although the main source of serum IGF-I is the liver (Yakar et al., 1999),
other peripheral tissues and cell types, including muscle and skeleton,
also produce IGF-1 (Sievers et al., 2008). Exercise enhances both central
and peripheral IGF-1 levels (Carro et al., 2000; Ehrnborg et al., 2003;
Kraemer et al., 2004; Nakajima et al., 2010). After graded intensity
exercise, total IGF-1 increases first at higher intensity (Dall et al., 2001;
Ehrnborg et al., 2003; Elias et al., 2000; Kraemer et al., 2004), though
studies of the effects of exercise on the circulating IGF-1 have yielded
inconsistent results (Frystyk, 2010).
IGF-1 is the primary downstream mediator of growth hormone (GH)
actions, and all types of exercise stimulate the secretion of GH (Roth
et al., 1963). However, contraction-induced increases in muscle IGF-1
mRNA may be GH-independent, and so is the acute release of total
IGF-1 in response to exercise (Berg and Bang, 2004). IGF-1 can act
directly at the brain since IGF-I and its receptor are widespread and
distributed throughout the central nervous system (Bondy et al., 1992).
IGF-1 is locally and abundantly expressed in both neurons and glial cells
in several brain regions where it exerts autocrine and paracrine func­
tions and circulating IGF1 via, or by-passing, the BBB, reaches the brain
(Sievers et al., 2008). Furthermore, exercise induces uptake of blood
IGF-I by specific groups of neurons throughout the brain. Systemic in­
jection of IGF-I mimicked the effects of exercise in the brain, increasing
expression of hippocampal BDNF (Carro et al., 2000). In addition,
improved insulin sensitivity associated with exercise/training may also
be accounted for this inconsistency of effects of exercise on the circu­
lating IGF-1.
The function of IGF1/IGF1R signaling in pain modulation is still
controversial. IGF-1 released from infiltrating macrophages activates
30
Brain Research Bulletin 179 (2022) 25–35
IGF-1R, resulting in noxious heat or mechanical hypersensitivity (For­
ster et al., 2019; Sugawara et al., 2019). The IGF-1R inhibitor success­
fully alleviated mechanical allodynia, heat hyperalgesia, and
spontaneous pain observed after plantar incision (Miura et al., 2011).
However, intrathecal administration of IGF-1 could induce a central
antinociceptive effect and reduce neuroinflammation in normal rats
(Bitar et al., 1996). Bjersing et al. (2012) found that a higher level of
IGF-1 in cerebrospinal fluid indicates less pain during exercise in fi­
bromyalgia. In addition, intraventricular injection of IGF-I increased
basal serotonin levels in the ventral hippocampus (Hoshaw et al., 2008).
In experimental diabetic neuropathy, subcutaneous injections of IGF-
1 reversed neuronal hyperactivity, normalized the levels of serotonin
and noradrenaline at the PAG and spinal cord in rats, and prevented
behavioral signs of pain (Morgado et al., 2011). Administration of IGF-1
also led to an increase of the proportion of the NR2B subunit mRNA
transcript of the NMDA receptor in rat hippocampus (Le Grevès et al.,
2005) and a reduction in intracortical GABA levels (Maya-Vetencourt
et al., 2012), which have been suggested be crucial for pain modulation.
Although whether the major source of IGF-1 originates from skeletal
muscle or not, IGF-1 signaling pathways in the brain are seemly
enhanced by the exercise.
The separate effects of IGF-1 on pain are not well established, but the
available data suggest that myokine IGF-1 regulates pain in a different, if
not opposite, direction compared with IGF-1 produced by macrophages
or at the site of injury. Therefore, we speculate that the mechanism of
IGF-1 analgesia may act on the brain, exerting a downstream inhibitory
effect, at least in part. In addition the relative contribution of peripheral
or central IGF-1 produced by the liver and muscle during and after ex­
ercise to the analgesic effect should be further estimated.
4. Summary
There is convincing evidence that exercise induces hypoalgesia. As
an essential exercise factor, myokines released from the skeletal muscles
may contribute to analgesic mechanisms. Importantly, myokines
mediate cross-talk between muscle and brain and may affect descending
control of pain. However, there is little evidence directly reporting the
roles of myokines in EIH. Instead of being secreted from skeletal muscle,
some myokines are also secreted by other organs or tissues such as
neurotrophic factors, inflammatory cytokines, and hepokines. Addi­
tionally, molecular characteristics of exercise-induced myokines and
their direct effects on the brain controlling pain remain obscure. There is
a possibility that myokines produced in periphery indirectly affect brain
functions without penetrating BBB (eg, via changes in microbiomes).
Furthermore, other mechanisms also contribute to pain modulation
during exercise.
Unraveling these unanswered questions would expand our knowl­
edge and understanding of underpinning mechanisms of EIH, and help
yield yet further novel therapeutic approaches. Pain is a systemic and
holistic disorder. Although treatment targeting myokines would be
beneficial, more effective analgesics with fewer side effects may be
developed when considered in the context of a systemic disorder,
especially for those who are unable to participate in physical exercise.
Declaration of Competing Interest
The authors declare no conflicts of interest.
Acknowledgments
This study was supported by grants from the National Natural Sci­
ence Foundation of China (81974171, 81703482 and 82101270),
Innovative and Entrepreneurial Team of Jiangsu Province
(JSSCTD202144), and Natural Science Foundation of Jiangsu Province
(BK20211382, and BK20210975).
Y. Wang et al. Brain Research Bulletin 179 (2022) 25–35

References Celik, M., Labuz, D., Keye, J., Glauben, R., Machelska, H., 2020. IL-4 induces M2
macrophages to produce sustained analgesia via opioids. JCI Insight 5 (4). https://
doi.org/10.1172/jci.insight.133093.
Ambrose, K.R., Golightly, Y.M., 2015. Physical exercise as non-pharmacological
Chen, F.L., Dong, Y.L., Zhang, Z.J., Cao, D.L., Xu, J., Hui, J., Zhu, L., Gao, Y.J., 2012.
treatment of chronic pain: why and when. Best Pract. Res. Clin. Rheumatol. 29 (1),
Activation of astrocytes in the anterior cingulate cortex contributes to the affective
120–130. https://doi.org/10.1016/j.berh.2015.04.022.
component of pain in an inflammatory pain model. Brain Res. Bull. 87 (1), 60–66.
Anderson, M.F., Aberg, M.A., Nilsson, M., Eriksson, P.S., 2002. Insulin-like growth factor-
https://doi.org/10.1016/j.brainresbull.2011.09.022.
I and neurogenesis in the adult mammalian brain. Brain Res. Dev. Brain Res. 134
Chen, W., Nyasha, M.R., Koide, M., Tsuchiya, M., Suzuki, N., Hagiwara, Y., Aoki, M.,
(1–2), 115–122. https://doi.org/10.1016/s0165-3806(02)00277-8.
Kanzaki, M., 2019. In vitro exercise model using contractile human and mouse
Andrade, A., Dominski, F.H., Sieczkowska, S.M., 2020. What we already know about the
hybrid myotubes. Sci. Rep. 9 (1), 11914. https://doi.org/10.1038/s41598-019-
effects of exercise in patients with fibromyalgia: an umbrella review. Semin. Arthritis
48316-9.
Rheum. 50 (6), 1465–1480. https://doi.org/10.1016/j.semarthrit.2020.02.003.
Chen, W., Wang, L., You, W., Shan, T., 2021. Myokines mediate the cross talk between
Anheyer, D., Haller, H., Lauche, R., Dobos, G., Cramer, H., 2021. Yoga for treating low
skeletal muscle and other organs. J. Cell. Physiol. 236 (4), 2393–2412. https://doi.
back pain: a systematic review and meta-analysis. Pain. https://doi.org/10.1097/j.
org/10.1002/jcp.30033.
pain.0000000000002416.
Cianciulli, A., Dragone, T., Calvello, R., Porro, C., Trotta, T., Lofrumento, D.D.,
Austin, P.J., Moalem-Taylor, G., 2010. The neuro-immune balance in neuropathic pain:
Panaro, M.A., 2015. IL-10 plays a pivotal role in anti-inflammatory effects of
involvement of inflammatory immune cells, immune-like glial cells and cytokines.
resveratrol in activated microglia cells. Int. Immunopharmacol. 24 (2), 369–376.
J. Neuroimmunol. 229 (1–2), 26–50. https://doi.org/10.1016/j.
https://doi.org/10.1016/j.intimp.2014.12.035.
jneuroim.2010.08.013.
Cieza, A., Causey, K., Kamenov, K., Hanson, S.W., Chatterji, S., Vos, T., 2021. Global
Balasingam, V., Yong, V.W., 1996. Attenuation of astroglial reactivity by interleukin-10.
estimates of the need for rehabilitation based on the Global Burden of Disease study
J. Neurosci.: Off. J. Soc. Neurosci. 16 (9), 2945–2955. https://doi.org/10.1523/
2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet 396
jneurosci.16-09-02945.1996.
(10267), 2006–2017. https://doi.org/10.1016/s0140-6736(20)32340-0.
Banks, W.A., Kastin, A.J., Broadwell, R.D., 1995. Passage of cytokines across the blood-
Cirulli, F., Berry, A., Alleva, E., 2000. Intracerebroventricular administration of brain-
brain barrier. Neuroimmunomodulation 2 (4), 241–248. https://doi.org/10.1159/
derived neurotrophic factor in adult rats affects analgesia and spontaneous
000097202.
behaviour but not memory retention in a Morris Water Maze task. Neurosci. Lett.
Berg, U., Bang, P., 2004. Exercise and circulating insulin-like growth factor I. Horm. Res.
287 (3), 207–210. https://doi.org/10.1016/s0304-3940(00)01173-3.
62 (Suppl 1), 50–58. https://doi.org/10.1159/000080759.
Cunha, F.Q., Poole, S., Lorenzetti, B.B., Ferreira, S.H., 1992. The pivotal role of tumour
Bianchi, M., Maggi, R., Pimpinelli, F., Rubino, T., Parolaro, D., Poli, V., Ciliberto, G.,
necrosis factor alpha in the development of inflammatory hyperalgesia. Br. J.
Panerai, A.E., Sacerdote, P., 1999. Presence of a reduced opioid response in
Pharmacol. 107 (3), 660–664. https://doi.org/10.1111/j.1476-5381.1992.tb14503.
interleukin-6 knock out mice. Eur. J. Neurosci. 11 (5), 1501–1507. https://doi.org/
x.
10.1046/j.1460-9568.1999.00563.x.
Członkowski, A., Stein, C., Herz, A., 1993. Peripheral mechanisms of opioid
Bitar, M.S., Al-Bustan, M., Nehme, C.L., Pilcher, C.W., 1996. Antinociceptive action of
antinociception in inflammation: involvement of cytokines. Eur. J. Pharmacol. 242
intrathecally administered IGF-I and the expression of its receptor in rat spinal cord.
(3), 229–235. https://doi.org/10.1016/0014-2999(93)90246-e.
Brain Res. 737 (1–2), 292–294. https://doi.org/10.1016/0006-8993(96)00747-0.
Da Silva Santos, R., Galdino, G., 2018. Endogenous systems involved in exercise-induced
Bjersing, J.L., Dehlin, M., Erlandsson, M., Bokarewa, M.I., Mannerkorpi, K., 2012.
analgesia. J. Physiol. Pharmacol.: Off. J. Pol. Physiol. Soc. 69 (1), 3–13. https://doi.
Changes in pain and insulin-like growth factor 1 in fibromyalgia during exercise: the
org/10.26402/jpp.2018.1.01.
involvement of cerebrospinal inflammatory factors and neuropeptides. Arthritis Res.
Daenen, L., Varkey, E., Kellmann, M., Nijs, J., 2015. Exercise, not to exercise, or how to
Ther. 14 (4), R162. https://doi.org/10.1186/ar3902.
exercise in patients with chronic pain? Applying science to practice. Clin. J. Pain. 31
Bobinski, F., Ferreira, T.A.A., Córdova, M.M., Dombrowski, P.A., da Cunha, C., Santo, C.,
(2), 108–114. https://doi.org/10.1097/ajp.0000000000000099.
Poli, A., Pires, R.G.W., Martins-Silva, C., Sluka, K.A., Santos, A.R.S., 2015. Role of
Dall, R., Lange, K.H., Kjaer, M., Jørgensen, J.O., Christiansen, J.S., Orskov, H.,
brainstem serotonin in analgesia produced by low-intensity exercise on neuropathic
Flyvbjerg, A., 2001. No evidence of insulin-like growth factor-binding protein 3
pain after sciatic nerve injury in mice. Pain 156 (12), 2595–2606. https://doi.org/
proteolysis during a maximal exercise test in elite athletes. J. Clin. Endocrinol.
10.1097/j.pain.0000000000000372.
Metab. 86 (2), 669–674. https://doi.org/10.1210/jcem.86.2.7180.
Bobinski, F., Teixeira, J.M., Sluka, K.A., Santos, A.R.S., 2018. Interleukin-4 mediates the
Dameni, S., Janzadeh, A., Yousefifard, M., Nasirinezhad, F., 2018. The effect of
analgesia produced by low-intensity exercise in mice with neuropathic pain. Pain
intrathecal injection of irisin on pain threshold and expression rate of GABAB
159 (3), 437–450. https://doi.org/10.1097/j.pain.0000000000001109.
receptors in peripheral neuropathic pain model. J. Chem. Neuroanat. 91, 17–26.
Bondy, C., Werner, H., Roberts Jr., C.T., LeRoith, D., 1992. Cellular pattern of type-I
https://doi.org/10.1016/j.jchemneu.2018.02.010.
insulin-like growth factor receptor gene expression during maturation of the rat
Dang, Y.H., Zhao, Y., Xing, B., Zhao, X.J., Huo, F.Q., Tang, J.S., Qu, C.L., Chen, T., 2010.
brain: comparison with insulin-like growth factors I and II. Neuroscience 46 (4),
The role of dopamine receptors in ventrolateral orbital cortex-evoked anti-
909–923. https://doi.org/10.1016/0306-4522(92)90193-6.
nociception in a rat model of neuropathic pain. Neuroscience 169 (4), 1872–1880.
Booth, J., Moseley, G.L., Schiltenwolf, M., Cashin, A., Davies, M., Hübscher, M., 2017.
https://doi.org/10.1016/j.neuroscience.2010.06.050.
Exercise for chronic musculoskeletal pain: a biopsychosocial approach.
Dang, Y.H., Xing, B., Zhao, Y., Zhao, X.J., Huo, F.Q., Tang, J.S., Qu, C.L., Chen, T., 2011.
Musculoskelet. Care 15 (4), 413–421. https://doi.org/10.1002/msc.1191.
The role of dopamine receptors in ventrolateral orbital cortex-evoked
Borghi, S.M., Pinho-Ribeiro, F.A., Zarpelon, A.C., Cunha, T.M., Alves-Filho, J.C.,
antinociception in a rat formalin test model. Eur. J. Pharmacol. 657 (1–3), 97–103.
Ferreira, S.H., Cunha, F.Q., Casagrande, R., Verri Jr., W.A., 2015. Interleukin-10
https://doi.org/10.1016/j.ejphar.2011.01.064.
limits intense acute swimming-induced muscle mechanical hyperalgesia in mice.
De Assis, G.G., Gasanov, E.V., de Sousa, M.B.C., Kozacz, A., Murawska-Cialowicz, E.,
Exp. Physiol. 100 (5), 531–544. https://doi.org/10.1113/ep085026.
2018. Brain derived neutrophic factor, a link of aerobic metabolism to
Borisovskaya, A., Chmelik, E., Karnik, A., 2020. Exercise. Adv. Exp. Med. Biol. 1228,
neuroplasticity. J. Physiol. Pharmacol.: Off. J. Pol. Physiol. Soc. 69 (3) https://doi.
233–253. https://doi.org/10.1007/978-981-15-1792-1_16.
org/10.26402/jpp.2018.3.12.
Boström, P., Wu, J., Jedrychowski, M.P., Korde, A., Ye, L., Lo, J.C., Rasbach, K.A.,
Delezie, J., Handschin, C., 2018. Endocrine crosstalk between skeletal muscle and the
Boström, E.A., Choi, J.H., Long, J.Z., Kajimura, S., Zingaretti, M.C., Vind, B.F.,
brain. Front. Neurol. 9, 698. https://doi.org/10.3389/fneur.2018.00698.
Tu, H., Cinti, S., Højlund, K., Gygi, S.P., Spiegelman, B.M., 2012. A PGC1-
Deltheil, T., Guiard, B.P., Guilloux, J.P., Nicolas, L., Deloménie, C., Repérant, C., Le
α-dependent myokine that drives brown-fat-like development of white fat and
Maitre, E., Leroux-Nicollet, I., Benmansour, S., Coudoré, F., David, D.J., Gardier, A.
thermogenesis. Nature 481 (7382), 463–468. https://doi.org/10.1038/nature10777.
M., 2008. Consequences of changes in BDNF levels on serotonin neurotransmission,
Burrows, N.J., Booth, J., Sturnieks, D.L., Barry, B.K., 2014. Acute resistance exercise and
5-HT transporter expression and function: studies in adult mice hippocampus.
pressure pain sensitivity in knee osteoarthritis: a randomised crossover trial.
Pharmacol. Biochem. Behav. 90 (2), 174–183. https://doi.org/10.1016/j.
Osteoarthr. Cartil. 22 (3), 407–414. https://doi.org/10.1016/j.joca.2013.12.023.
pbb.2007.09.018.
Cappoli, N., Tabolacci, E., Aceto, P., Dello Russo, C., 2020. The emerging role of the
Dengler, E.C., Alberti, L.A., Bowman, B.N., Kerwin, A.A., Wilkerson, J.L., Moezzi, D.R.,
BDNF-TrkB signaling pathway in the modulation of pain perception.
Limanovich, E., Wallace, J.A., Milligan, E.D., 2014. Improvement of spinal non-viral
J. Neuroimmunol. 349, 577406 https://doi.org/10.1016/j.jneuroim.2020.577406.
IL-10 gene delivery by D-mannose as a transgene adjuvant to control chronic
Carbone, D.L., Handa, R.J., 2013. Sex and stress hormone influences on the expression
neuropathic pain. J. Neuroinflamm. 11, 92. https://doi.org/10.1186/1742-2094-11-
and activity of brain-derived neurotrophic factor. Neuroscience 239, 295–303.
92.
https://doi.org/10.1016/j.neuroscience.2012.10.073.
Derecki, N.C., Cardani, A.N., Yang, C.H., Quinnies, K.M., Crihfield, A., Lynch, K.R.,
Carro, E., Nuñez, A., Busiguina, S., Torres-Aleman, I., 2000. Circulating insulin-like
Kipnis, J., 2010. Regulation of learning and memory by meningeal immunity: a key
growth factor I mediates effects of exercise on the brain. J. Neurosci.: Off. J. Soc.
role for IL-4. J. Exp. Med. 207 (5), 1067–1080. https://doi.org/10.1084/
Neurosci. 20 (8), 2926–2933. https://doi.org/10.1523/jneurosci.20-08-02926.2000.
jem.20091419.
Castelnuovo, G., Giusti, E.M., Manzoni, G.M., Saviola, D., Gatti, A., Gabrielli, S.,
Di Liegro, C.M., Schiera, G., Proia, P., Di Liegro, I., 2019. Physical activity and brain
Lacerenza, M., Pietrabissa, G., Cattivelli, R., Spatola, C.A., Corti, S., Novelli, M.,
health. Genes 10 (9). https://doi.org/10.3390/genes10090720.
Villa, V., Cottini, A., Lai, C., Pagnini, F., Castelli, L., Tavola, M., Torta, R.,
Dinakar, P., Stillman, A.M., 2016. Pathogenesis of pain. Semin. Pediatr. Neurol. 23 (3),
Arreghini, M., Zanini, L., Brunani, A., Capodaglio, P., D’Aniello, G.E., Scarpina, F.,
201–208. https://doi.org/10.1016/j.spen.2016.10.003.
Brioschi, A., Priano, L., Mauro, A., Riva, G., Repetto, C., Regalia, C., Molinari, E.,
Dun, S.L., Lyu, R.M., Chen, Y.H., Chang, J.K., Luo, J.J., Dun, N.J., 2013. Irisin-
Notaro, P., Paolucci, S., Sandrini, G., Simpson, S.G., Wiederhold, B., Tamburin, S.,
immunoreactivity in neural and non-neural cells of the rodent. Neuroscience 240,
2016. Psychological treatments and psychotherapies in the neurorehabilitation of
155–162. https://doi.org/10.1016/j.neuroscience.2013.02.050.
pain: evidences and recommendations from the italian consensus conference on pain
Ehrnborg, C., Lange, K.H., Dall, R., Christiansen, J.S., Lundberg, P.A., Baxter, R.C.,
in neurorehabilitation. Front. Psychol. 7, 115. https://doi.org/10.3389/
Boroujerdi, M.A., Bengtsson, B.A., Healey, M.L., Pentecost, C., Longobardi, S.,
fpsyg.2016.00115.
Napoli, R., Rosén, T., 2003. The growth hormone/insulin-like growth factor-I axis

31
Y. Wang et al.
hormones and bone markers in elite athletes in response to a maximum exercise test.
J. Clin. Endocrinol. Metab. 88 (1), 394–401. https://doi.org/10.1210/jc.2002-
020037.
Elias, A.N., Pandian, M.R., Wang, L., Suarez, E., James, N., Wilson, A.F., 2000. Leptin and
IGF-I levels in unconditioned male volunteers after short-term exercise.
Psychoneuroendocrinology 25 (5), 453–461. https://doi.org/10.1016/s0306-4530
(99)00070-0.
Ellingson, L.D., Stegner, A.J., Schwabacher, I.J., Koltyn, K.F., Cook, D.B., 2016. Exercise
strengthens central nervous system modulation of pain in fibromyalgia. Brain Sci. 6
(1) https://doi.org/10.3390/brainsci6010008.
Eto, K., Kim, S.K., Takeda, I., Nabekura, J., 2018. The roles of cortical astrocytes in
chronic pain and other brain pathologies. Neurosci. Res. 126, 3–8. https://doi.org/
10.1016/j.neures.2017.08.009.
Faouzi, M., Leshan, R., Björnholm, M., Hennessey, T., Jones, J., Münzberg, H., 2007.
Differential accessibility of circulating leptin to individual hypothalamic sites.
Endocrinology 148 (11), 5414–5423. https://doi.org/10.1210/en.2007-0655.
Fischer, C.P., 2006. Interleukin-6 in acute exercise and training: what is the biological
relevance? Exerc Immunol. Rev. 12, 6–33.
Forshee, B.A., 2006. The aging brain: is function dependent on growth hormone/insulin-
like growth factor-1 signaling? Age 28 (2), 173–180. https://doi.org/10.1007/
s11357-006-9005-9.
Forster, R., Sarginson, A., Velichkova, A., Hogg, C., Dorning, A., Horne, A.W.,
Saunders, P.T.K., Greaves, E., 2019. Macrophage-derived insulin-like growth factor-
1 is a key neurotrophic and nerve-sensitizing factor in pain associated with
endometriosis. FASEB J.: Off. Publ. Fed. Am. Soc. Exp. Biol. 33 (10), 11210–11222.
https://doi.org/10.1096/fj.201900797R.
Frystyk, J., 2010. Exercise and the growth hormone-insulin-like growth factor axis. Med.
Sci. Sports Exerc. 42 (1), 58–66. https://doi.org/10.1249/MSS.0b013e3181b07d2d.
Gadani, S.P., Cronk, J.C., Norris, G.T., Kipnis, J., 2012. IL-4 in the brain: a cytokine to
remember. J. Immunol. 189 (9), 4213–4219. https://doi.org/10.4049/
jimmunol.1202246.
Gajsar, H., Titze, C., Hasenbring, M.I., Vaegter, H.B., 2017. Isometric back exercise has
different effect on pressure pain thresholds in healthy men and women. Pain. Med.
18 (5), 917–923. https://doi.org/10.1093/pm/pnw176.
Galdino, G., Romero, T., Silva, J.F., Aguiar, D., Paula, A.M., Cruz, J., Parrella, C.,
Piscitelli, F., Duarte, I., Di Marzo, V., Perez, A., 2014a. Acute resistance exercise
induces antinociception by activation of the endocannabinoid system in rats. Anesth.
Analg. 119 (3), 702–715. https://doi.org/10.1213/ane.0000000000000340.
Galdino, G., Romero, T.R., Silva, J.F., Aguiar, D.C., de Paula, A.M., Cruz, J.S.,
Parrella, C., Piscitelli, F., Duarte, I.D., Di Marzo, V., Perez, A.C., 2014b. The
endocannabinoid system mediates aerobic exercise-induced antinociception in rats.
Neuropharmacology 77, 313–324. https://doi.org/10.1016/j.
neuropharm.2013.09.022.
García-Correa, H.R., Sánchez-Montoya, L.J., Daza-Arana, J.E., Ordoñez-Mora, L.T., 2021.
Aerobic physical exercise for pain intensity, aerobic capacity, and quality of life in
patients with chronic pain: a systematic review and meta-analysis. J. Phys. Act.
Health 1–17. https://doi.org/10.1123/jpah.2020-0806.
Geneen, L.J., Moore, R.A., Clarke, C., Martin, D., Colvin, L.A., Smith, B.H., 2017. Physical
activity and exercise for chronic pain in adults: an overview of Cochrane Reviews.
Cochrane Database Syst. Rev. 4 (4), Cd011279 https://doi.org/10.1002/14651858.
CD011279.pub3.
Geva, N., Defrin, R., 2013. Enhanced pain modulation among triathletes: a possible
explanation for their exceptional capabilities. Pain 154 (11), 2317–2323. https://
doi.org/10.1016/j.pain.2013.06.031.
Goldstein, M.S., 1961. Humoral nature of the hypoglycemic factor of muscular work.
Diabetes 10, 232–234. https://doi.org/10.2337/diab.10.3.232.
Görgens, S.W., Eckardt, K., Jensen, J., Drevon, C.A., Eckel, J., 2015. Exercise and
regulation of adipokine and myokine production. Prog. Mol. Biol. Transl. Sci. 135,
313–336. https://doi.org/10.1016/bs.pmbts.2015.07.002.
Guo, W., Robbins, M.T., Wei, F., Zou, S., Dubner, R., Ren, K., 2006. Supraspinal brain-
derived neurotrophic factor signaling: a novel mechanism for descending pain
facilitation. J. Neurosci.: Off. J. Soc. Neurosci. 26 (1), 126–137. https://doi.org/
10.1523/jneurosci.3686-05.2006.
He, X.F., Liu, D.X., Zhang, Q., Liang, F.Y., Dai, G.Y., Zeng, J.S., Pei, Z., Xu, G.Q., Lan, Y.,
2017. Voluntary exercise promotes glymphatic clearance of amyloid beta and
reduces the activation of astrocytes and microglia in aged mice. Front. Mol.
Neurosci. 10, 144. https://doi.org/10.3389/fnmol.2017.00144.
Heiberg Agerbeck, A., Martiny, F.H.J., Jauernik, C.P., Due Bruun, K., Rahbek, O.J.,
Bissenbakker, K.H., Brodersen, J., 2021. Validity of current assessment tools aiming
to measure the affective component of pain: a systematic review. Patient Relat.
Outcome Meas. 12, 213–226. https://doi.org/10.2147/prom.S304950.
Hillard, C.J., 2018. Circulating endocannabinoids: from whence do they come and where
are they going? Neuropsychopharmacol.: Off. Publ. Am. Coll.
Neuropsychopharmacol. 43 (1), 155–172. https://doi.org/10.1038/npp.2017.130.
Hillman, B.G., Gupta, S.C., Stairs, D.J., Buonanno, A., Dravid, S.M., 2011. Behavioral
analysis of NR2C knockout mouse reveals deficit in acquisition of conditioned fear
and working memory. Neurobiol. Learn. Mem. 95 (4), 404–414. https://doi.org/
10.1016/j.nlm.2011.01.008.
Holden, J.E., Jeong, Y., Forrest, J.M., 2005. The endogenous opioid system and clinical
pain management. AACN Clin. Issues 16 (3), 291–301. https://doi.org/10.1097/
00044067-200507000-00003.
Homberg, J.R., Molteni, R., Calabrese, F., Riva, M.A., 2014. The serotonin-BDNF duo:
developmental implications for the vulnerability to psychopathology. Neurosci.
Biobehav. Rev. 43, 35–47. https://doi.org/10.1016/j.neubiorev.2014.03.012.
32
Brain Research Bulletin 179 (2022) 25–35
Hori, T., Oka, T., Hosoi, M., Aou, S., 1998. Pain modulatory actions of cytokines and
prostaglandin E2 in the brain. Ann. N. Y. Acad. Sci. 840, 269–281. https://doi.org/
10.1111/j.1749-6632.1998.tb09567.x.
Hoshaw, B.A., Hill, T.I., Crowley, J.J., Malberg, J.E., Khawaja, X., Rosenzweig-Lipson, S.,
Schechter, L.E., Lucki, I., 2008. Antidepressant-like behavioral effects of IGF-I
produced by enhanced serotonin transmission. Eur. J. Pharmacol. 594 (1–3),
109–116. https://doi.org/10.1016/j.ejphar.2008.07.023.
Huang, E.J., Reichardt, L.F., 2001. Neurotrophins: roles in neuronal development and
function. Annu. Rev. Neurosci. 24, 677–736. https://doi.org/10.1146/annurev.
neuro.24.1.677.
Huo, F.Q., Qu, C.L., Li, Y.Q., Tang, J.S., Jia, H., 2008. GABAergic modulation is involved
in the ventrolateral orbital cortex 5-HT 1A receptor activation-induced
antinociception in the rat. Pain 139 (2), 398–405. https://doi.org/10.1016/j.
pain.2008.05.013.
Huo, F.Q., Huang, F.S., Lv, B.C., Chen, T., Feng, J., Qu, C.L., Tang, J.S., Li, Y.Q., 2010.
Activation of serotonin 1A receptors in ventrolateral orbital cortex depresses
persistent nociception: a presynaptic inhibition mechanism. Neurochem. Int. 57 (7),
749–755. https://doi.org/10.1016/j.neuint.2010.08.011.
Hurley, M.V., Walsh, N.E., Mitchell, H., Nicholas, J., Patel, A., 2012. Long-term outcomes
and costs of an integrated rehabilitation program for chronic knee pain: a pragmatic,
cluster randomized, controlled trial. Arthritis Care Res. 64 (2), 238–247. https://doi.
org/10.1002/acr.20642.
Ibeas, K., Herrero, L., Mera, P., Serra, D., 2021. Hypothalamus-skeletal muscle crosstalk
during exercise and its role in metabolism modulation. Biochem. Pharmacol. 190,
114640 https://doi.org/10.1016/j.bcp.2021.114640.
Inoue, K., Tsuda, M., 2018. Microglia in neuropathic pain: cellular and molecular
mechanisms and therapeutic potential. Nat. Rev. Neurosci. 19 (3), 138–152. https://
doi.org/10.1038/nrn.2018.2.
Islam, M.R., Young, M.F., Wrann, C.D., 2017. The role of FNDC5/Irisin in the nervous
system and as a mediator for beneficial effects of exercise on the brain. In:
Spiegelman, B. (Ed.), Hormones, Metabolism and the Benefits of Exercise. Springer,
Cham (CH).
Itakura, E., Huang, R.R., Wen, D.R., Paul, E., Wünsch, P.H., Cochran, A.J., 2011. IL-10
expression by primary tumor cells correlates with melanoma progression from radial
to vertical growth phase and development of metastatic competence. Mod. Pathol.
24 (6), 801–809. https://doi.org/10.1038/modpathol.2011.5.
Jensen, M., Day, M., Miró, J., 2014. Neuromodulatory treatments for chronic pain:
efficacy and mechanisms. Nat. Rev. Neurol. 10 (3), 167–178. https://doi.org/
10.1038/nrneurol.2014.12.
Jin, Y., Sumsuzzman, D.M., Choi, J., Kang, H., Lee, S.-R., Hong, Y., 2018. Molecular and
functional interaction of the myokine irisin with physical exercise and alzheimer’s
disease. Molecules 23 (12), E3229. https://doi.org/10.3390/molecules23123229.
Jones, M.D., Booth, J., Taylor, J.L., Barry, B.K., 2016. Limited association between
aerobic fitness and pain in healthy individuals: a cross-sectional study. Pain. Med. 17
(10), 1799–1808. https://doi.org/10.1093/pm/pnv084.
Jones, M.D., Valenzuela, T., Booth, J., Taylor, J.L., Barry, B.K., 2017. Explicit education
about exercise-induced hypoalgesia influences pain responses to acute exercise in
healthy adults: a randomized controlled trial. J. Pain. 18 (11), 1409–1416. https://
doi.org/10.1016/j.jpain.2017.07.006.
Jung, J.S., Shin, J.A., Park, E.M., Lee, J.E., Kang, Y.S., Min, S.W., Kim, D.H., Hyun, J.W.,
Shin, C.Y., Kim, H.S., 2010. Anti-inflammatory mechanism of ginsenoside Rh1 in
lipopolysaccharide-stimulated microglia: critical role of the protein kinase A
pathway and hemeoxygenase-1 expression. J. Neurochem. 115 (6), 1668–1680.
https://doi.org/10.1111/j.1471-4159.2010.07075.x.
Kanaan, S.A., Poole, S., Saadé, N.E., Jabbur, S., Safieh-Garabedian, B., 1998. Interleukin-
10 reduces the endotoxin-induced hyperalgesia in mice. J. Neuroimmunol. 86 (2),
142–150. https://doi.org/10.1016/s0165-5728(98)00027-7.
Khan, J., Wang, Q., Ren, Y., Eliav, R., Korczeniewska, O.A., Benoliel, R., Eliav, E., 2021.
Exercise induced hypoalgesia profile in rats is associated with IL-10 and IL-1 β levels
and pain severity following nerve injury. Cytokine 143, 155540. https://doi.org/
10.1016/j.cyto.2021.155540.
Kight, K.E., McCarthy, M.M., 2017. Sex differences and estrogen regulation of BDNF gene
expression, but not propeptide content, in the developing hippocampus. J. Neurosci.
Res. 95 (1–2), 345–354. https://doi.org/10.1002/jnr.23920.
Kim, S., Choi, J.Y., Moon, S., Park, D.H., Kwak, H.B., Kang, J.H., 2019. Roles of myokines
in exercise-induced improvement of neuropsychiatric function. Pflug. Arch.: Eur. J.
Physiol. 471 (3), 491–505. https://doi.org/10.1007/s00424-019-02253-8.
Kim, S.K., Hayashi, H., Ishikawa, T., Shibata, K., Shigetomi, E., Shinozaki, Y., Inada, H.,
Roh, S.E., Kim, S.J., Lee, G., Bae, H., Moorhouse, A.J., Mikoshiba, K., Fukazawa, Y.,
Koizumi, S., Nabekura, J., 2016. Cortical astrocytes rewire somatosensory cortical
circuits for peripheral neuropathic pain. J. Clin. Investig. 126 (5), 1983–1997.
https://doi.org/10.1172/jci82859.
Koltyn, K.F., 2002. Exercise-induced hypoalgesia and intensity of exercise. Sports Med.
32 (8), 477–487. https://doi.org/10.2165/00007256-200232080-00001.
Kraemer, R.R., Durand, R.J., Acevedo, E.O., Johnson, L.G., Kraemer, G.R., Hebert, E.P.,
Castracane, V.D., 2004. Rigorous running increases growth hormone and insulin-like
growth factor-I without altering ghrelin. Exp. Biol. Med. 229 (3), 240–246. https://
doi.org/10.1177/153537020422900304.
Kroll, H.R., 2015. Exercise therapy for chronic pain. Phys. Med. Rehabil. Clin. N. Am. 26
(2), 263–281. https://doi.org/10.1016/j.pmr.2014.12.007.
Labuz, D., Celik, M., Seitz, V., Machelska, H., 2021. Interleukin-4 induces the release of
opioid peptides from M1 macrophages in pathological pain. J. Neurosci.: Off. J. Soc.
Neurosci. 41 (13), 2870–2882. https://doi.org/10.1523/jneurosci.3040-20.2021.
Lannersten, L., Kosek, E., 2010. Dysfunction of endogenous pain inhibition during
exercise with painful muscles in patients with shoulder myalgia and fibromyalgia.
Pain 151 (1), 77–86. https://doi.org/10.1016/j.pain.2010.06.021.
Y. Wang et al.
Lapirot, O., Melin, C., Modolo, A., Nicolas, C., Messaoudi, Y., Monconduit, L., Artola, A.,
Luccarini, P., Dallel, R., 2011. Tonic and phasic descending dopaminergic controls of
nociceptive transmission in the medullary dorsal horn. Pain 152 (8), 1821–1831.
https://doi.org/10.1016/j.pain.2011.03.030.
Le Grevès, M., Le Grevès, P., Nyberg, F., 2005. Age-related effects of IGF-1 on the NMDA-
, GH- and IGF-1-receptor mRNA transcripts in the rat hippocampus. Brain Res. Bull.
65 (5), 369–374. https://doi.org/10.1016/j.brainresbull.2005.01.012.
Ledeboer, A., Brevé, J.J., Wierinckx, A., van der Jagt, S., Bristow, A.F., Leysen, J.E.,
Tilders, F.J., Van Dam, A.M., 2002. Expression and regulation of interleukin-10 and
interleukin-10 receptor in rat astroglial and microglial cells. Eur. J. Neurosci. 16 (7),
1175–1185. https://doi.org/10.1046/j.1460-9568.2002.02200.x.
Lemley, K.J., Senefeld, J., Hunter, S.K., Hoeger Bement, M., 2016. Only women report
increase in pain threshold following fatiguing contractions of the upper extremity.
Eur. J. Appl. Physiol. 116 (7), 1379–1385. https://doi.org/10.1007/s00421-016-
3389-8.
Lesnak, J.B., Sluka, K.A., 2020. Mechanism of exercise-induced analgesia: what we can
learn from physically active animals. Pain. Rep. 5 (5), e850 https://doi.org/
10.1097/pr9.0000000000000850.
Leung, A., Gregory, N.S., Allen, L.H., Sluka, K.A., 2016. Regular physical activity
prevents chronic pain by altering resident muscle macrophage phenotype and
increasing interleukin-10 in mice. Pain 157 (1), 70–79. https://doi.org/10.1097/j.
pain.0000000000000312.
Li, D.J., Li, Y.H., Yuan, H.B., Qu, L.F., Wang, P., 2017. The novel exercise-induced
hormone irisin protects against neuronal injury via activation of the Akt and ERK1/2
signaling pathways and contributes to the neuroprotection of physical exercise in
cerebral ischemia. Metab.: Clin. Exp. 68, 31–42. https://doi.org/10.1016/j.
metabol.2016.12.003.
Lourenco, M.V., Frozza, R.L., de Freitas, G.B., Zhang, H., Kincheski, G.C., Ribeiro, F.C.,
Gonçalves, R.A., Clarke, J.R., Beckman, D., Staniszewski, A., Berman, H., Guerra, L.
A., Forny-Germano, L., Meier, S., Wilcock, D.M., de Souza, J.M., Alves-Leon, S.,
Prado, V.F., Prado, M.A.M., Abisambra, J.F., Tovar-Moll, F., Mattos, P., Arancio, O.,
Ferreira, S.T., De Felice, F.G., 2019. Exercise-linked FNDC5/irisin rescues synaptic
plasticity and memory defects in Alzheimer’s models. Nat. Med. 25 (1), 165–175.
https://doi.org/10.1038/s41591-018-0275-4.
Lynch, A.M., Loane, D.J., Minogue, A.M., Clarke, R.M., Kilroy, D., Nally, R.E., Roche, O.
J., O’Connell, F., Lynch, M.A., 2007. Eicosapentaenoic acid confers neuroprotection
in the amyloid-beta challenged aged hippocampus. Neurobiol. Aging 28 (6),
845–855. https://doi.org/10.1016/j.neurobiolaging.2006.04.006.
Ma, S.H., Zhuang, Q.X., Shen, W.X., Peng, Y.P., Qiu, Y.H., 2015. Interleukin-6 reduces
NMDAR-mediated cytosolic Ca2+ overload and neuronal death via JAK/CaN
signaling. Cell Calcium 58 (3), 286–295. https://doi.org/10.1016/j.
ceca.2015.06.006.
Mackay, C.P., Kuys, S.S., Brauer, S.G., 2017. The effect of aerobic exercise on brain-
derived neurotrophic factor in people with neurological disorders: a systematic
review and meta-analysis. Neural Plast. 2017, 4716197 https://doi.org/10.1155/
2017/4716197.
Marks, R., 2019. Qigong and musculoskeletal pain. Curr. Rheumatol. Rep. 21 (11), 59.
https://doi.org/10.1007/s11926-019-0861-6.
Martinez Munoz, I.Y., Camarillo Romero, E.D.S., Garduno Garcia, J.J., 2018. Irisin a
novel metabolic biomarker: present knowledge and future directions. Int. J.
Endocrinol. 2018, 7816806 https://doi.org/10.1155/2018/7816806.
Martinowich, K., Lu, B., 2008. Interaction between BDNF and serotonin: role in mood
disorders. Neuropsychopharmacol.: Off. Publ. Am. Coll. Neuropsychopharmacol. 33
(1), 73–83. https://doi.org/10.1038/sj.npp.1301571.
Matthews, V.B., Aström, M.B., Chan, M.H., Bruce, C.R., Krabbe, K.S., Prelovsek, O.,
Akerström, T., Yfanti, C., Broholm, C., Mortensen, O.H., Penkowa, M., Hojman, P.,
Zankari, A., Watt, M.J., Bruunsgaard, H., Pedersen, B.K., Febbraio, M.A., 2009.
Brain-derived neurotrophic factor is produced by skeletal muscle cells in response to
contraction and enhances fat oxidation via activation of AMP-activated protein
kinase. Diabetologia 52 (7), 1409–1418. https://doi.org/10.1007/s00125-009-
1364-1.
Maya-Vetencourt, J.F., Baroncelli, L., Viegi, A., Tiraboschi, E., Castren, E., Cattaneo, A.,
Maffei, L., 2012. IGF-1 restores visual cortex plasticity in adult life by reducing local
GABA levels. Neural Plast. 2012, 250421 https://doi.org/10.1155/2012/250421.
Mee-Inta, O., Zhao, Z.W., Kuo, Y.M., 2019. Physical exercise inhibits inflammation and
microglial activation. Cells 8 (7). https://doi.org/10.3390/cells8070691.
Meldrum, B.S., 2000. Glutamate as a neurotransmitter in the brain: review of physiology
and pathology. J. Nutr. 130 (4S Suppl), 1007s–1015s. https://doi.org/10.1093/jn/
130.4.1007S.
Metsios, G.S., Kitas, G.D., 2018. Physical activity, exercise and rheumatoid arthritis:
effectiveness, mechanisms and implementation. Best practice & research. Clin.
Rheumatol. 32 (5), 669–682. https://doi.org/10.1016/j.berh.2019.03.013.
Michalak, S., Kalinowska-Lyszczarz, A., Rybacka-Mossakowska, J., Zaborowski, M.,
Kozubski, W., 2019. The associations between serum vascular endothelial growth
factor, tumor necrosis factor and interleukin 4 with the markers of blood-brain
barrier breakdown in patients with paraneoplastic neurological syndromes. J. Neural
Trans. 126, 149–158. https://doi.org/10.1007/s00702-018-1950-9.
Mika, J., Zychowska, M., Popiolek-Barczyk, K., Rojewska, E., Przewlocka, B., 2013.
Importance of glial activation in neuropathic pain. Eur. J. Pharmacol. 716 (1–3),
106–119. https://doi.org/10.1016/j.ejphar.2013.01.072.
Millan, M.J., 2002. Descending control of pain. Prog. Neurobiol. 66 (6), 355–474.
https://doi.org/10.1016/s0301-0082(02)00009-6.
Miura, M., Sasaki, M., Mizukoshi, K., Shibasaki, M., Izumi, Y., Shimosato, G., Amaya, F.,
2011. Peripheral sensitization caused by insulin-like growth factor 1 contributes to
pain hypersensitivity after tissue injury. Pain 152 (4), 888–895. https://doi.org/
10.1016/j.pain.2011.01.004.
33
Brain Research Bulletin 179 (2022) 25–35
Moon, H.Y., Becke, A., Berron, D., Becker, B., Sah, N., Benoni, G., Janke, E., Lubejko, S.
T., Greig, N.H., Mattison, J.A., Duzel, E., van Praag, H., 2016. Running-induced
systemic cathepsin B secretion is associated with memory function. Cell Metab. 24
(2), 332–340. https://doi.org/10.1016/j.cmet.2016.05.025.
Morgado, C., Silva, L., Pereira-Terra, P., Tavares, I., 2011. Changes in serotoninergic and
noradrenergic descending pain pathways during painful diabetic neuropathy: the
preventive action of IGF1. Neurobiol. Dis. 43 (1), 275–284. https://doi.org/
10.1016/j.nbd.2011.04.001.
Munneke, W., Ickmans, K., Voogt, L., 2020. The association of psychosocial factors and
exercise-induced hypoalgesia in healthy people and people with musculoskeletal
pain: a systematic review. Pain. Pract.: Off. J. World Inst. Pain. 20 (6), 676–694.
https://doi.org/10.1111/papr.12894.
Nakajima, S., Ohsawa, I., Ohta, S., Ohno, M., Mikami, T., 2010. Regular voluntary
exercise cures stress-induced impairment of cognitive function and cell proliferation
accompanied by increases in cerebral IGF-1 and GST activity in mice. Behav. Brain
Res. 211 (2), 178–184. https://doi.org/10.1016/j.bbr.2010.03.028.
Nakata, M., Yamamoto, S., Okada, T., Gantulga, D., Okano, H., Ozawa, K., Yada, T.,
2016. IL-10 gene transfer upregulates arcuate POMC and ameliorates hyperphagia,
obesity and diabetes by substituting for leptin. Int. J. Obes. 40 (3), 425–433. https://
doi.org/10.1038/ijo.2015.201 (2005).
Naugle, K.M., Riley 3rd, J.L., 2014. Self-reported physical activity predicts pain
inhibitory and facilitatory function. Med. Sci. Sports Exerc. 46 (3), 622–629. https://
doi.org/10.1249/MSS.0b013e3182a69cf1.
Naugle, K.M., Fillingim, R.B., Riley 3rd, J.L., 2012. A meta-analytic review of the
hypoalgesic effects of exercise. J. Pain. 13 (12), 1139–1150. https://doi.org/
10.1016/j.jpain.2012.09.006.
Naugle, K.M., Naugle, K.E., Fillingim, R.B., Samuels, B., Riley 3rd, J.L., 2014. Intensity
thresholds for aerobic exercise-induced hypoalgesia. Med. Sci. Sports Exerc. 46 (4),
817–825. https://doi.org/10.1249/mss.0000000000000143.
Nawa, H., Pelleymounter, M.A., Carnahan, J., 1994. Intraventricular administration of
BDNF increases neuropeptide expression in newborn rat brain. J. Neurosci.: Off. J.
Soc. Neurosci. 14 (6), 3751–3765. https://doi.org/10.1523/jneurosci.14-06-
03751.1994.
Nelson, M.E., Rejeski, W.J., Blair, S.N., Duncan, P.W., Judge, J.O., King, A.C., Macera, C.
A., Castaneda-Sceppa, C., 2007. Physical activity and public health in older adults:
recommendation from the American College of Sports Medicine and the American
Heart Association. Med. Sci. Sports Exerc. 39 (8), 1435–1445. https://doi.org/
10.1249/mss.0b013e3180616aa2.
Ni, H.D., Yao, M., Huang, B., Xu, L.S., Zheng, Y., Chu, Y.X., Wang, H.Q., Liu, M.J., Xu, S.
J., Li, H.B., 2016. Glial activation in the periaqueductal gray promotes descending
facilitation of neuropathic pain through the p38 MAPK signaling pathway.
J. Neurosci. Res. 94 (1), 50–61. https://doi.org/10.1002/jnr.23672.
Noga, O., Peiser, M., Altenähr, M., Knieling, H., Wanner, R., Hanf, G., Grosse, R.,
Suttorp, N., 2007. Differential activation of dendritic cells by nerve growth factor
and brain-derived neurotrophic factor. Clin. Exp. Allergy: J. Br. Soc. Allergy Clin.
Immunol. 37 (11), 1701–1708. https://doi.org/10.1111/j.1365-2222.2007.02832.x.
Numakawa, T., Suzuki, S., Kumamaru, E., Adachi, N., Richards, M., Kunugi, H., 2010.
BDNF function and intracellular signaling in neurons. Histol. Histopathol. 25 (2),
237–258. https://doi.org/10.14670/hh-25.237.
Ogborn, D.I., Gardiner, P.F., 2010. Effects of exercise and muscle type on BDNF, NT-4/5,
and TrKB expression in skeletal muscle. Muscle Nerve 41 (3), 385–391. https://doi.
org/10.1002/mus.21503.
Orihuela, R., McPherson, C.A., Harry, G.J., 2016. Microglial M1/M2 polarization and
metabolic states. Br. J. Pharmacol. 173 (4), 649–665. https://doi.org/10.1111/
bph.13139.
Pan, W., Banks, W.A., Fasold, M.B., Bluth, J., Kastin, A.J., 1998. Transport of brain-
derived neurotrophic factor across the blood-brain barrier. Neuropharmacology 37
(12), 1553–1561. https://doi.org/10.1016/s0028-3908(98)00141-5.
Peciña, M., Martínez-Jauand, M., Love, T., Heffernan, J., Montoya, P., Hodgkinson, C.,
Stohler, C.S., Goldman, D., Zubieta, J.K., 2014. Valence-specific effects of BDNF
Val66Met polymorphism on dopaminergic stress and reward processing in humans.
J. Neurosci.: Off. J. Soc. Neurosci. 34 (17), 5874–5881. https://doi.org/10.1523/
jneurosci.2152-13.2014.
Pedersen, B.K., 2011. Muscles and their myokines. J. Exp. Biol. 214 (Pt 2), 337–346.
https://doi.org/10.1242/jeb.048074.
Pedersen, B.K., 2013. Muscle as a secretory organ. Compr. Physiol. 3 (3), 1337–1362.
https://doi.org/10.1002/cphy.c120033.
Pedersen, B.K., 2019. Physical activity and muscle-brain crosstalk. Nat. Rev. Endocrinol.
15 (7), 383–392. https://doi.org/10.1038/s41574-019-0174-x.
Pedersen, B.K., Febbraio, M.A., 2008. Muscle as an endocrine organ: focus on muscle-
derived interleukin-6. Physiol. Rev. 88 (4), 1379–1406. https://doi.org/10.1152/
physrev.90100.2007.
Pedersen, B.K., Febbraio, M.A., 2012. Muscles, exercise and obesity: skeletal muscle as a
secretory organ. Nat. Rev. Endocrinol. 8 (8), 457–465. https://doi.org/10.1038/
nrendo.2012.49.
Pedersen, B.K., Fischer, C.P., 2007. Beneficial health effects of exercise–the role of IL-6 as
a myokine. Trends Pharmacol. Sci. 28 (4), 152–156. https://doi.org/10.1016/j.
tips.2007.02.002.
Pedersen, B.K., Akerström, T.C., Nielsen, A.R., Fischer, C.P., 2007. Role of myokines in
exercise and metabolism. J. Appl. Physiol. 103 (3), 1093–1098. https://doi.org/
10.1152/japplphysiol.00080.2007.
Peek, A.L., Rebbeck, T., Puts, N.A., Watson, J., Aguila, M.R., Leaver, A.M., 2020. Brain
GABA and glutamate levels across pain conditions: a systematic literature review and
meta-analysis of 1H-MRS studies using the MRS-Q quality assessment tool.
NeuroImage 210, 116532. https://doi.org/10.1016/j.neuroimage.2020.116532.
Y. Wang et al.
Peferoen, L., Kipp, M., van der Valk, P., van Noort, J.M., Amor, S., 2014.
Oligodendrocyte-microglia cross-talk in the central nervous system. Immunology
141 (3), 302–313. https://doi.org/10.1111/imm.12163.
Perrin, L., Loizides-Mangold, U., Skarupelova, S., Pulimeno, P., Chanon, S., Robert, M.,
Bouzakri, K., Modoux, C., Roux-Lombard, P., Vidal, H., Lefai, E., Dibner, C., 2015.
Human skeletal myotubes display a cell-autonomous circadian clock implicated in
basal myokine secretion. Mol. Metab. 4 (11), 834–845. https://doi.org/10.1016/j.
molmet.2015.07.009.
Pertwee, R.G., 2001. Cannabinoid receptors and pain. Prog. Neurobiol. 63 (5), 569–611.
https://doi.org/10.1016/s0301-0082(00)00031-9.
Petersen, A.M., Pedersen, B.K., 2005. The anti-inflammatory effect of exercise. J. Appl.
Physiol. 98 (4), 1154–1162. https://doi.org/10.1152/japplphysiol.00164.2004.
Pietrelli, A., Matković, L., Vacotto, M., Lopez-Costa, J.J., Basso, N., Brusco, A., 2018.
Aerobic exercise upregulates the BDNF-Serotonin systems and improves the
cognitive function in rats. Neurobiol. Learn. Mem. 155, 528–542. https://doi.org/
10.1016/j.nlm.2018.05.007.
Plunkett, J.A., Yu, C.G., Easton, J.M., Bethea, J.R., Yezierski, R.P., 2001. Effects of
interleukin-10 (IL-10) on pain behavior and gene expression following excitotoxic
spinal cord injury in the rat. Exp. Neurol. 168 (1), 144–154. https://doi.org/
10.1006/exnr.2000.7604.
Porro, C., Cianciulli, A., Panaro, M.A., 2020. The regulatory role of IL-10 in
neurodegenerative diseases. Biomolecules 10 (7). https://doi.org/10.3390/
biom10071017.
Rasmussen, P., Brassard, P., Adser, H., Pedersen, M.V., Leick, L., Hart, E., Secher, N.H.,
Pedersen, B.K., Pilegaard, H., 2009. Evidence for a release of brain-derived
neurotrophic factor from the brain during exercise. Exp. Physiol. 94 (10),
1062–1069. https://doi.org/10.1113/expphysiol.2009.048512.
Ren, K., Dubner, R., 2007. Pain facilitation and activity-dependent plasticity in pain
modulatory circuitry: role of BDNF-TrkB signaling and NMDA receptors. Mol.
Neurobiol. 35 (3), 224–235. https://doi.org/10.1007/s12035-007-0028-8.
Rice, D., Nijs, J., Kosek, E., Wideman, T., Hasenbring, M.I., Koltyn, K., Graven-
Nielsen, T., Polli, A., 2019. Exercise-induced hypoalgesia in pain-free and chronic
pain populations: state of the art and future directions. J. Pain. 20 (11), 1249–1266.
https://doi.org/10.1016/j.jpain.2019.03.005.
Ropelle, E.R., Flores, M.B., Cintra, D.E., Rocha, G.Z., Pauli, J.R., Morari, J., de Souza, C.
T., Moraes, J.C., Prada, P.O., Guadagnini, D., Marin, R.M., Oliveira, A.G., Augusto, T.
M., Carvalho, H.F., Velloso, L.A., Saad, M.J.A., Carvalheira, J.B.C., 2010. IL-6 and IL-
10 anti-inflammatory activity links exercise to hypothalamic insulin and leptin
sensitivity through IKKbeta and ER stress inhibition. PLoS Biol. 8 (8), e1000465
https://doi.org/10.1371/journal.pbio.1000465.
Rosa Neto, J.C., Lira, F.S., Zanchi, N.E., Oyama, L.M., Pimentel, G.D., Santos, R.V.,
Seelaender, M., Oller do Nascimento, C.M., 2011. Acute exhaustive exercise
regulates IL-2, IL-4 and MyoD in skeletal muscle but not adipose tissue in rats. Lipids
Health Dis. 10, 97. https://doi.org/10.1186/1476-511x-10-97.
Roth, J., Glick, S.M., Yalow, R.S., Berson, S.A., 1963. Secretion of human growth
hormone: physiologic and experimental modification. Metab.: Clin. Exp. 12,
577–579.
Ruan, Q., Zhang, L., Ruan, J., Zhang, X., Chen, J., Ma, C., Yu, Z., 2018. Detection and
quantitation of irisin in human cerebrospinal fluid by tandem mass spectrometry.
Peptides 103, 60–64. https://doi.org/10.1016/j.peptides.2018.03.013.
Sacheli, M.A., Neva, J.L., Lakhani, B., Murray, D.K., Vafai, N., Shahinfard, E., English, C.,
McCormick, S., Dinelle, K., Neilson, N., McKenzie, J., Schulzer, M., McKenzie, D.C.,
Appel-Cresswell, S., McKeown, M.J., Boyd, L.A., Sossi, V., Stoessl, A.J., 2019.
Exercise increases caudate dopamine release and ventral striatal activation in
Parkinson’s disease. Mov. Disord.: Off. J. Mov. Disord. Soc. 34 (12), 1891–1900.
https://doi.org/10.1002/mds.27865.
Sanchis-Gomar, F., Lopez-Lopez, S., Romero-Morales, C., Maffulli, N., Lippi, G., Pareja-
Galeano, H., 2019. Neuromuscular electrical stimulation: a new therapeutic option
for chronic diseases based on contraction-induced myokine secretion. Front. Physiol.
10, 1463. https://doi.org/10.3389/fphys.2019.01463.
Santos, Jd.M.B.D., Bachi, A.L.L., Luna Junior, L.A., Foster, R., Sierra, A.P.R., Benetti, M.,
Araújo, J.R., Ghorayeb, N., Kiss, M.A.P.D.M., Vieira, R.P., Bullens, D.M.A.,
Vaisberg, M., 2020. The relationship of IL-8 and IL-10 myokines and performance in
male marathon runners presenting exercise-induced bronchoconstriction. Int. J.
Environ. Res. Public Health 17 (8), E2622. https://doi.org/10.3390/
ijerph17082622.
Saraiva, M., O’Garra, A., 2010. The regulation of IL-10 production by immune cells. Nat.
Rev. Immunol. 10 (3), 170–181. https://doi.org/10.1038/nri2711.
Saraiva, M., Christensen, J.R., Veldhoen, M., Murphy, T.L., Murphy, K.M., O’Garra, A.,
2009. Interleukin-10 production by Th1 cells requires interleukin-12-induced STAT4
transcription factor and ERK MAP kinase activation by high antigen dose. Immunity
31 (2), 209–219. https://doi.org/10.1016/j.immuni.2009.05.012.
Sauer, H., Campbell, K., Wiegand, S.J., Lindsay, R.M., Björklund, A., 1994. Brain-derived
neurotrophic factor enhances striatal neuropeptide expression in both the intact and
the dopamine-depleted rat striatum. Neuroreport 5 (5), 609–612. https://doi.org/
10.1097/00001756-199401000-00019.
Schnyder, S., Handschin, C., 2015. Skeletal muscle as an endocrine organ: PGC-1α,
myokines and exercise. Bone 80, 115–125. https://doi.org/10.1016/j.
bone.2015.02.008.
Sessions, J., Bourbeau, K., Rosinski, M., Szczygiel, T., Nelson, R., Sharma, N., Zuhl, M.,
2016. Carbohydrate gel ingestion during running in the heat on markers of
gastrointestinal distress. Eur. J. Sport Sci. 16 (8), 1064–1072. https://doi.org/
10.1080/17461391.2016.1140231.
Shao, Q., Li, Y., Wang, Q., Zhao, J., 2015. IL-10 and IL-1β mediate neuropathic-pain like
behavior in the ventrolateral orbital cortex. Neurochem. Res. 40 (4), 733–739.
https://doi.org/10.1007/s11064-015-1521-5.
34
Brain Research Bulletin 179 (2022) 25–35
Shemer, A., Scheyltjens, I., Frumer, G.R., Kim, J.S., Grozovski, J., Ayanaw, S., Dassa, B.,
Van Hove, H., Chappell-Maor, L., Boura-Halfon, S., Leshkowitz, D., Mueller, W.,
Maggio, N., Movahedi, K., Jung, S., 2020. Interleukin-10 prevents pathological
microglia hyperactivation following peripheral endotoxin challenge. Immunity 53
(5). https://doi.org/10.1016/j.immuni.2020.09.018 (1033-1049.e1037).
Sievers, C., Schneider, H.J., Stalla, G.K., 2008. Insulin-like growth factor-1 in plasma and
brain: regulation in health and disease. Front. Biosci.: A J. Virtual Libr. 13, 85–99.
https://doi.org/10.2741/2662.
Siuciak, J.A., Altar, C.A., Wiegand, S.J., Lindsay, R.M., 1994. Antinociceptive effect of
brain-derived neurotrophic factor and neurotrophin-3. Brain Res. 633 (1–2),
326–330. https://doi.org/10.1016/0006-8993(94)91556-3.
Siuciak, J.A., Wong, V., Pearsall, D., Wiegand, S.J., Lindsay, R.M., 1995. BDNF produces
analgesia in the formalin test and modifies neuropeptide levels in rat brain and
spinal cord areas associated with nociception. Eur. J. Neurosci. 7 (4), 663–670.
https://doi.org/10.1111/j.1460-9568.1995.tb00670.x.
Siuciak, J.A., Clark, M.S., Rind, H.B., Whittemore, S.R., Russo, A.F., 1998. BDNF
induction of tryptophan hydroxylase mRNA levels in the rat brain. J. Neurosci. Res.
52 (2), 149–158. https://doi.org/10.1002/(sici)1097-4547(19980415)52:2<149::
Aid-jnr3>3.0.Co;2-a.
Sluka, K.A., Frey-Law, L., Hoeger Bement, M., 2018. Exercise-induced pain and
analgesia? Underlying mechanisms and clinical translation. Pain 159 Suppl 1 (Suppl
1), S91–S97. https://doi.org/10.1097/j.pain.0000000000001235.
Stagg, N.J., Mata, H.P., Ibrahim, M.M., Henriksen, E.J., Porreca, F., Vanderah, T.W.,
Philip Malan Jr., T., 2011. Regular exercise reverses sensory hypersensitivity in a rat
neuropathic pain model: role of endogenous opioids. Anesthesiology 114 (4),
940–948. https://doi.org/10.1097/ALN.0b013e318210f880.
Starkie, R., Ostrowski, S.R., Jauffred, S., Febbraio, M., Pedersen, B.K., 2003. Exercise and
IL-6 infusion inhibit endotoxin-induced TNF-alpha production in humans. FASEB J.:
Off. Publ. Fed. Am. Soc. Exp. Biol. 17 (8), 884–886. https://doi.org/10.1096/fj.02-
0670fje.
Steensberg, A., Fischer, C.P., Keller, C., Møller, K., Pedersen, B.K., 2003. IL-6 enhances
plasma IL-1ra, IL-10, and cortisol in humans. Am. J. Physiol. Endocrinol. Metab. 285
(2), E433–E437. https://doi.org/10.1152/ajpendo.00074.2003.
Stefani, L.C., Torres, I.L., de Souza, I.C., Rozisky, J.R., Fregni, F., Caumo, W., 2012. BDNF
as an effect modifier for gender effects on pain thresholds in healthy subjects.
Neurosci. Lett. 514 (1), 62–66. https://doi.org/10.1016/j.neulet.2012.02.057.
Sternberg, W.F., Bokat, C., Kass, L., Alboyadjian, A., Gracely, R.H., 2001. Sex-dependent
components of the analgesia produced by athletic competition. J. Pain. 2 (1), 65–74.
https://doi.org/10.1054/jpai.2001.18236.
Sugawara, S., Shinoda, M., Hayashi, Y., Saito, H., Asano, S., Kubo, A., Shibuta, I.,
Furukawa, A., Toyofuku, A., Iwata, K., 2019. Increase in IGF-1 expression in the
injured infraorbital nerve and possible implications for orofacial neuropathic pain.
Int. J. Mol. Sci. 20 (24), E6360 https://doi.org/10.3390/ijms20246360.
Suso-Ribera, C., Sullivan, M., Suso-Vergara, S., 2018. Pain intensity is not always
associated with poorer health status: exploring the moderating role of spouse
personality. Pain. Res. Manag. 2018, 7927656 https://doi.org/10.1155/2018/
7927656.
Tanaka, T., Murakami, K., Bando, Y., Yoshida, S., 2015. Interferon regulatory factor 7
participates in the M1-like microglial polarization switch. Glia 63 (4), 595–610.
https://doi.org/10.1002/glia.22770.
Tang, J.S., Qu, C.L., Huo, F.Q., 2009. The thalamic nucleus submedius and ventrolateral
orbital cortex are involved in nociceptive modulation: a novel pain modulation
pathway. Prog. Neurobiol. 89 (4), 383–389. https://doi.org/10.1016/j.
pneurobio.2009.10.002.
Tesarz, J., Schuster, A.K., Hartmann, M., Gerhardt, A., Eich, W., 2012. Pain perception in
athletes compared to normally active controls: a systematic review with meta-
analysis. Pain 153 (6), 1253–1262. https://doi.org/10.1016/j.pain.2012.03.005.
Timmerman, K.L., Amonette, W.E., Markofski, M.M., Ansinelli, H.A., Gleason, E.A.,
Rasmussen, B.B., Mossberg, K.A., 2015. Blunted IL-6 and IL-10 response to maximal
aerobic exercise in patients with traumatic brain injury. Eur. J. Appl. Physiol. 115
(1), 111–118. https://doi.org/10.1007/s00421-014-2997-4.
Topcuoglu, A., Gokkaya, N.K., Ucan, H., Karakuş, D., 2015. The effect of upper-extremity
aerobic exercise on complex regional pain syndrome type I: a randomized controlled
study on subacute stroke. Top. Stroke Rehabil. 22 (4), 253–261. https://doi.org/
10.1179/1074935714z.0000000025.
Tu, H., Juelich, T., Smith, E.M., Tyring, S.K., Rady, P.L., Hughes Jr., T.K., 2003. Evidence
for endogenous interleukin-10 during nociception. J. Neuroimmunol. 139 (1–2),
145–149. https://doi.org/10.1016/s0165-5728(03)00126-7.
Turk, D.C., Okifuji, A., 2002. Psychological factors in chronic pain: evolution and
revolution. J. Consult. Clin. Psychol. 70 (3), 678–690. https://doi.org/10.1037//
0022-006x.70.3.678.
Tyler, W.J., Alonso, M., Bramham, C.R., Pozzo-Miller, L.D., 2002. From acquisition to
consolidation: on the role of brain-derived neurotrophic factor signaling in
hippocampal-dependent learning. Learn. Mem. 9 (5), 224–237. https://doi.org/
10.1101/lm.51202.
Urits, I., Schwartz, R.H., Orhurhu, V., Maganty, N.V., Reilly, B.T., Patel, P.M., Wie, C.,
Kaye, A.D., Mancuso, K.F., Kaye, A.J., Viswanath, O., 2021. A comprehensive review
of alternative therapies for the management of chronic pain patients: acupuncture,
Tai Chi, osteopathic manipulative medicine, and chiropractic care. Adv. Ther. 38 (1),
76–89. https://doi.org/10.1007/s12325-020-01554-0.
Vaegter, H.B., Jones, M.D., 2020. Exercise-induced hypoalgesia after acute and regular
exercise: experimental and clinical manifestations and possible mechanisms in
individuals with and without pain. Pain. Rep. 5 (5), e823 https://doi.org/10.1097/
pr9.0000000000000823.
Y. Wang et al.
Vaegter, H.B., Handberg, G., Graven-Nielsen, T., 2014. Similarities between exercise-
induced hypoalgesia and conditioned pain modulation in humans. Pain 155 (1),
158–167. https://doi.org/10.1016/j.pain.2013.09.023.
Varkey, E., Cider, A., Carlsson, J., Linde, M., 2011. Exercise as migraine prophylaxis: a
randomized study using relaxation and topiramate as controls. Cephalalgia: Int. J.
Headache 31 (14), 1428–1438. https://doi.org/10.1177/0333102411419681.
Vranken, J.H., 2012. Elucidation of pathophysiology and treatment of neuropathic pain.
Cent. Nerv. Syst. Agents Med. Chem. 12 (4), 304–314. https://doi.org/10.2174/
187152412803760645.
Waddell, G., 1987. 1987 Volvo award in clinical sciences. A new clinical model for the
treatment of low-back pain. Spine 12 (7), 632–644. https://doi.org/10.1097/
00007632-198709000-00002.
Wang, J., Yue, B., Zhang, X., Guo, X., Sun, Z., Niu, R., 2021. Effect of exercise on
microglial activation and transcriptome of hippocampus in fluorosis mice. Sci. Total
Environ. 760, 143376 https://doi.org/10.1016/j.scitotenv.2020.143376.
Wang, K., Li, H., Wang, H., Wang, J.H., Song, F., Sun, Y., 2018. Irisin exerts
neuroprotective effects on cultured neurons by regulating astrocytes. Mediat.
Inflamm. 2018, 9070341 https://doi.org/10.1155/2018/9070341.
Wang, M., Thyagarajan, B., 2020. Pain pathways and potential new targets for pain
relief. Biotechnol. Appl. Biochem. https://doi.org/10.1002/bab.2086.
Watkins, L.R., Maier, S.F., 2003. Glia: a novel drug discovery target for clinical pain. Nat.
Rev. Drug Discov. 2 (12), 973–985. https://doi.org/10.1038/nrd1251.
Watkins, L.R., Milligan, E.D., Maier, S.F., 2003. Glial proinflammatory cytokines mediate
exaggerated pain states: implications for clinical pain. Adv. Exp. Med. Biol. 521,
1–21.
Wei, F., Wang, G.D., Kerchner, G.A., Kim, S.J., Xu, H.M., Chen, Z.F., Zhuo, M., 2001.
Genetic enhancement of inflammatory pain by forebrain NR2B overexpression. Nat.
Neurosci. 4 (2), 164–169. https://doi.org/10.1038/83993.
Whitham, M., Febbraio, M.A., 2016. The ever-expanding myokinome: discovery
challenges and therapeutic implications. Nat. Rev. Drug Discov. 15 (10), 719–729.
https://doi.org/10.1038/nrd.2016.153.
WHO, 2015. Physical activity. 〈www.who.int/mediacentre/factsheets/fs385/en/〉.
Woolf, C.J., Ma, Q., 2007. Nociceptors–noxious stimulus detectors. Neuron 55 (3),
353–364. https://doi.org/10.1016/j.neuron.2007.07.016.
Wrann, C.D., White, J.P., Salogiannnis, J., Laznik-Bogoslavski, D., Wu, J., Ma, D., Lin, J.
D., Greenberg, M.E., Spiegelman, B.M., 2013. Exercise induces hippocampal BDNF
through a PGC-1α/FNDC5 pathway. Cell Metab. 18 (5), 649–659. https://doi.org/
10.1016/j.cmet.2013.09.008.
Wu, H.Y., Mao, X.F., Tang, X.Q., Ali, U., Apryani, E., Liu, H., Li, X.Y., Wang, Y.X., 2018.
Spinal interleukin-10 produces antinociception in neuropathy through microglial
β-endorphin expression, separated from antineuroinflammation. Brain Behav.
Immun. 73, 504–519. https://doi.org/10.1016/j.bbi.2018.06.015.
Xiong, X., Barreto, G.E., Xu, L., Ouyang, Y.B., Xie, X., Giffard, R.G., 2011. Increased brain
injury and worsened neurological outcome in interleukin-4 knockout mice after
transient focal cerebral ischemia. Stroke 42 (7), 2026–2032. https://doi.org/
10.1161/STROKEAHA.110.593772.
Xu, W.J., Zhao, Y., Huo, F.Q., Du, J.Q., Tang, J.S., 2013. Involvement of ventrolateral
orbital cortex 5-HT 1-7 receptors in 5-HT induced depression of spared nerve injury
allodynia. Neuroscience 238, 252–257. https://doi.org/10.1016/j.
neuroscience.2013.02.036.
Yakar, S., Liu, J.L., Stannard, B., Butler, A., Accili, D., Sauer, B., LeRoith, D., 1999.
Normal growth and development in the absence of hepatic insulin-like growth factor
35
Brain Research Bulletin 179 (2022) 25–35
I. Proc. Natl. Acad. Sci. USA 96 (13), 7324–7329. https://doi.org/10.1073/
pnas.96.13.7324.
Yang, C., Luo, A.L., 2017. Myokines: a promising therapeutic target for hepatic
encephalopathy. J. Hepatol. 66 (5), 1099–1100. https://doi.org/10.1016/j.
jhep.2016.10.040.
Yang, X., Brobst, D., Chan, W.S., Tse, M.C.L., Herlea-Pana, O., Ahuja, P., Bi, X., Zaw, A.
M., Kwong, Z.S.W., Jia, W.H., Zhang, Z.G., Zhang, N., Chow, S.K.H., Cheung, W.H.,
Louie, J.C.Y., Griffin, T.M., Nong, W., Hui, J.H.L., Du, G.H., Noh, H.L.,
Saengnipanthkul, S., Chow, B.K.C., Kim, J.K., Lee, C.W., Chan, C.B., 2019. Muscle-
generated BDNF is a sexually dimorphic myokine that controls metabolic flexibility.
Sci. Signal. 12 (594) https://doi.org/10.1126/scisignal.aau1468.
Yeh, M.L., Selvam, R., Levine, E.S., 2017. BDNF-induced endocannabinoid release
modulates neocortical glutamatergic neurotransmission. Synapse 71 (5). https://doi.
org/10.1002/syn.21962.
Yue, L., Ma, L.-Y., Cui, S., Liu, F.-Y., Yi, M., Wan, Y., 2017. Brain-derived neurotrophic
factor in the infralimbic cortex alleviates inflammatory pain. Neurosci. Lett. 655,
7–13. https://doi.org/10.1016/j.neulet.2017.06.028.
Zanno, A.E., Romer, M.A., Fox, L., Golden, T., Jaeckle-Santos, L., Simmons, R.A.,
Grinspan, J.B., 2019. Reducing Th2 inflammation through neutralizing IL-4 antibody
rescues myelination in IUGR rat brain. J. Neurodev. Disord. 11 (1), 34. https://doi.
org/10.1186/s11689-019-9297-6.
Zhang, C., Li, Y., Zhong, Y., Feng, C., Zhang, Z., Wang, C., 2021. Effectiveness of motor
control exercise on non-specific chronic low back pain, disability and core muscle
morphological characteristics: a meta-analysis of randomized controlled trials. Eur.
J. Phys. Rehabil. Med. https://doi.org/10.23736/s1973-9087.21.06555-2.
Zhang, J., Terreni, L., De Simoni, M.G., Dunn, A.J., 2001. Peripheral interleukin-6
administration increases extracellular concentrations of serotonin and the evoked
release of serotonin in the rat striatum. Neurochem. Int. 38 (4), 303–308. https://
doi.org/10.1016/s0197-0186(00)00099-1.
Zhang, R., Chomistek, A.K., Dimitrakoff, J.D., Giovannucci, E.L., Willett, W.C., Rosner, B.
A., Wu, K., 2015. Physical activity and chronic prostatitis/chronic pelvic pain
syndrome. Med. Sci. Sports Exerc. 47 (4), 757–764. https://doi.org/10.1249/
mss.0000000000000472.
Zhang, Y.Q., Tang, J.S., Yuan, B., Jia, H., 1997. Inhibitory effects of electrically evoked
activation of ventrolateral orbital cortex on the tail-flick reflex are mediated by
periaqueductal gray in rats. Pain 72 (1–2), 127–135. https://doi.org/10.1016/
s0304-3959(97)00025-0.
Zhou, J., Zhang, H., Cohen, R.S., Pandey, S.C., 2005. Effects of estrogen treatment on
expression of brain-derived neurotrophic factor and cAMP response element-binding
protein expression and phosphorylation in rat amygdaloid and hippocampal
structures. Neuroendocrinology 81 (5), 294–310. https://doi.org/10.1159/
000088448.
Zhu, J.X., Xu, F.Y., Xu, W.J., Zhao, Y., Qu, C.L., Tang, J.S., Barry, D.M., Du, J.Q., Huo, F.
Q., 2013. The role of α₂ adrenoceptor in mediating noradrenaline action in the
ventrolateral orbital cortex on allodynia following spared nerve injury. Exp. Neurol.
248, 381–386. https://doi.org/10.1016/j.expneurol.2013.07.004.
Zhuo, M., 2002. Glutamate receptors and persistent pain: targeting forebrain NR2B
subunits. Drug Discov. Today 7 (4), 259–267. https://doi.org/10.1016/s1359-6446
(01)02138-9.
Zsuga, J., Tajti, G., Papp, C., Juhasz, B., Gesztelyi, R., 2016. FNDC5/irisin, a molecular
target for boosting reward-related learning and motivation. Med. Hypotheses 90,
23–28. https://doi.org/10.1016/j.mehy.2016.02.020.