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Neurobiology of Pain 14 (2023) 100143
Available online 4 September 2023
2452-073X/© 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
Exercise therapy for chronic pain: How does exercise change the limbic
brain function?
Emiko Senba
a
,
c
,
*
, Katsuya Kami
b
,
c
a
Department of Physical Therapy, Osaka Yukioka College of Health Science, 1-1-41 Sojiji, Ibaraki-City, Osaka 567-0801, Japan
b
Department of Rehabilitation, Wakayama Faculty of Health Care Sciences, Takarazuka University of Medical and Health Care, 2252 Nakanoshima, Wakayama City,
Wakayama 640-8392, Japan
c
Department of Rehabilitation Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama City, Wakayama 641-8509, Japan
ARTICLE INFO
Keywords:
Chronic pain
Mesocortico-limbic system
Amygdala
Fear-avoidance model
Exercise therapy
Brain networks
ABSTRACT
We are exposed to various external and internal threats which might hurt us. The role of taking exible and
appropriate actions against threats is played by “the limbic system” and at the heart of it there is the ventral
tegmental area and nucleus accumbens (brain reward system). Pain-related fear causes excessive excitation of
amygdala, which in turn causes the suppression of medial prefrontal cortex, leading to chronication of pain.
Since the limbic system of chronic pain patients is functionally impaired, they are maladaptive to their situ-
ations, unable to take goal-directed behavior and are easily caught by fear-avoidance thinking.
We describe the neural mechanisms how exercise activates the brain reward system and enables chronic pain
patients to take goal-directed behavior and overcome fear-avoidance thinking. A key to getting out from chronic
pain state is to take advantage of the behavioral switching function of the basal nucleus of amygdala. We show
that exercise activates positive neurons in this nucleus which project to the nucleus accumbens and promote
reward behavior.
We also describe fear conditioning and extinction are affected by exercise. In chronic pain patients, the fear
response to pain is enhanced and the extinction of fear memories is impaired, so it is difcult to get out of “fear-
avoidance thinking”. Prolonged avoidance of movement and physical inactivity exacerbate pain and have
detrimental effects on the musculoskeletal and cardiovascular systems.
Based on the recent ndings on multiple bran networks, we propose a well-balanced exercise prescription
considering the adherence and pacing of exercise practice. We conclude that therapies targeting the mesocortico-
limbic system, such as exercise therapy and cognitive behavioral therapy, may become promising tools in the
ght against chronic pain.
Introduction
In developed countries, about 15–20% of the population suffers from
chronic pain (Dahlhamer et al., 2016; Yong et al., 2022), which means
not only a disruption of patients’ healthy lives, but also a socioeconomic
burden. Prevalence is consistently higher in women and elderly people
(Fayaz et al., 2016). Elucidating the mechanism by which pain becomes
chronic is an urgent task from the viewpoint of prevention and treat-
ment. The restructuring of synaptic plasticity and neural networks at
various levels of the nervous system sustains chronic pain even when
there are no longer peripheral pain stimuli (pain centralization). The
development of brain imaging to clarify the structure, function, and
networks of the brain has led to a rapid understanding of the role of the
brain in the chronication of pain (Schmidt-Wilcke, 2015). Chronic
refractory pain includes neuropathic pain (NPP), complex regional pain
syndrome (CRPS), postherpetic neuralgia, etc., in which we can identify
the disease or injury that triggers the onset of pain, and nociplastic pain
(Kosek et al., 2021), which does not show any structural abnormalities
that cause pain and may include bromyalgia (FM), temporomandibular
disorder (TMD), chronic low back pain (CBP), irritable bowel syndrome
(IBS) etc.
At present, there is no medicine that works for such chronic pain
states. For example, gabapentinoid, tricyclic antidepressant, SNRI are
designated as rst-line drugs for neuropathic pain. Nevertheless, the
* Corresponding author at: Department of Physical Therapy, Osaka Yukioka College of Health Science, 1-1-41 Sojiji, Ibaraki-City, Osaka 567-0801, Japan.
E-mail address: emiko-senba@yukioka-u.ac.jp (E. Senba).
Contents lists available at ScienceDirect
Neurobiology of Pain
journal homepage: www.sciencedirect.com/journal/neurobiology-of-pain
https://doi.org/10.1016/j.ynpai.2023.100143
Received 4 January 2023; Received in revised form 31 August 2023; Accepted 31 August 2023
Neurobiology of Pain 14 (2023) 100143
2
NPT (number needed to treat) is rather high. Because they do not work
well, many patients suffer from side effects by increasing the dose of the
drug or taking it for a long time. It is still fresh in our memories that
uncontrolled opioid use for chronic pain patients has caused a disaster in
North America. In such a situation, non-pharmacological treatments,
such as exercise therapy and cognitive behavioral therapy (CBT) have
attracted attention as a safe and effective treatment for chronic pain
without side effects and are strongly recommended in the guidelines for
the treatment of chronic pain in many countries.
Patients with chronic pain have stress or anxiety. Chronic pain is
stressful, and long-lasting pain causes psychosocial problems and lowers
the QOL of sufferers. In particular, chronic pain, depression, and sleep
disorders are all easily complicated symptoms, and are called Triads
(Senba, 2015). The psychosocial factors of each patient act as stressors
to further aggravate the symptoms, such as cognitive decits, hyper-
vigilance, emotional changes, memory decits, and decreased motiva-
tion (Simons et al., 2014).
Now we are aware that brain systems working in acute pain and
chronic pain are quite different. The former uses traditional pain
transmission system, while the limbic system plays a crucial role in the
latter (Simons et al., 2014). It has been demonstrated that brain activity
for back pain in the early, acute/subacute back pain group is limited to
regions involved in acute pain, whereas in the chronic back pain group,
activity expands to emotion-related circuitry of the limbic system
(Apkarian et al., 2013; Hashmi et al., 2013; Vachon-Presseau et al.,
2016a; Baria et al., 2016).
It is interesting and suggestive that persistent inammatory pain in
rats activates the network which is dependent on the activity of the right
amygdala (Amyg), including bilateral infralimbic cortex (IL), bilateral
nucleus accumbens (NAc), bilateral caudate putamen (CP), right globus
pallidus (GP), bilateral ventral tegmental area (VTA), and bilateral
substantia nigra (SN), in addition to the so-called pain transmission
areas (Arimura et al., 2019). Persistent pain is somewhere between
acute/experimental pain and chronic pain. So, activation of limbic
system, reward system and basal ganglia may indicate the transition of
activated brain areas accompanying the pain chronication.
To confront and overcome chronic pain, we must know the function
and role of the limbic system. The ability to determine the surrounding
situation, changes in the environment, and whether to avoid or get close
to them through sensory input, and to link them to action is extremely
important for the survival of living organisms, including humans. It is
the “limbic system” that plays such a role, and its work constitutes a
large part of our brain function. Whether you run away in fear or
approach a reward, this mode of judgment and behavior is an essential
ability for all living things, including humans, to survive, and has been
acquired and developed over the course of a long evolutionary process.
In fear conditioning, when a cue such as a sound stimulus is given along
with an electric shock, it will show a fear response to the cue, in which
case the Amyg is playing a central role. In addition, when an animal
shows a fear response due to memory of the situation or place to which
he/she has been given an electric shock, not only the Amyg but also the
hippocampus (HPC) is required (Izquierdo et al., 2016).
The decision or motivation to ee or get close is transmitted to the
nucleus accumbens (NAc), which is the interface between the limbic and
motor systems (Mogenson et al., 1980). But you can’t react to all the
incoming information. Therefore, the prefrontal cortex was developed to
properly control the Amyg. In particular, the medial prefrontal cortex
(mPFC) communicates cognition-based decisions to the NAc, and we can
cope with the environment. In addition to the brain reward system, i.e.,
projection from the ventral tegmental area (VTA) to the NAc, the limbic
system includes the Amyg, mPFC, and HPC, therefore it is also called the
mesocortico-limbic system. Limbic regions are now expanding to
include a part of basal ganglia and hypothalamus. Limbic brain science
has been advancing at a remarkable pace in recent years, and this review
introduces the latest ndings and considers the relationship with pain
and pain behavior.
In this review, we will rst describe the characteristics of brain
function in patients with such chronic pain and explain how they change
with the implementation of exercise. Furthermore, we approach this
problem from three aspects of the brain function: (i) the limbic system,
(ii) fear conditioning, and (iii) brain networks. The limbic system allows
us to act appropriately in the situation we are in. Since the fear-
avoidance thinking plays an important role in pain chronication,
breaking out from that thinking is very important for the treatment of
chronic pain (Kami et al., 2022). It is also essential to understand that
the brain does not work separately but by forming multiple brain net-
works. We consider that understanding these three dimensions of brain
function is essential for the development of effective exercise therapy
prescriptions for chronic pain.
The limbic system is dysfunctional in chronic pain state
It is well known that the chronication of pain involves a dysfunction
of the mesocortico-limbic system, including the brain reward system.
The activity of the NAc is reduced in chronic pain patients by the
following two mechanisms. One is (1) in chronic pain conditions
glutamate (Glu) neurons in the lateral habenular nucleus (LHb) are
activated by the direction of globus pallidus (GP) and γ-aminobutyric
acid (GABA) neurons in the rostromedial tegmental nucleus (RMTg) are
activated, which then suppress DA neurons in the latVTA (Jhou et al.,
2009) and reduce DA-ergic input to the NAc lateral shell. The GP neu-
rons projecting to the LHb (GPh) are located in the border region of the
GP (GPb) in primates (Hong and Hikosaka, 2013), which corresponds to
the entopeduncular nucleus (EPN) in rodents (Li et al., 2019). This in-
volves a GPh(EPN)-LHb-RMTg-latVTA-NAc system. The second is (2)
Glu neurons in the basolateral nucleus of amygdala (BLA) that are
overexcited by persistent pain and pain-related fear, project to the mPFC
and activate GABA interneurons that in turn inhibit Glu neurons in the
mPFC projecting to the NAc (Ji et al., 2010; Ji and Neugebauer, 2011).
This involves an BLA-mPFC-NAc system. Then activity of the NAc
GABA neurons is reduced through these two feed-forward inhibitions via
activation of GABA neurons. Parabrachial nucleus (PBN)-SN pars
reticulata-VTA system may also contribute to the deactivation of VTA
DA neurons (Yang et al., 2021).
In patients with chronic low back pain, reward network dysfunction
and dopaminergic dysregulation have been observed (Yu et al., 2020),
and NAc activation does not occur at the time of relief from pain stimuli
compared to healthy patients (Baliki et al., 2010). In patients who have
subacute low back pain that becomes chronic low back pain after 1 year,
high functional connectivity between the PFC and NAc was observed
from the rst consultation (Baliki et al., 2012). Furthermore, in a group
of patients who had persistent low back pain for 3 years, it was found
that the white matter connections between the dorsomedial PFC
(dmPFC)-Amyg-NAc were strong from the rst consultation (Vachon-
Presseau et al., 2016b). Since high functional or white matter connec-
tivity means that these areas work synchronously, those patients tend to
be susceptible to the effects of fear of pain and their pain may be more
likely to become chronic. The mPFC is an area related to anxiety and
emotions associated with pain (Ong et al., 2019), and dmPFC (prelimbic
cortex in rodents) is involved in fear conditioning (Sierra-Mercado et al.
2011). The strong functional connectivity of dmPFC-Amyg-NAc means
that they cannot move their bodies (=immobility) due to fear of causing
pain, and therefore they easily fall into a “fear-avoidance thinking” by
which pain is enhanced and chronied. If you as a medical staff grasp the
characteristics of patients’ brain that are prone to transition to chronic
pain at the time of the rst visit, and apply interventions, such as ex-
ercise therapy and/or CBT from an early stage, there is a possibility that
the transition to chronic pain can be prevented.
E. Senba and K. Kami
Neurobiology of Pain 14 (2023) 100143
3
Structure and function of the mesocortico-limbic system
An overview of the mesocortico-limbic system
The limbic system is driven by two powerful motors, “emotion” and
“reward”, to produce “action”. Fig. 1 summarizes the structure and
functions of the limbic system. The NAc is the linchpin of the limbic
system and acts as the interface connecting the limbic and motor systems
by which “motivation” gets translated into “action” (Mogenson et al.,
1980; Grace et al., 2007; Floresco, 2015). NAc receives glutamatergic
(Glu-ergic) projections from the BLA, mPFC, and ventral hippocampus
(vHPC). Based on emotional, cognitive, and experiential information,
NAc determines the direction of action and inform it onto the ventral
pallidum (VP) (Grace et al., 2007). The VP, through the thalamic dorsal
medial nucleus (TMD), gives feedback to mPFC, and LHb also get
feedback from the VP. Then LHb makes a judgment and modify the
action through the reward system.
The VP is a critical node in the mesolimbic network, being the pri-
mary output of the NAc and projecting to the LHb and VTA (Wulff et al.,
2019). The VP plays a crucial role in the processing and execution of
motivated behaviors (Root et al., 2018). The VP has reciprocal con-
nections with the mPFC, Amyg, LH, VTA, PBN, subthalamic nucleus and
other reward-related structures. It has direct projections to mPFC, and
dense projections to TMD, which relays in turn to mPFC. It should be
emphasized that the VP mediates reward and motivation functions at
many levels in the brain, in addition to aiding translation to movement
(Smith et al., 2009; Wulff et al., 2019). Although most of VP neurons are
GABA-ergic, substantial proportion of them are Glu-ergic (Hur and
Z´
aborszky, 2005). These Glu-ergic VP neurons increase activity of the
LHb, RMTg, and GABA-ergic VTA neurons (Tooley et al., 2018), leading
to inhibition of VTA DA neurons. Selective activation of Glu-ergic VP
neurons induced a place avoidance (Tooley et al., 2018). GABAergic VP
neurons are essential for movements toward reward, while Glu-ergic VP
neurons work for movements to avoid a threat (Stephenson-Jones et al.,
2020).
The LHb also has rich afferent and efferent interconnections and has
been regarded as a linchpin of ‘limbic’ and ‘pallidal’ parts of the brain,
which enables adaptive behaviors to environment (Zahm and Root,
2017). The LHb is a phylogenetically well conserved ancient brain
structure identied in virtually all vertebrate species (Freudenmacher,
et al.,2020; Hu et al., 2020). How good or how bad judgment of the
surrounding situation is carried out by the GPe-GPi border region (GPb)
in primate, and in the worst case GPb neurons excites LHb (Hong and
Hikosaka, 2008, 2013). These GPb neurons projecting to LHb (GPh) are
excited by the no-reward predicting cues, such as stress and pain, and
inhibited by the reward-predicting cues (Hong and Hikosaka, 2008; Li
et al., 2019). In rodents the EPN is homologous to the GPi in primates
and human (Li et al., 2019). Chronic pain/stress activates EPN → LHb
→ VTA pathway (Cerniauskas et al., 2019). The LHb receives excitatory
inputs from a wide range of limbic structures including the EPN, lateral
hypothalamic area (LHA), bed nucleus of stria terminalis (BNST) and
medVTA (Nuno-Perez et al., 2021). Although the output of the basal
ganglia is primarily inhibitory, GPi inputs to the LHb is excitatory and
Glu-ergic (Shabel et al., 2014). These GPh neurons are phasically excited
by punishment-predictive tones (Stephenson-Jones et al., 2016). LHb
receives co-transmitted Glu and GABA from VTA and EPN. In these
terminals, Glu and GABA are distributed in separate synaptic vesicles
(Root et al., 2018). These Glu-GABA co-transmitting neurons in the VTA
preferentially project to the LHb (Root et al., 2018).
Ventral tegmental area (VTA)-
The brain reward system is a system in which VTA DA neurons
project onto the NAc to act on GABA-ergic medium spiny neurons
(MSNs) in the NAc. Since injection of apomorphine (D2/D1 agonist) into
the NAc causes analgesia (Sarkis et al., 2011), DA input to NAc is
Fig. 1. Structure and function of the
mesocortico-limbic system The phasic/
tonic activities of the VTA DA neurons are
maintained by inputs from LDT and VP,
respectively. NAc receives information
about various aspects of environment and
emotion from mPFC, Amyg, and ventral
hippocampus(vHPC). DA neurons project
to the NAc to control medium spiny neu-
rons (MSNs). DA excites the direct
pathway MSN (dMSN) of the NAc and
suppresses the indirect pathway MSN
(iMSN). iMSN controls the motor system
through disinhibition of VP, and VP neu-
rons cause tonic ring of VTA DA neurons
by disinhibition. LHb receives information
from the EPN (GPi in human) of the basal
ganglia. In chronic pain state, excitation of
EPN-LHb pathway excites RMTg GABA
neurons, which inhibit VTA DA neurons
(blue arrows). Conversely, exercise acti-
vates these nuclei in the limbic system (red
arrows). Injection of DA agonist into the
NAc works on analgesia. DA excites dMSN
expressing D1-R and inhibits iMSN
expressing D2-R (Grace et al, 2007). Exci-
tation of iMSN inhibits VP GABA neurons,
causing tonic ring of DA neuron in the
VTA by disinhibition. Abbreviations: ACh,
acetylcholine; BLA, basolateral nucleus of
amygdala; DA, dopamine; dMSN, direct pathway MSN; EPN, entopedunclar nucleus; GABA, γ-aminobutyric acid; Glu, glutamate; GPi, internal segment of globus
pallidus; iMSN, indirect pathway MSN; IL, infralimbic cortex; LDT, laterodorsal tegmental nucleus; LHb, lateral habenular nucleus; mPFC, medial prefrontal cortex;
MSN, medium spiny neuron; NAc, nucleus accumbens; PL, prelimbic cortex; RMTg, rostromedial tegmental nucleus; vHPC, ventral hippocampus; VP, ventral pal-
lidum; VTA, ventral tegmental area. (For interpretation of the references to colour in this gure legend, the reader is referred to the web version of this article.)
E. Senba and K. Kami
Neurobiology of Pain 14 (2023) 100143
4
thought to act as analgesic (Fig. 1).
Until now, the role of DA has been discussed based on the reward
prediction error (RPE) hypothesis (Schulz, 2016). However, not all DA
neurons strictly follow this RPE model. Increased DA release in response
to aversive events, such as acute stress or pain produced by injection of
hypertonic saline, has been reported (Wood, 2004; Wood et al., 2007).
On the other hand, bromyalgia patients showed disrupted dopami-
nergic reactivity in response to acute pain (Wood et al., 2007).
VTA dopamine-releasing neurons are heterogeneous in their afferent
and efferent connectivity and, in some cases, release GABA or glutamate
in addition to dopamine (Morales and Margolis, 2017; Verharen et al.,
2020). About 65% of VTA neurons are DA-ergic and 35% are GABA-
ergic, although different DA/GABA ratios were seen among the
different subnuclei of VTA. Only 2–3% of total VTA neurons are gluta-
matergic (Nair-Roberts et al., 2008; Bouarab et al., 2019).
The main sources of input to the VTA are the LHb and the later-
odorsal tegmental nucleus (LDT) of the brainstem. The latter causes
phasic activity of VTA DA neurons LHb receives GPi (EPN) inputs (co-
release of Glu and GABA) (Root et al., 2018) that are activated by
aversive stimuli such as chronic pain and chronic stress. LHb then sends
Glu-ergic projections to DA neurons of medVTA, while RMTg, which
receives LHb inputs, inhibits DA neurons of latVTA via its GABA-ergic
input (Grace et al., 2007; Jhou et al., 2009) (Figs. 1, 2). That is, the
LHb-medVTA-NAc’s medial shell pathway is associated with aversion
and LDT-latVTA-NAc’s lateral shell pathway is involved in preference/
reward behavior (Lammel et al., 2008, Lammel et al., 2012, Lammel
et al., 2014). Thus, medial, and lateral VTA DA neurons have totally
different functions (Fig. 2).
The nucleus accumbens (NAc)
The NAc, which is also called the ventral striatum, is divided into a
core in the center and a shell around it, with different input and pro-
jection regions, suggesting that they contribute differentially to goal-
directed behaviors (Baliki et al., 2013, Floresco, 2015).
NAc consists of 90–95% GABAergic medium spiny neurons (MSNs)
(projection neurons), the rest are ACh-ergic and GABA-ergic in-
terneurons. MSNs express AMPA/NMDA glutamate (Glu) receptors and
receive Glu-ergic projections from the mPFC, BLA, and the vHPC, in
addition to DA-nergic inputs from the VTA (Grace et al, 2007) (Fig. 1).
The output system from the NAc is divided into direct and indirect
pathways, and the direct pathway MSN (dMSN) has D1-R and coexists
with dynorphin and projects directly into the VTA. The indirect pathway
MSN (iMSN) expresses D2-R, coexists with enkephalin, and project to
the VP or indirectly to the VTA via the VP (Fig. 1).
Selective stimulation of dMSN or iMSN by means of optogenetic
technique resulted in sustained reward behavior and transient escape
behavior, respectively (Kravitz et al., 2012). Recently, it was demon-
strated that both selective activation of dMSN and selective suppression
of iMSN in the NAc led to a signicant relief of neuropathic pain (NPP)
(Sato et al., 2022). In NPP model animals, iMSNs were selectively
upregulated in the NAc (Ren et al., 2016). Moreover, injury-induced
tactile allodynia was reversed by inhibiting and exacerbated by
exciting iMSNs. These changes were overcome by supplementing
dopamine levels with L-DOPA in combination with a D2/D3 receptor
agonist, implicating that DA can be applied for the treatment of chronic
pain (Ren et al., 2016). Moreover, precise reciprocal projections be-
tween the dMSNs and iMSN in the NAc and VTA neurons were reported
(Yang et al., 2018). Heterogenous reactions of DA terminals in NAc
subregions to aversive and reward predicting cues have been demon-
strated (de Jong et al., 2019, 2022).
In human, alterations of NAc circuitry and connectivity have been
implicated as denitive risk factors for pain chronication (Baliki et al.,
2012; Apkarian et al., 2013; Hashmi et al., 2013; Vachon-Presseau et al.,
2016a, 2016b).
Amygdala (Amyg)
Amyg is involved in pain-related emotion and defense behavior.
Polymodal sensory information processed through the thalamus and
cerebral cortex, inputs to the BLA (Veinante et al., 2013; Duvarci and
Pare, 2014). BLA consists of Glu-ergic pyramidal neurons (80–85%) and
GABA-ergic interneurons (15–20%) (Spampanato et al., 2011). From the
BLA, Glu-ergic neurons project to the central nucleus of Amyg (CeA),
which is the main output system of the Amyg. Pain information from the
peripheral tissues via the spinal dorsal horn and PBN (external lateral
division) terminates directly in the capsular region of the CeA (CeC).
This PBN-CeC pathway transmits aversive signals important for threat
and avoidance (Sato et al., 2015).
The CeA consists of its lateral and medial parts (CeL and CeM), in
addition to the CeC, is occupied by GABA neurons expressing a variety of
molecular markers, including somatostatin (SOM), protein kinase C-δ
(PKC-δ), corticotropin-releasing hormone(CRH) neurotensin etc.
(Duvarci and Pare, 2014; Kim et al., 2017; McCullough et al., 2018).
PKC-δ
+
CeA neurons and SOM
+
CeA neurons, two major subpopulations
of CeA neurons, show distinct electrophysiological and morphologic
properties (Adke et al., 2021) and opposing functions, i.e., the former is
pro-nociceptive and occupies about 60% of CeA neurons, while the latter
Fig. 2. Dual DA-ergic system in the VTA → NAc
pathway The brain reward system consists of two
systems, the lateral system, and the medial system,
and in conditions of chronic pain and stress, the
medial system is activated by the excitation of the
lateral habenular nucleus (LHb), and the lateral sys-
tem is suppressed via GABA neurons in the RMTg
(green arrows). On the other hand, when exercising,
LDT neurons are activated, so the DA neurons in the
latVTA are activated and project to the lateral shell of
NAc (red arrows). Thus, exercise activates the lateral
system which promote reward behavior. This sche-
matic model is based on Lammel et al., 2012. (For
interpretation of the references to colour in this
gure legend, the reader is referred to the web
version of this article.)
E. Senba and K. Kami
Neurobiology of Pain 14 (2023) 100143
5
is anti-nociceptive and occupies 40% (Wilson et al., 2019; Miller-Neilan
et al., 2021; Chen et al., 2022). CeL/CeM neurons send robust pro-
jections to various brain regions, including forebrain, thalamus, hypo-
thalamus, and brain stem (Liu et al., 2021; Singh et al., 2022) (Fig. 3). By
projecting to the hypothalamus and PAG, they cause freezing, auto-
nomic reactions responding to fear, stress, and pain (LeDoux et al., 1988;
Johansen et al., 2011). PKC-δ
+
CeL neurons were shown to project to
the zone incerta (ZI) to augment pain-related behavior (Singh et al.,
2022). SOM
+
CeL neurons project to the vlPAG to initiate passive
freezing behavior, while CRH
+
neurons were shown to mediate condi-
tioned ight, positive response (Yu et al., 2016; Fadok et al., 2017).
BLA neurons projecting to the CeA mediates momentary arrests, i.e.,
freezing (Botta et al., 2020). An inhibitory pathway from the CeA to the
vlPAG produces freezing by disinhibition of vlPAG excitatory outputs to
pre-motor targets in the medullary reticular formation (Tovote et al.,
2016).
In addition to CeA, BLA neurons project to the mPFC, NAc, HPC, etc.,
but their functions differ depending on the projection destination. When
BLA neurons projecting onto the CeA or NAc were stimulated opto-
genetically, the former showed aversive behavior and the latter showed
reward behavior (Namburi et al., 2015). Furthermore, those projecting
to the CeA are mainly located on the lateral part (latBA) of the basal
amygdala (BA) and those projecting to the NAc are on its medial part
(medBA).
The heterogeneity of BLA neurons has been studied in detail by Kim
et al. (2016). They discovered one gene whose expression increases due
to electric shock (negative stimulus) (Rspo2) and another gene whose
expression increases by cohabiting with a female (positive stimulus)
(Ppp1r1b), and revealed that BLA neurons have different projection
regions; positive neurons expressing Ppp1r1b and located on the pos-
terior part of it (BLAp) project to the NAc and infralimbic cortex (IL) and
negative neurons expressing Rspo2 and located on the anterior part of it
(BLAa) project to CeA and prelimbic cortex (PL) (Kim et al., 2016).
The highest density of GABA-ergic neurons is present in the so-called
intercalated cell mass (ITC), which surround the deep amygdaloid nuclei
(Millhouse, 1986; Pitk¨
anen et al., 1997; Duvarci and Pare, 2014). The
ITC is interposed between the BLA and CeA and receives excitatory input
from the infralimbic cortex (IL) and BLA (Neugebauer, 2015; Thompson
and Neugebauer, 2017), and sends GABA-ergic projections to CeA pro-
jection neurons and control amygdala output via feedforward inhibition.
The selective lesioning of ITC cells results in a marked decit in
extinction retrieval (Likhtik et al., 2008), suggesting that they play a
central role in extinction of pain-related fear memory (See the section of
“The role of IL in fear extinction”).
The structure and functions of the Amyg are summarized in Fig. 3.
Medial prefrontal cortex (mPFC)
Divisions of mPFC and differential roles of PL/IL
The prefrontal cortex (PFC) consists of the mPFC, orbitofrontal cor-
tex, ventrolateral PFC (vlPFC), and dorsolateral PFC (dlPFC). Here, we
focus on the mPFC, which has a strong connection with limbic system
such as Amyg, NAc and HPC.
The mPFC is further divided into dorsomedial PFC (dmPFC)/
ventromedial PFC (vmPFC) in humans and prelimbic (PL)/infralimbic
(IL) in rodents. The mPFC consists of 80–90% of Glu-ergic neurons and
10–20% of GABA-ergic interneurons, with interneurons containing
parvalbumin (PV) (~52%), cholecystokinin (CCK), vasoactive intestinal
peptide (VIP), and somatostatin (SOM) (McKlveen et al.,2015).
It is well known that activation of GABA neurons in the mPFC, either
by Glu-ergic inputs from the BLA or selectively by optogenetics, exac-
erbate pain by inhibiting mPFC pyramidal neurons projecting to the NAc
Fig. 3. Structure and function of the amygdala Pain information processed in the central nervous system mainly input to the basolateral nucleus (BLA), and pain
information from the periphery directly input to the capsular region of the central nucleus (CeC) via the PBN. The central nucleus of amygdala (CeA) consists of GABA
neurons with various genetic markers, such as protein kinase C-δ (PKC-δ). somatostatin (SOM), corticotropin-releasing hormone (CRH) etc. CeM and CeL neurons
project to various brain regions, including thalamus, forebrain, hypothalamus, and brainstem. For example, SOM +CeL neurons project to the vlPAG and para-
ventricular nucleus of thalamus (PVT) and regulate fear expression (Penzo et al., 2014). Basal nucleus of amygdala (BA) consists of negative and positive neurons and
sort the actions into negative “freezing” reactions, or positive (goal-directed) behaviors, the latter of which may have an advantage in the race for survival (LeDoux
et al., 2017). Intercalated cell mass (ITC) receives excitatory input from the infralimbic cortex (IL) and project to the CeA. This schematic model is based on Johansen
et al., 2011. Abbreviations; BNST, bed nucleus of stria terminalis; GP, globus pallidus; ITC, intercalated cell mass; LC, locus coeruleus; PBN, parabrachial nucleus;
PVH, paraventricular nucleus of hypothalamus; PVT, paraventricular nucleus of thalamus; SN, substantia nigra; ZI, zona incerta.
E. Senba and K. Kami
Neurobiology of Pain 14 (2023) 100143
6
(Lee et al., 2015) or to the PAG, a key midbrain structure involved in
descending pain control (Cheriyan and Sheets, 2018). When BLA is over-
excited by persistent pain, projection neurons in mPFC are suppressed
via feed-forward inhibition, and the NAc and PAG are also suppressed,
which may intensify pain (Ong et al., 2019).
In NPP model mice, cortico-PAG (C-P) neurons in layer 5 (L5) of PL,
but not IL, showed a signicant reduction in excitability (Cheriyan and
Sheets, 2018, 2020). This infers that the functional roles of PL and IL in
descending pain modulation are distinct.
Interaction between Amyg and PL/IL
BLA → mPFC projection. BLA inputs to the mPFC are involved in pain-
related cognitive dysfunction and in fear conditioning (Klavir et al.,
2017; Neugebauer, 2015; Thompson and Neugebauer, 2017), and
preferentially target C-P projection neurons in layer 5 of the IL and
cortico-amygdalar (C-A) projection neurons in layer 2/3 of the PL
(Cheriyan et al., 2016). BLA projections to the mPFC synapse on layers
2–6 with a small percentage of these projections targeting PV-containing
GABA-ergic interneurons (Gabbott et al., 2006). Thus, BLA projections
can functionally modulate mPFC output via feed-forward inhibitory
mechanisms (Giustino and Maren, 2015, 2017).
The relationship between BLA and PL/IL, which plays a central role
in emotional learning through pain and fear, has been claried in detail
(Cheriyan et al., 2016) (Fig. 4A). The primary target of layer 5 (L5)
neurons is the PAG. In IL, inputs from BLA preferentially terminate on C-
P neurons, whereas in PL, BLA neurons primarily terminate on C-A
neurons that project back to the BLA. It means that projection of BLA →
IL is mainly involved in the descending pain inhibition than that of BLA
→ PL, and that the excitation of positive neurons of BLA (which project
to the IL) acts on analgesia (Fig. 4). Photo-stimulation of the BLA-PL
projection increased freezing, while activation of BLA-IL neurons
contributed to fear-extinction (Senn et al, 2014; Burgos-Robles et al.,
2017).
PL/IL → Amyg projection. The distinct connections of PL/IL with Amyg
nuclei are now clear; the PL-Amyg projection neurons predominantly
target the BLA, whereas those of the IL project to the BLA and other
Amyg divisions including the lateral amygdala (LA), ITC (Pinard et al.,
2012), and possibly to the CeL. The projection to the ITC, directly or
indirectly via BLA, is important in fear extinction (Duvarci and Pare,
2014; Giustino and Maren, 2015, 2017).
On the other hand, C-A neurons in the PL project back to the BLA. It
has been demonstrated that 10–15% of BLA neurons are GABA-ergic
(Spampanato et al., 2011). Since activity of BLA may be tightly regu-
lated by these GABA interneurons, and a small dysregulation of GABA-
ergic mechanisms in the BLA might result in hyperexcitation of BLA,
which might lead to exacerbation of fear and pain (Prager et al., 2016), it
will be of interest to know if these C-A neurons terminate on the in-
terneurons or projection neurons in the BLA.
Pathway from mPFC to NAc
One of the primary prefrontal targets is the NAc (Brog et al., 1993;
Ishikawa et al., 2008). It has been shown that IL projection neurons
project onto the NAc to participate in reward behavior (Schwartz et al.,
2017). In animals, when fear conditioning is formed with electric shock
combined with pain predicted cues, the intake of rewarding sugar water
decreases, but repeated sound stimuli extinct this fear conditioning and
increase sugar water intake. In this situation, the pyramidal cells of IL
are excited and the projection to NAc is increased. However, in NPP
model animals (selective injury of sciatic nerve sensory branches), both
IL activity and IL → NAc projection are decreased, and animals are
unable to take reward actions against pain (Schwartz et al., 2017).
Therefore, the suppression of reward behavior in chronic pain patients is
thought to be partly due to a decrease in the projection of IL → NAc.
In humans, IL corresponds to vmPFC, and human brain imaging
study shows that pain rating is suppressed by the activation of vmPFC
(Eisenberger et al., 2011). If you look at a picture of your lover or
partner, your pain rating for the same thermal stimulus will be lowered.
At that time, the blood ow of vmPFC increases in the brain image, and
the stronger the activation of vmPFC, the lower the pain rating. Acti-
vation of vmPFC-NAc pathway may have contributed to the lowered
pain rating. Activation of vmPFC may also be involved in the extinction
of fear responses, contributing to the feeling of “learned safety”
(Eisenberger et al., 2011).
Exercise is a universal prescription for chronic pain states
Mechanisms of EIH
Recently, it has been clinically noted that exercise suppresses pain,
and it has been reported that pain-related behavior is suppressed by
loading exercise on model animals of NPP (exercise-induced hypo-
algesia: EIH). The mechanisms of the analgesic effect of voluntary ex-
ercise (EIH) have been proposed, which involve changes at various
Fig. 4. Structure of the mPFC and interactions with subcortical structures A: The relationship between BLA inputs and PL/IL projection neurons. BLA inputs to
the mPFC preferentially target cortico-PAG (C-P) projection neurons in layer 5 of the IL and cortico-amygdalar (C-A) projection neurons in layer 2/3 of the PL.
Projection of BLA positive neurons to the IL is mainly involved in the descending pain inhibition, while those of BLA negative neurons to PL terminate on C-A
projection neurons enhancing reciprocal connection (BLA-PL). This schematic model is based on Cheriyan et al., 2016. B: Projection neurons of mPFC project to the
PAG (C-P neurons), the NAc (C-S neurons) and the BLA (C-A neurons). The former two projections are analgesic. C-A neurons may control the activity of BLA
probably via GABA neurons in the BLA. medVTA DA neurons were shown to project to C-P neurons and contribute to the descending pain modulation (Huang
et al., 2020).
E. Senba and K. Kami
Neurobiology of Pain 14 (2023) 100143
7
levels of the nervous system, such as the descending pain modulatory
system (Sluka et al., 2020) and the limbic system (for review, see Kami
et al., 2017, 2022; Senba and Kami, 2017). We also reported that the
function of GABA neurons in the dorsal horn of the spinal cord is
maintained by exercise (Kami et al., 2016a; Senba and Kami, 2020).
Epigenetic mechanisms are also driven in the spinal dorsal horn (Kami
et al., 2016b). Moreover, it has been argued that myokines secreted from
contracted muscles may play a role in EIH (Wang et al., 2022) and
enhanced wound healing of injured skin by treadmill running may
contribute to EIH (Kawanishi et al., 2022). In this review we focus on
brain mechanisms, especially on the limbic system.
In animal studies using mice, we have shown that exercise 1) acti-
vates the brain-reward system (Senba and Kami, 2017; Kami et al.,
2018), 2) enables goal-directed behavior by activating the Amyg → NAc
pathway (Kami et al., 2020), and 3) suppress fear conditioning by
inhibiting the vHPC → Amyg pathway (Minami et al., 2023). When a
running wheel is equipped in a cage, a mouse will run on the running
wheel voluntarily. The distance traveled is monitored by recording the
number of revolutions. After a two-week acclimatization period, model
mice of neuropathic pain underwent partial sciatic nerve ligation (PSL)
surgery (Seltzer et al., 1990) and were allowed to do spontaneous ex-
ercise for further two weeks. As the mice recover after surgery, the
mileage recovered to 70–80% of preoperative.On the other hand, the
sedentary group of mice were kept in their cages with a locked running
wheel by tape.
Exercise activates the NAc / brain reward system
When we examined the changes in pain behavior after PSL, the group
that exercised (PSL-exercise) showed marked improvements in me-
chanical allodynia and thermal hyperalgesia compared to the group that
did not run (PSL-sedentary). It also showed a positive correlation be-
tween total mileage and improvement of pain behavior at 2 weeks after
PSL and found that mice that ran longer distance had a higher analgesic
effect (Senba and Kami, 2017; Kami et al., 2018).
We looked at the brain reward system of such mice. DA-producing
neurons in the VTA were immuno-stained with antibodies to the DA-
producing enzyme Tyrosine hydroxylase (TH). We used the expression
of nuclear protein FosB/ΔFosB in the nucleus as an indicator of neuronal
activation.
DA neurons of the lateral VTA project exclusively into the lateral
shell of the NAc, while medial ones to the medial shell of the NAc, and to
the mPFC (Lammel et al., 2008, Lammel et al., 2012, Lammel et al.,
2014) (Fig. 2). We focused on the lateral VTA and found that activated
DA neurons in the lateral VTA were increased in Naïve- or Sham (Sham-
operated)-Runner groups. Although they were decreased after PSL sur-
gery, the reduction was prevented signicantly in PSL-Runner group
mice. (Kami et al., 2018). Since P-CREB (phosphorylated cAMP response
element- binding protein), a main transcription factor of TH-gene,
immunoreactivity was expressed in these FosB/ΔFosB-positive, TH-
positive neurons, the synthesis of DA seems to be increased in these
neurons (Senba and Kami, 2017).
DA neurons in the lateral VTA may project to lateral shell of the NAc
(Lammel et al., 2008, Lammel et al., 2012, Lammel et al., 2014). Then,
what are the functions of the pathways from the medial VTA to the
medial shell of the NAc, and mPFC? Chaudhury et al. (2013) used the
length of social interaction and the amount of sugar water consumption
as indicators of depression. Selective activation of the medial VTA-NAc
pathway increased depressive symptoms and aversive behavior.
On the other hand, selective activation, or inhibition of the pathway
projecting to the mPFC did not cause any behavioral changes (Chaud-
hury et al., 2013). However, recently, Huang et al. (2020) showed that
dopaminergic projections from the VTA to mPFC modulate pain re-
sponses in a mouse model of neuropathic pain (spared nerve injury
neuropathic pain model). DA enhances the activity of neurons projecting
from mPFC layer 5 pyramidal neurons to the ventrolateral
periaqueductal gray (vlPAG), culminating in analgesia. Thus, medial
VTA → mPFC DA-nergic projection plays a role in descending pain
modulation (Fig. 4 B).
When animals do exercise, Glu and/or ACh neurons in the later-
odorsal tegmental nucleus (LDT) are activated, which then activates DA
neurons in the lateral VTA and neurons in the lateral shell of the NAc, i.
e., the reward system (lateral system), leading to improved pain and
quality of life (Kami et al., 2018). Moreover, Orexin neurons in the
lateral hypothalamic area (LHA), which were shown to project to the
VTA and activated by voluntary exercise, may contribute to the EIH
(Kami et al., 2018). It has been demonstrated that the VTA is an
important site of action for orexin’s role in reward processing (Aston-
Jones et al., 2010).
It has been demonstrated that exercise increases DA production in
the VTA and activates the brain reward system (Greenwood et al., 2011).
Moreover, when the DA neurons of the VTA were selectively suppressed,
analgesia due to treadmill running was not observed in NPP model mice
(Wakaizumi et al., 2016).
Exercise activates BLA → NAc pathway which enables goal-directed
behavior
Glu-ergic pyramidal cells in the BLA are known to be overexcited due
to fear of pain. They project to GABA-ergic interneurons in the mPFC
and suppress pyramidal neurons projecting to the PAG and NAc, which
surely contributes to the chronication of pain (Ji et al., 2010; Ji and
Neugebauer, 2011; Lee et al., 2015).
Then, how can we regulate the excitability of BLA? We have found
that voluntary exercise affects not only the VTA, but also the Amyg and
NAc. Although the Amyg is closely related to pain, its relationship to the
EIH has not been studied so far.
The basal amygdala (BA) consists of the medial (medBA) and lateral
BA (latBA), We have already described that neurons in the latBA pref-
erentially project to the CeA and those in the medBA preferentially
project to the NAc (See, the section of Amygdala). Therefore, we divided
the BA into lateral and medial parts to examine the response of neurons
to PSL and locomotor activity.
First, many neurons in the BA are Glu-ergic and immuno-stained
positive for EAAC1 antibodies. When these neurons are activated by
exercise, they express FosB/ΔFosB. In the Sham-Sedentary group,
almost no activated Glu neurons were observed in the BA, but in the PSL-
Sedentary group, higher numbers of activated Glu neurons were
observed in the lateral part compared to the medial part. Conversely, in
the PSL-Runner group higher numbers of activated Glu neurons were
identied on the medial part compared to the lateral part. That is,
neurons in the latBA are activated by PSL and those in the medBA. Glu-
ergic neurons are activated predominantly by voluntary exercise (Fig. 5
A). Then, we injected a trace amount of the retrograde tracer Retro
Beads Red (RBR) into the NAc and compared the BA of the voluntarily
exercised mice. Then, about 60% of RBR signals were observed in the
medBA, and 70% of NAc lateral shell projecting activated Glu neurons
were detected in the medBA and 30% of them were observed in the
latBA (Kami et al., 2020) (Fig. 5 A). From these ndings, it is reasonable
to assume that exercise preferentially activates “positive neurons” of
medBA that project particularly onto the NAc (Kami et al., 2020).
That is, in the defensive response when we are faced with a crisis or
threat, a goal-directed behavior such as “ght or ight” occurs by the
activation of the BA → NAc pathway, while negative reactions, such as
freezing in the face of crisis, occur due to the activation of the BA → CeA
pathway (LeDoux et al., 2017; LeDoux & Daw, 2018). More specically,
activation of somatostatin-positive (SOM
+
) neurons in the CeA initiates
passive freezing behavior (Fadok et al., 2017) and it has been shown that
learned avoidance behavior requires an intact BA-NAc Shell circuit
(Ramirez et al., 2015).
Next, we examined changes in neurons in the CeA in response to PSL
and voluntary exercise. First, the majority of CeA neurons were
E. Senba and K. Kami
Neurobiology of Pain 14 (2023) 100143
8
glutamate decarboxylase (GAD) -positive, i.e., GABA-ergic. We found
that almost all these neurons were activated by PSL, but the activation of
these neurons was almost completely abolished in the PSL-Runner
group. That is, analgesia induced by exercise seems to reduce the
input of pain information into the amygdala and attenuate the reactions
of CeA neurons associated with pain (Kami et al., 2020) (Fig. 5 B). It is
also possible that projection neurons in the IL activated by exercise (See
section 4–4) may have projected to the ITC to activate GABA neurons
projecting to the CeA to inhibit GABA neurons there (Kiritoshi and
Neugebauer, 2018).
Then, what is “freezing”? Freezing is an evolutionarily conserved
passive fear response. The idea that freezing is simply a negative reac-
tion is disputed and suggested that it is a hold to the next action. More
hopeless reactions that renounce everything are given the name
“Quiescent immobility” (Kozlowska et al., 2015), which is a reaction to
“deep or inescapable” pain or chronic injury, or injury by a predator, in
animals. In humans, it occurs in response to severe visceral, skeletal
muscle, or joint pain or to a stressful event. It is often prolonged beyond
the period needed for physical healing and becomes maladaptive.
Chronic pain such as complex regional pain syndrome type I may
represent this type of immobility (Kozlowska et al., 2015).
On the other hand, LeDoux & Daw (2018) divided defensive re-
sponses into innate reactions and instrumental behaviors. These are all
reactions mediated by sensory systems and Amyg, and the former appear
as Freezing and/or Flight via PAG. The latter, instrumental behaviors,
are further divided into goal-directed avoidance via NAc and habitual
avoidance via dorsolateral striatum. If we take their argument into
account, exercise will allow us to adopt goal-directed avoidance
behavior rather than innate reaction in the face of a crisis.
Exercise activates pyramidal neurons in the mPFC
It has been demonstrated that 3 weeks of voluntary wheel running
signicantly increased c-Fos positive neurons in the PL in rats (Zlebnik
et al., 2014) and 4 weeks of voluntary exercise increased FosB
+
neurons
in the mPFC in prairie voles (Watanasriyakul et al., 2019). We also
examined the relationship between PL/IL neurons and EIH and found
that non-GABA-ergic FosB
+
neurons in the Pl and IL were increased by
voluntary exercise (Kami and Senba, 2019). These neurons may be py-
ramidal neurons activated by disinhibition.
Exercise-induced changes in the brain revealed by our experimental
study using mice are summarized in Fig. 6.
Fear conditioning and fear-avoidance thinking
Fear-avoidance thinking and chronication of pain
The “fear-avoidance model” that works on chronication of pain is
well recognized (Lethem et al., 1983) (Fig. 7). When humans are injured
and feel pain, they try to recover by confronting it and seek for therapy,
but when they fall into catastrophic thoughts due to negative emotions
and scary information, strong fear occurs, and they avoid movement
which might cause pain. As a result, a vicious cycle of intense pain due to
depression and physical dysfunction occurs, and the pain becomes
chronic without being cured.
In this section, we will focus on the “fear” of pain, and examine the
behavior born from the emotion of “fear” and fear conditioning, the
brain mechanism that makes pain chronic. The central concept of the
fear-avoidance model is fear of pain (Vlaeyen and Linton, 2000).
Mechanisms of fear conditioning
Contextual fear memory and ventral hippocampus (vHPC)
Phillips and LeDoux (1992) examined how the Amyg and hippo-
campus (HPC) that are affected by cues (such as sounds) and context
(the background location) respectively, were involved in the formation
of fear conditioning using rats. In rats whose Amyg were destroyed,
sound and location could not be conditioned, while the destruction of
the HPC, impaired only conditioning by location, so the HPC was shown
to be involved in the formation of the context fear conditioning.
Marschner et al. (2008) performed fMRI study in humans and reported
that activation of the right Amyg was observed in cued conditioning, and
activation of the left HPC was observed in the context conditioning.
The HPC is organized into dorsal and ventral subregions with distinct
functions; the dorsal HPC is involved in cognitive functions such as
conditioning and memory, and the vHPC is involved in emotional con-
trol (Strange et al., 2014; Vasic and Schmidt, 2017).
Functional difference of projections from BLA to NAc, CeA and vHPC
Fear and anxiety are emotional reactions that arise from feeling
threatened. As to the difference between fear and anxiety, one popular
distinction is that while fear occurs in response to a specic object,
anxiety does not have a specic eliciting stimulus (Perusini and Fanse-
low, 2015). In normal conditions, fear or anxiety triggers a suitable
avoidance response to protect oneself from threats. If the response is
excessive or inappropriate, it is maladjusted. Anxiety disorders in
humans are characterized by a response that overestimates the threat
and tries to overdo it. Chronic pain can also be recognized as a kind of
adjustment disorders.
BLA receives diverse sensory information and plays an important
role in the formation of memories with positive and negative elements.
The neural mechanisms that help identify them are preserved in many
animal species, in which the BLA plays the central role. When Beyeler
Fig. 5. Effects of exercise on BA neurons and CeA GABA neurons A: Neu-
rons in the medial part of the basal amygdala (medBA) primarily project to the
NAc, and neurons in the lateral part (latBA) mainly project to the CeA. When
retrograde uorescent tracer RBR was injected into the NAc, many of them
were incorporated into medBA neurons, and these neurons expressed FosB in
the nucleus by exercise. That is, exercise preferentially activates “positive”
neurons in the medBA. B: Changes in CeA neurons in response to partial sciatic
nerve ligation (PSL) and voluntary exercise were examined. The majority of
CeA neurons are GABAergic, and almost all these neurons were activated by
PSL, while the activation of these neurons was almost completely suppressed in
the mice of PSL-Runner group (Kami et al., 2020). It should be noted that CGRP-
immunoreactive bers (blue) in the CeC are originated from CGRP neurons in
the PBN. (For interpretation of the references to colour in this gure legend, the
reader is referred to the web version of this article.)
E. Senba and K. Kami
Neurobiology of Pain 14 (2023) 100143
9
Fig. 6. Summary of exercise-induced changes in the mesocortico-limbic system (from experimental data in rodents) The NAc, an interface between the limbic and motor systems, links emotions to action. Whether
the behavior is appropriate or not is monitored by the VP and LHb, and behavior correction is made via the brain reward system. In chronic pain states, EPN → LHb → RMTg pathway suppresses VTA DA neurons (green
arrows). Exercise activates VTA DA neurons via activating LDT and orexin neurons in the lateral hypothalamic area (LHA), and positive neurons in the basal amygdala (BA) projecting to the NAc are also activated by
exercise (red arrows), which enables goal-directed behavior. Negative response, like freezing, is inhibited by exercise, because CeA-GABA neurons are suppressed (blue dotted arrows). Note that a part of basal ganglia, such
as ventral striatum (NAc), VP and EPN (GPi) are also involved in the mesocortico-limbic system. (For interpretation of the references to colour in this gure legend, the reader is referred to the web version of this article.)
E. Senba and K. Kami
Neurobiology of Pain 14 (2023) 100143
10
et al. (2018) examined the function of neurons projecting from BLA to
NAc, CeA, and vHPC, respectively, they found that BLA → NAc neurons
are more excited by the reward-containing cues, and BLA → CeA neu-
rons are more excited by disgusted cues. BLA → vHPC neurons, on the
other hand, cause behaviors due to anxiety.
Projections from vHPC to Amyg and mPFC
Conversely, regarding projection from vHPC, Ciocchi et al. (2015)
showed that neurons of vHPC are classied by their projection desti-
nations, mPFC, NAc, and Amyg, and anxiety-related behavior excited
vHPC neurons projecting to mPFC. Reward-oriented actions primarily
excited neurons projecting onto NAc and suppressed neurons projecting
onto Amyg.
There are two types of vHPC pyramidal neurons projecting to the
Amyg, one projecting to the BA and the other projecting to the CeA, and
although the distribution region is the same, they do not overlap at all,
and are functionally different (Xu et al., 2016) (Fig. 8). They showed
that the vHPC → BA pathway works to form contextual fear memories,
and the vHPC → CeA pathway works to reproduce fear memories.
The extinction of fear memories does not last forever. Four experi-
mental phenomena have been widely regarded as demonstrating the
resurgent reappearance of the fear responses: spontaneous recovery,
rapid reacquisition, renewal, and reinstatement (Bouton, 2004; Monls
et al., 2009; Storsve et al., 2012).
When the communication between vHPC and mPFC is severed, the
fear renewal that has been extinguished will not occur. Wang et al.
(2016) revealed that the vHPC-PL pathway is involved in fear renewal as
well as fear conditioning.
The role of IL in fear extinction
Extinction of fear memory is an important adaptation process for
organisms to overcome threats from the environment, adapt to their
environment and survive. It is well recognized that extinction is an
active learning process that is obtained by repeated exposure to CS
without harmful US and results in a reduction of conditioned fear re-
sponses (Kaplan and Moore, 2011).
The mPFC plays an important role in the extinction of fear due to the
close communication between mPFC and Amyg. When the IL region is
activated, the output from CeA is suppressed (Quirk et al., 2003), due to
dense projections from IL to GABA neurons of ITC. Optogenetical acti-
vation of IL neurons during extinction training reduced fear expression
and strengthened extinction memory (Do-Monte et al.,2015). From IL,
there are Glu-ergic projections to BLA and NAc, and IL-BLA projection
neurons were activated by the process of extinction of the fear response
(Lingawi et al., 2019). But activation of IL-NAc projection neurons was
not observed. Bloodgood et al.(2018) also found that inhibition of IL-
BLA projection neurons by the DREADD technique impaired the
extinction of fear responses.
Clinically, impaired extinction of fear memories has been the cause
of mental illness stemming from various traumas and stress. In patients
with posttraumatic stress disorder (PTSD), dysfunction of the brain re-
gions involved in the extinction of fear conditioning, such as vmPFC, has
been noted in a state of persistent fear response to events that caused the
trauma (Marschner et al., 2008; Milad et al., 2009). Therefore, chronic
pain has been proposed to be “persistence of the memory of pain and/or
the inability to extinguish the memory of pain evoked by an initial
inciting injury” (Apkarian et al., 2009).
The roles of vHPC, mPFC and Amyg in fear conditioning and extinction
Sierra-Mercado et al. (2011) have claried that a triad of brain re-
gions, including the mPFC, vHPC, and Amyg, form an essential brain
circuit involved in fear conditioning and extinction. Within this circuit,
the mPFC is thought to exert top-down control over subcortical struc-
tures to regulate appropriate behavioral responses (Giustino and Maren,
2015). Recently, it has been demonstrated that GPi (EPN) inactivation
Fig. 7. Fear-Avoidance Behavior and Pain Chronication When we are
injured and suffer pain, we try to recover by confronting it, but when negative
emotions and scary information lead to catastrophizing thoughts, strong fear
occurs, and actions are avoided. As a result, a vicious cycle occurs in which pain
intensies due to depression and bodily dysfunction, and the pain becomes
chronic without being cured. When a certain movement caused pain, we will be
frozen and won’t move again, which means that fear conditioning (fear mem-
ory) is formed. On the other hand, when we experience that it does not hurt
even if we move, the fear memory is extinct, and we can face the problem at
hand and recover. Exercise plays a part in this process by suppressing fear
conditioning (Minami et al., 2023) and probably by promoting fear extinction.
This schematic model is based on Lethem et al., 1983.
Fig. 8. Neural mechanisms of Fear conditioning and
Fear extinction Fear conditioning and its extinction
involve the vHPC, mPFC, and Amy. PL, BLA and vHPC are
involved in the development of fear conditioning, and IL,
BLA, and vHPC are involved in fear extinction (Sierra-
Mercado et al., 2011). EPN → vHPC pathway also contrib-
utes to the acquisition of fear memory (Chen et al., 2020).
Positive neurons of BA project to the IL and promote fear
extinction (BA → IL → ITC → CeA pathway), on the other
hand, reciprocal connection of BA negative neurons and PL
enhance the activation of BA and strengthen the BA → CeA
connection, promoting fear conditioning. Positive neurons
and negative neurons may correspond to “fear cells (F-
cells)” and “extinction cells (E-cells)” of Duvarci and Pare
(2014), respectively. vHPC-BA connection promotes
contextual fear conditioning and vHPC-CeA connection
promotes fear renewal (Xu et al., 2016). Thus, a triad of
mPFC, vHPC, and Amyg, form an essential brain circuit
involved in fear conditioning and extinction. This schematic
model is based on Sierra-Mercado et al., 2011.
E. Senba and K. Kami
Neurobiology of Pain 14 (2023) 100143
11
impaired acquisition of fear memory and reduced freezing (Chen et al.,
2020) (Fig. 8). EPN, which is a member of basal ganglia, plays non-
motor function by projecting to the vHPC, Amyg and LHb (Fig. 1).
Neurons in the ITC receive CS information from the BLA, and send
inhibitory projections to the CeA, the output system of the fear response,
producing feed-forward inhibition to CeA neurons (Fig. 3). It was found
that reducing ITC neurons by the neurotoxin saporin impaired the
extinction process of fear reactions (Likhtik et al., 2008) (Fig. 8).
Fear memory extinction disorders in chronic pain state
In mouse models of neuropathic pain (NPP), spared nerve injury
model, the extinction of contextual fear memories is impaired. These
mice have been reported to have reduced neurogenesis in the DG of
vHPC and impaired LTP formation between DG to CA3 (Mutso
et al.,2012). Patients with chronic pain show anxiety, depression, and
learning and memory impairment, which may be related to hippocam-
pal atrophy and dysfunction. In patients with chronic low back pain or
CRPS, a decrease in bilateral hippocampal volume has been noted
(Mutso et al., 2012).
Exercise affects fear conditioning and extinction
Voluntary exercise has been shown in many studies to improve
hippocampal function. Greenwood et al. (2009) therefore examined the
effects of voluntary exercise on HPC-dependent conditioning, i.e.,
contextual fear conditioning. When rats were subjected to voluntary
exercise for 6 weeks prior to fear conditioning, contextual fear memory
was improved and fear response was enhanced, but extinction condi-
tioning or extinction memory was not affected. In these rats, BDNF
mRNA was increased in the dentate gyrus (DG), CA1 in the HPC and BLA
(Greenwood et al., 2009).
On the other hand, in fear extinction conditioning, the question of
whether an acute exercise bout, in the absence of a history of exercise,
occurring in close temporal proximity to fear extinction can augment
extinction was rst addressed by Siette et al. (2014) and Mika et al.
(2015), who reported that exercise only during and just after the
acquisition of fear extinction learning improves fear extinction memory
recall and reduces fear relapse. Bouchet et al., (2017) also found that 2 h
of voluntary exercise attenuated contextual fear responses after 1 week
and suppressed fear renewal, indicating that even in patients without
exercise habits, short-term voluntary exercise may enhance extinction
conditioning and increase the effectiveness of exposure therapy. This
effect was pronounced in male rats (Bouchet et al., 2017).
These results show that a single bout of running can enhance fear
extinction.
Recently, we have revealed that exercise suppressed vHPC-Amyg
pathway by activating PV-containing GABA interneurons, i.e., via
feed-forward inhibition (Minami et al., 2023), which might have pre-
vented the formation of contextual fear conditioning. If IL pyramidal
neurons are activated by voluntary exercise (See the section of “Exercise
activates pyramidal neurons in the mPFC”), activation of the IL-BA-ITC
pathway and/or IL-ITC pathway (Likhtik et al., 2008; Sierra-Mercado
et al., 2011) may also contribute to the exercise-induced extinction of
fear memory.
IL, or vmPFC in human, plays an important role in extinction
learning (Sierra-Mercado et al., 2011), pyramidal neurons of which are
activated by exercise and positive emotions. BLA’s “positive” neurons
also project to IL/vmPFC (Kim et al, 2016) to create a sense of learned
safety and work to extinguish fear memories.
First-line treatment of chronic pain
Aiming to break out from fear-avoidance thinking
What can be said from the above is that: in patients with chronic
pain, the limbic system, including the Amyg, HPC, mPFC, and the
reward system, is dysfunctional, the fear response to pain is enhanced,
and the extinction of fear memories is also impaired, which makes it
difcult for chronic pain patients to get out of “fear-avoidance thinking”.
We propose that the key to getting out is to take advantage of the
amygdala BA’s behavioral sorting function (Kami et al., 2020, 2022), as
we found that exercise activates BA → NAc neurons.
It is now clear that prolonged avoidance and physical inactivity
exacerbate pain and have detrimental effects on our physical tness and
QOL. BLA → CeA neurons are more excited by aversive cues, while BLA
→ NAc neurons are more excited by rewarding cues (Namburi et al.,
2015; Beyeler et al., 2016). If we only respond to disgusted cues in our
environment, negative neurons will be activated and we can only take
negative behavior, like freezing or immobility, but by nding cues that
contain even a little reward that we can enjoy our life and get positive
emotion, BLA → NAc neurons will be activated, and then we can take
positive action like “goal-directed behavior” and ght against what
threaten our healthy pain-free life. The opponent we ght against is our
past inactive lifestyle. It means making exercise a habit and acquiring an
active lifestyle. It is the “royal road” that leads to overcoming chronic
pain by breaking out from fear-avoidance thinking.
We have recently demonstrated that 3 weeks of exercise therapy
could change the functional connectivity in the mesocortico-limbic
system and such alterations were related to improved motor activity
of bromyalgia patients (Kan et al., 2023 in this special issue).
Patients-oriented treatment of chronic pain
Cognitive reappraisal and fear extinction represent two different
approaches to emotion regulation, which is critical for the treatment of
chronic pain patients. If positive reappraisal (interpreting one’s situa-
tion in a positive way) is successful and negative emotions are sup-
pressed, brain imaging shows an increase of blood ow in the vlPFC and
NAc, and a decrease of blood ow in the Amyg (Wager et al., 2008).
Cognitive reappraisal activated lateral temporal cortex and modulated
bilateral Amyg (Buhle et al., 2014). On the contrary, negative appraisal
of internal and external stimuli may arouse negative emotion, which
exacerbates pain state (Vlaeyen and Linton, 2000). It is thought-
provoking that simply changing one’s interpretation of one’s situation
can affect the brain function and change the way one feels in pain. CBT
also acts on these brain regions to cause behavioral transformation and
emotional changes (Seminowicz et al., 2013; Bao et al., 2022). Down-
regulation of emotions is accompanied by effective connectivity alter-
ations between the Amyg and prefrontal cortical regions (dlPFC, vlPFC
and dmPFC) (Pic´
o-P´
erez et al., 2019; Berboth & Morawetz, 2021).
These are thought to be brain mechanisms that work effectively in
“patient oriented medical care” such as exercise therapy, CBT, mindful
acceptance, and combination of them. Clinical trials of multidisciplinary
pain rehabilitation have been increasing tremendously recently and
their effectiveness has been demonstrated in patients suffering bro-
myalgia and musculoskeletal pain (Serrat et al., 2020; Ll`
adser et al.,
2022; Liechti et al., 2023). These concepts are summarized in Fig. 9.
Prescriptions for the exercise therapy
The brain works as multiple networks
Finally, we will consider the pacing and adherence of exercise
therapy from the aspect of the function of the brain working as net-
works. Recent advances in systems neuroscience have revealed impor-
tant networks in the resting or active brain (Menon, 2011), such as the
central executive network (CEN) (Smith and Jonides, 1999) including
the dlPFC and the posterior parietal lobe (PPC), which is activated when
performing cognitive tasks and plays an important role in working
memory and for judgment and decision-making in goal-directed actions,
and the default mode network (DMN), (Raichle et al., 2001), which is
dynamically suppressed during tasks that require recognition, to make it
possible to carry out accurate actions. The core areas of the DMN are
E. Senba and K. Kami
Neurobiology of Pain 14 (2023) 100143
12
vmPFC and posterior cingulate cortex (PCC)/precuneus (PreCn).
The insula (INS) is highly sensitive to prominent (salient) events or
stimuli, such as pain. In particular, the anterior insula (aINS) serves as an
important hub for dynamic interaction with other large brain networks.
Seeley et al. (2007) dened the “salience network (SN)” in which aINS
and ACC work as the core component. Responding to various stimuli, the
right aINS plays a decisive role in switching the other two major net-
works, i.e., activating CEN and inactivating DMN (Sridharan et al. 2008;
Menon and Uddin, 2010).
A number of network alterations have been detected in various
chronic pain patients. Key ndings have been reported for the DMN
(Baliki et al., 2014; Kucyi et al., 2014; Alshelh et al., 2017; Fallon et al.,
2016; Iwatsuki et al., 2021). Chronic widespread pain patients showed
decreased connectivity in the DMN and increased connectivity in the SN
(van Ettinger-Veenstra et al., 2019; Hays Weeks et al., 2022). Exercise
challenge has been shown to alter DMN dynamics in patients suffering
chronic pain and fatigue (Rayhan et al., 2019; Li et al., 2022).
Prescription for exercise therapy based on the function of the brain networks
The brain network that is activated when you are not doing any task
is the DMN, which is the state of the brain when you are dimly or
ramblingly thinking. At times like these, original ideas come to mind.
When some noticeable (salient) stimulus enters, the salience network is
activated and the brain switches to work mode, and the DMN is sup-
pressed. If you’re too much absorbed in an assignment and so busy with
work, the DMN won’t work, and you may feel like you’ve lost your mind
and yourself. However, once you become procient in the task, both
networks become cooperative and balanced. To improve QOL, it is
important to balance both networks (Fig. 10). In patients with chronic
pain, DMN function is thought to be weakened because the mind is
trapped in pain as stated above. Therefore, in order to improve the QOL
of patients with chronic pain, it is important to acquire lifestyle habits
that activate DMN, suppress SN, and balance DMN and CEN (Fig. 10).
There are various kinds of exercise and walking in the natural
environment enjoying the change of the seasons may activate the DMN
Fig. 9. Therapeutic interventions targeting the mesocortico-limbic
system Even if we suffer chronic pain, it shows how exercise and/or posi-
tive emotions (e.g., immersing oneself in what one likes) and CBT (knowing
the habits of one’s way of thinking and changing one’s behavior towards
positive direction) activate the mesocortico-limbic system including the
NAc, VTA, Amyg, mPFC etc. and suppresses pain behavior and depression.
Successful “positive reappraisal” also targets vlPFC, NAc and Amyg (Wager
et al., 2008). All these interventions are called “patient-oriented medicine”
which promotes patients to change their lifestyle and way of thinking.
Fig. 10. The brain networks and their involve-
ment in exercise habits in daily life When we are
not doing any task, the default mode network (DMN)
is activated. Our mind is free and relaxed, so original
ideas might come to mind. When some salient stim-
ulus such as pain enters, the salience network (SN) is
activated and the brain switches to work mode (ECN).
If we are too busy with work, we may feel like we’ve
lost ourselves. It is essential to balance both networks
to improve QOL. If we do exercise, pacing of exercise
should be considered. Prescriptions based on the
function of brain networks is essential for effective
exercise therapy.
E. Senba and K. Kami
Neurobiology of Pain 14 (2023) 100143
13
and mPFC. From this perspective, it is noteworthy that Amyg activation
during a fearful faces task and a social stress task decreases after the
walking in nature, whereas it remains stable after the walk in an urban
environment (Sudimac and Kühn, 2022). Women seem to prot more
from this salutogenic effects of nature (Sudimac et al., 2022).
The “pacing” of exercise by yourself is important. If you think that
the more you do it, the more effective it is, you will do too much exer-
cise, it may become biased toward a task-seeking CEN, and the pain may
be enhanced due to stress and activated sympathetic function (Fig. 10).
Even if you start exercise therapy as a challenge and continue it every
day or even 2–3 times a week, it becomes established as a lifestyle and a
habit, and you will be able to move your body without thinking (Tricomi
et al., 2009; Balleine and O’Doherty, 2010; LeDoux et al., 2017). This is
the state in which the “adherence” of the exercise is established, and the
CEN and DMN are coordinated in a well-balanced manner. Therefore, it
is necessary to create a new exercise prescription with awareness of the
brain networks in the future.
At rst, it is important to maintain the motivation to continue
exercising, but if you continue to exercise, it will become a habit and you
will continue without being too conscious of it. This habituation in-
volves the dorsolateral striatum (DLS), instead of NAc, as a neural circuit
(Tricomi et al., 2009; Balleine and O’Doherty, 2010; LeDoux et al.,
2017). It is similar to the fact that rehabilitation of motor function re-
covery activates the NAc to maintain motivation in the early stages, but
if rehabilitation becomes a habit after several weeks or months, acti-
vation of the NAc is no longer necessary (Isa, 2017). Furthermore, when
you lose control from the mPFC, the exercise therapy loses the goal and
becomes compulsive (Burgui`
ere et al., 2015; Lüscher et al., 2020). To
prevent this, it is necessary that mPFC is constantly activated, and
cognitive therapeutic approaches will play a role.
Conclusion
So far, we have discussed the neuroscientic evidence how exercise
activates the brain reward system/limbic system and reached a
conclusion that exercise habits are essential for the prevention and
treatment of chronic pain. In this review article, the authors took on a
difcult task of integrating the daily-updated ndings of neuroscience to
provide a scientic basis for practical use in everyday pain clinic and
pain rehabilitation situations. We hope that this objective has been
achieved. We hope that patients with chronic pain will be able to
overcome their chronic pain states by understanding the causes and
processes of pain chronication, break free from fear-avoidance
thinking, and proactively work to improve their daily lives, rather
than just cringing in the face of the wall of chronic pain.
Funding
The authors disclosed receipt of the following nancial support for
the research execution, authorship, and/or publication of this article:
This study was supported in part by research grants from KAKENHI
(Grants-in-Aid for Scientic Research [C] 18K07372 (E.S.) and
18K10719 (K.K.) of the Japan Society for the Promotion of Science).
CRediT authorship contribution statement
Emiko Senba: Conceptualization, Writing – original draft, Writing –
review & editing, Visualization. Katsuya Kami: Data curation, Investi-
gation, Methodology, Formal analysis, Visualization.
Declaration of Competing Interest
The authors declare that they have no known competing nancial
interests or personal relationships that could have appeared to inuence
the work reported in this paper.
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