Progress in Neuropsychopharmacology & Biological Psychiatry xxx (xxxx) xxx–xxx

Contents lists available at ScienceDirect

Progress in Neuropsychopharmacology
& Biological Psychiatry
journal homepage: www.elsevier.com/locate/pnp

Effects of stress on the corticolimbic system: implications for chronic pain

Etienne Vachon-Presseau
Department of Physiology, Northwestern University Feinberg School of Medicine, 710 N Lake Shore Drive, Room 1020, Chicago, IL 60611, USA

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

Keywords: Stress has multifaceted effects on pain. On the one hand, it is a powerful inhibitor of nociception and in-
Chronic pain flammation; on the other hand, it contributes to enhanced pathological states including the establishment and
Maladaptive stress response continuation of chronic pain. These seemingly paradoxical effects can be better understood by investigating how
Hippocampus stress-induced plasticity in particular brain circuitry contributes to the chronic pain state. This review presents
Medial prefrontal cortex
the rationale and evidence for the interactions between stress and pain, emphasizing underlying mechanisms and
Resilience
Vulnerability
putting forth the hypothesis that stress partly mediates the deleterious effects of pain on the corticolimbic
system. First, a general description of the corticolimbic circuitry predisposing and amplifying chronic pain will
be discussed, followed by an overview of the neurotoxic effects of stress hormones on this circuitry. Recent
studies show that the resulting perturbations to these brain circuits have significant consequences both for
chronic pain and for general regulation of the stress response, primarily through feedback mechanisms con-
trolling the hypothalamic–pituitary–adrenal axis. This overlap in effected circuitry provides a key point of
comparison between stress and pain, and the similarities between the plasticity induced by chronic pain and
chronic stress will be examined here. Chronic pain patients have been shown to exhibit maladaptive stress
responses in general and in response to pain; the cause of this response and its consequence on pain severity will
then be reviewed. Finally, factors that have been shown to lead to resilience or vulnerability for chronic pain and
maladaptive stress responses will be summarized.

1. Introduction response; and that these structures show plasticity as a consequence of

From an evolutionary perspective, stress is a powerful moderator of
the pain system – through anti-nociceptive and acute analgesic me-
chanisms, it promotes the fight or flight response, which not only en-
ables an organism facing a threat to escape in that moment, but also
increases its survival potential overall (Butler and Finn, 2009; Madden
et al., 1977). Perhaps some of the best examples of stress-induced an-
algesia come from Henry Beecher's World War II observations, where
only 1/3 of severely wounded soldiers requested morphine to manage
their pain (Beecher, 1946); it is thought that the intense stresses of
battle enabled these soldiers to persevere despite grave injuries that
would have otherwise been excruciating or debilitating. However,
while stress is often adaptive under acute pain conditions, several stu-
dies have demonstrated that stress measured in situations involving
chronic pain usually exacerbates the severity of patients' symptoms
rather than suppressing them (Borsook et al., 2012; Vachon-Presseau
et al., 2013b). In this review, I propose a model accounting for this
paradoxical effect of stress on pain. I argue that chronic pain depends
on the corticolimbic system; that this circuitry regulates the stress
long-term exposure to stress hormones. I will secondly discuss a model
of maladaptive stress response observed in chronic pain patients and its
contribution to pain symptomology. Lastly, I will review the specific
corticolimbic characteristics predisposing an individual to be resilient
or vulnerable to stress and chronic pain.
1.1. Chronic pain depends on corticolimbic brain circuitry
Historically, chronic pain has been conceptualized as an enhanced
state of nociceptive activity, implying that it depends on peripheral
inflammation and central sensitization (Woolf, 2011). New evidence,
however, challenges this assumption. If chronic pain was the actual
consequence of higher nociception, it would be reflected by higher or
increased activity in brain regions processing acute pain such as the
somatosensory cortices, the anterior cingulate cortex, the insula, and
midbrain structures commonly referred to as the pain matrix (Apkarian
et al., 2005; Melzack, 1999). On the contrary, growing number of brain
imaging studies conducted in humans and animal models of chronic
pain have established that the brain circuitry underlying chronic pain is

Abbreviations: ACTH, Adrenocorticotropic hormone; CRH, corticotropin releasing hormones; DMN, default mode network; HPA, hypothalamic–pituitary–adrenal; mPFC, medial pre-
frontal cortex; NAc, nucleus accumbens; PVN, paraventricular nucleus; SBP, subacute back pain patients; vmPFC, ventromedial prefrontal cortex; VTA, ventral tegmentum area
E-mail address: etienne.vachon.presseau@gmail.com.

http://dx.doi.org/10.1016/j.pnpbp.2017.10.014
Received 25 July 2017; Received in revised form 18 October 2017; Accepted 23 October 2017
0278-5846/ © 2017 Published by Elsevier Inc.

Please cite this article as: Vachon-Presseau, E., Progress in Neuropsychopharmacology & Biological Psychiatry (2017),
http://dx.doi.org/10.1016/j.pnpbp.2017.10.014
E. Vachon-Presseau
mostly unrelated to these regions and instead depends mainly on re-
gions involved in the generation of motivation, value, and negative
affect in response to the nociceptive information received from the
periphery. Moreover, chronic pain has been associated with specific
differences in anatomy and physiology, many of which are unique to
the pathology and, importantly, unrelated to pain processing in healthy
subjects experiencing acute pain (Apkarian et al., 2011). Although some
studies have reported that chronic pain is associated with a re-
organization of the somatosensory cortices, the insula, and the anterior
cingulate cortex (Moseley and Flor, 2012), the brain should no longer
be considered as an organ passively processing nociception relayed
from the spinothalamic tract, but should rather be regarded as an es-
sential and active contributor in chronic pain (Vachon-Presseau et al.,
2016a).
A growing body of literature has revealed that the brain networks
mediating chronic pain involve circuitry that is unresponsive to noxious
stimulation. In chronic low back pain (CBP) patients, spontaneous
episodes of chronic pain elicited increased brain activity in the medial
prefrontal cortex instead of the traditional regions involved in proces-
sing nociception (Baliki et al., 2006a). In subacute back pain patients
(SBP; presenting with persisting pain experienced for < 12 weeks),
spontaneous episodes of pain were initially processed in brain regions
responsive to nociception and gradually shifted toward limbic circuitry
once patients transitioned to chronic pain (Hashmi et al., 2013). Resting
state functional connectivity further reflects distortion across several
chronic pain conditions in the default mode network (DMN) (Baliki
et al., 2014a), as the strength of the connectivity within the DMN
correlates with negative mood (Letzen and Robinson, 2017) and pain
rumination (Kucyi et al., 2014). Moreover, chronic pain du to anky-
losing spondylitis has also been shown to alter cross-network con-
nectivity (Hemington et al., 2016), and CBP, osteoarthritis (OA), and
complex regional pain syndrome (CRPS) have all been shown to modify
the degree count in highly connected nodes of the brain (Mansour et al.,
2016). These observations demonstrate that different chronic pain
conditions are characterized by plastic reorganization of the brain be-
yond what would have been expected if chronic pain was simply as-
sociated with higher nociceptive inputs to the cortex.
Several experiments conducted in healthy controls in the setting of a
laboratory have also revealed the presence of “alternative” circuits
contributing to acute pain beyond the spinothalamic tract. For instance,
inter-individual variability in the mesolimbic system can predict pain
report after regressing out the brain activity tracking the nociceptive
input (Woo et al., 2017). Moreover, analgesia in healthy individuals has
been associated with higher activation in the DMN, ventral striatum,
and periaqueductal grey when participants reported experiencing epi-
sodes of mind wandering (Kucyi et al., 2013). The first series of brain
imaging studies on acute pain had already observed that pain activated
emotion-related brain structures including the hippocampus during
anticipation of pain (Ploghaus et al., 2001), the nucleus accumbens
(NAc) during the initial phase of a tonic stimulus (Becerra et al., 2001),
and the cingulate cortex associated with the unpleasantness dimension
of the noxious stimulation (Rainville et al., 1997; Talbot et al., 1991).
More recently, some have suggested that the corticolimbic circuitry
may actually represent the primary system through which nociception
accesses consciousness and is perceived as pain (Baliki and Apkarian,
2015).
The corticolimbic circuitry plays a critical role in motivation and
learning, which contributes to determining the relevance and affective
value of spontaneous episodes of chronic pain (Apkarian et al., 2009).
The integrity of this system represents a mechanism common to several
somatosensory and psychiatric conditions, including mood disorders
(Russo and Nestler, 2013), multiple chronic pain conditions (Vachon-
Presseau, Centeno, 2016a), and tinnitus (Leaver et al., 2011). As dis-
played in Fig. 1a, value and motivation are encoded in the corticolimbic
system primarily comprising the medial prefrontal cortex (mPFC), the
NAc, the amygdala, the hippocampus, and the ventral tegmental area
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(VTA). The NAc is responsible for coding prediction errors for appeti-
tive (Schultz, 1998) and aversive (Becerra et al., 2001) stimuli gen-
erating motivated behavior. Aversive and reward prediction signals
involve different dopamine responses within the NAc (Bromberg-Martin
et al., 2010). Animal models of chronic pain that induce inflammatory
pain by means of injection of complete Freund’s adjuvant (CFA), and
neuropathic pain induced by means of selective injury of the sciatic
nerve (SNI), have indicated that diminished motivation depends upon
the indirect dopamine pathway of the NAc (Schwartz et al., 2014).
Likewise, human studies have showed that the reward value of cessa-
tion of pain is distorted in CBP patients (Baliki et al., 2010, 2012). In
line with those findings, a study using a longitudinal design revealed
that the functional connectivity between the NAc and the mPFC in SBP
predicted the development of chronic pain one year later (Baliki et al.,
2012). In a larger sample of patients from the same cohort, denser white
matter connections in a limbic module delimiting the mPFC, the NAc
and the medial inferior part of the amygdala represented an anatomical
risk factor accounting for unexplained variance from the mPFC-NAc
functional connectivity in predicting the transition to CBP (Vachon-
Presseau et al., 2016b). Together, these findings show the importance of
the corticostriatal system in chronic pain and suggest that its pre-ex-
isting properties put an individual at risk for the development of
chronic back pain.
1.2. The stress response
An adaptive stress response typically generates a cascade of reac-
tions that may engage with various endogenous systems, causing the
release of neurotransmitters (e.g., noradrenaline, dopamine, serotonin),
peptides (e.g., vasopressin), and/or hormones (e.g., cortisol) (McEwen,
1998b). Hypervigilance of the organism is initially triggered by ca-
techolamine released via a bioelectric pathway from hypothalamus
projecting to the locus coeruleus and the reticular formation, activating
the adrenal medulla. This is followed by a hormonal response where the
hypothalamus stimulates the pituitary gland through corticotropin re-
leasing hormones (CRH). Once activated, the pituitary gland secretes
the adrenocorticotropic hormone (ACTH) which, once released into the
bloodstream, stimulates the adrenal cortical gland responsible for the
production of cortisol (Chrousos, 1995). This hypothalamic–pituitar-
y–adrenal axis (HPA axis) therefore regulates levels of cortisol, a steroid
hormone that increases the pace and strength of heart contractions,
sensitizes blood vessels to norepinephrine, regulates the immune re-
sponse, and increases blood sugar levels (Chrousos, 1995). These mul-
tiple levels of a stereotypical adaptive stress response occur at multiple
time-scales. The monoamines and peptides have a quasi-instantaneous
action that begins a few seconds after a stressful event, working to
modify the synaptic response of regional neurons in order to promote
vigilance (de Kloet et al., 2005). Secondly, the monoamines and corti-
costeroids bind to the mineralocorticoid receptors, altering cellular
transcription factors on a scale of minutes (de Kloet et al., 2005). Fi-
nally, the more structural and genomic effects of corticosteroids begin
modifying the functioning of neurons hours after a stressor. This last
wave indicates the end of the stress response and the return to the
normal state of the organism (de Kloet et al., 2005).
1.3. The stress response is regulated by a feedback loop from the
corticolimbic system
The corticolimbic system plays an important and essential role in
the regulation of the stress response through retroactive feedback from
the HPA axis. In mammals, corticosteroids act mainly on miner-
alocorticoid and glucocorticoid receptors. Unlike mineralocorticoid
receptors, which have a high affinity for corticosteroids and are pre-
dominantly occupied when the corticosteroid level is low, glucocorti-
coid receptors are partially occupied and become more occupied in a
stressful situation (Reul and de Kloet, 1985). Although the response of
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Fig. 1. A. The corticolimbic circuitry amplifying chronic pain depends on the dopaminergic and GABAergic loops between the ventral tegmental area (VTA) and the nucleus accumbens
(NAc). These loops are massively controlled by glutaminergic projections from the amygdala, the hippocampus and the medial prefrontal cortex (mPFC). This panel was initially
presented in (Baliki and Apkarian, 2015). B. The regulation of the stress response is controlled by a feedback loop from the adrenal gland to the corticolimbic system. The hippocampus,
amygdala, and prefrontal cortex (PFC) project glutamatergic inputs to the hypothalamus (HYP) controlling the hypothalamic–pituitary–adrenal (HPA) axis activity. The HYP, PFC, and
hippocampus show high affinity with cortisol and control the hormonal stress response through this feedback loop. The noradrenergic (NAergic) descending inhibition pathways
contributing to the stress-induced analgesia is also presented in the image. C. Animal models of chronic pain have shown long-term structural plasticity in the NAc (Ren et al., 2016) and
the mPFC (Metz et al., 2009), increased excitability of amygdala neurons (Neugebauer et al., 2003), and diminished neurogenesis in the hippocampus (Mutso et al., 2012). D. Volumes of
the amygdala and hippocampus represent a predisposition for both maladaptive stress (Vachon-Presseau et al., 2013b) and chronic pain (Vachon-Presseau et al., 2016b). Additionally,
structural and functional connectivity between the NAc and the mPFC predispose patients to the transition to chronic pain (Baliki et al., 2012; Vachon-Presseau et al., 2016b), while
reactivity of the ventromedial prefrontal cortex (vmPFC) may contribute to resilience to maladaptive stress (Sinha et al., 2016). The arrows show that these structures are massively inter-
connected to one another and that resilience/risk factors may therefore not be exclusive to a single element. E. The maladaptive stress response observed in chronic pain patients depend
on plasticity of the corticolimbic system controlling the hormonal response (the purple pathway) regulating the HPA axis from projections to the HYP. Plasticity in the corticolimbic
structures may be induced by the injury, representing a recurring stressor activating and re-activating the stress response.

stress hormones is diffused across the body, the mineralocorticoid re-
ceptors are densely located in both the prefrontal cortex and the hip-
pocampus (Arnsten, 2009), whereas glucocorticoids are densely located
primarily in the hippocampus (Joels et al., 2008). Because of their high
affinity with stress hormones, both the prefrontal cortex and hippo-
campus have the capacity to regulate the HPA axis response (Radley
and Sawchenko, 2011). For instance, lesions in the mPFC can increase
HPA activity in response to an acute stressor, an effect that can be re-
versed by an implant of corticosterone (Diorio et al., 1993). Similarly,
lesions of the hippocampus can increase plasma corticosteroid levels,
and electrical stimulation of the hippocampus generates inhibitory ef-
fects over corticosterone secreted during stress (Jacobson and Sapolsky,
1991). Finally, previous findings have revealed that the hippocampus
exerts a continuous basal tonic inhibition on the HPA axis, giving it the
ability to shutdown the stress response (Fendler et al., 1961; Jacobson
and Sapolsky, 1991).
Fig. 1b displays the main circuitry through which the stress response
is controlled by the corticolimbic system. The hippocampus mainly
projects glutamatergic inputs to primarily inhibitory cells of the para-
ventricular nucleus (PVN) in the hypothalamus, and the amygdala
projects both GABAergic and glutamatergic inputs to the PVN (de Kloet
et al., 2005). The prefrontal cortex further facilitates or inhibits stress
response via direct projections to the PVN, including glutamatergic
projections to inhibitory PVN relays (de Kloet et al., 2005). Therefore,
the corticolimbic system is not solely involved in generating a stress
response; it is just as much involved in controlling and terminating the
stress response through the feedback loop outlined above.
1.4. The corticolimbic system is a bridge linking stress with chronic pain
The release of stress hormones produces adaptive and maladaptive
effects on the amygdala, which detect threats; the hippocampus, which
regulates anxiety and encodes new memories; the hypothalamus, which
controls the hormonal response through feedback loops; and the

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prefrontral cortex, which process decision making, affective meaning,
and neuroendocrine functions (McEwen and Gianaros, 2010). Stress
hormones therefore exert a specific influence on these regions as the
corticolimbic circuitry is responsible for coordinating the neuroendo-
crine, immune, and autonomic functions for selection of behaviors that
are optimal for coping with environmental stressors (Sapolsky, 2003).
A question that arises is whether the neurotoxic effects of stress
hormones can actually cause the corticolimbic plasticity observed in
chronic pain patients. One can hypothesize that stress partly mediates
brain reorganization following chronic pain because i. the corticolimbic
regions driving chronic pain are also the ones regulating the stress re-
sponse, and ii. these same regions are sensitive to the long term effects
of stress hormones (Fig. 1c). More precisely, chronic pain and stress
hormones induce plasticity in several regions of the corticolimbic
system including the prefrontal cortex, amygdala, and hippocampus.
The effects of pain and stress on each of these regions are outlined
below.
1.4.1. The prefrontal cortex
The mPFC's neuronal activity and morphology changes in various
animal models of persistent pain (Kiritoshi and Neugebauer, 2015; Metz
et al., 2009) and has been shown to reflect subjective chronic pain in-
tensity in CBP in humans (Baliki et al., 2006b, 2012; Hashmi et al.,
2013). Furthermore, the anatomical and functional connectivity of the
mPFC with the NAc predispose the development of CBP, and its func-
tional coupling with other regions of the DMN is altered in CBP and in
idiopathic temporomandibular disorder (TMD) patients (Baliki et al.,
2014b; Kucyi et al., 2014). The prefrontal cortex is also the region most
sensitive to stress mediators as prolonged exposure to stress hormones
can generate extensive dendritic spine loss (Arnsten, 2009; McEwen
and Morrison, 2013) similar to that observed in the mPFC in animal
models of neuropathic pain (Metz et al., 2009).
1.4.2. The amygdala
In rodent models of arthritis induced chronic pain, amygdala ex-
citability rapidly increases, which in turn modulates spinal cord excit-
ability and the excitability of mPFC inhibitory neurons (Ji and
Neugebauer, 2011; Neugebauer, 2015; Neugebauer et al., 2004). In
humans, the amygdala has been shown to change its response to
spontaneous episodes of low back pain as individuals’ transition from
subacute to chronic pain states (Baliki et al., 2006b; Hashmi et al.,
2013). In parallel, chronic stress changes the dendritic lengthening of
neurons in the basolateral amygdala (Mitra and Sapolsky, 2008) and
impairs the mPFC-amygdala circuitry by dysregulating GABAergic
functions (Akirav and Maroun, 2007). This aberrant plasticity is
thought to contribute to increases in anxiety and a decrease in fear
extinction, phenomena that may be important in the development of
posttraumatic stress disorder, among other disturbances.
1.4.3. The hippocampus
In humans, intrinsic hippocampal connectivity, as well as hippo-
campo-cortical connectivity, have both been shown to be altered in
patients with burning mouth syndrome and CBP patients. (Khan et al.,
2014; Mutso et al., 2013). Furthermore, smaller volumes have been
observed in CBP patients (Vachon-Presseau et al., 2016b) and shape
displacement in the left posterior hippocampus has been mediating the
relationship between sensitivity to loss aversion and memory bias in
CBP patients (Berger et al., 2017). These observations are supported by
evidence from SNI models of chronic pain indicating physiological
properties of the hippocampus are also altered with persistent pain,
including the finding that hippocampal adult neurogenesis is depressed
following establishment of neuropathic pain (Apkarian et al., 2015;
Mutso et al., 2012; Ren et al., 2011). In parallel, a whole body of lit-
erature has demonstrated stress-induced depression of neurogenesis in
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Progress in Neuropsychopharmacology & Biological Psychiatry xxx (xxxx) xxx–xxx
the hippocampus (Mirescu and Gould, 2006), and has exhibited the
effects of stress on hippocampal volume in both healthy (Sapolsky et al.,
1990) and aging (Lupien et al., 1998) populations.
1.5. Stress induced analgesia is different from maladaptive stress responses
Stress-induced analgesia refers to the inhibition of the pain response
after stress exposure, which represents an essential component of the
fight or flight response (Butler and Finn, 2009). It has been repeatedly
shown that an acute stress response is sufficient to inhibit the pain
system. The paraventricular CRH neurons project to proopiomelano-
cortin-containing neurons in the arcuate nucleus of the hypothalamus,
releasing several opioid peptides, as well as to neurons within a major
component of the noradrenaline system, the locus coeruleus (Chrousos,
1995). The stress mechanisms of pain regulation therefore involve a
combination of catecholamines and endogenous opioids that modulate
nociceptive inputs from the periphery and the dorsal horn of the spinal
cord (Fig. 1b). The importance of opioid peptides in stress-induced
analgesia has been demonstrated by the acute administration of na-
loxone, an opioid antagonist; injections of naloxone have been shown to
block stress-induced analgesia (Akil et al., 1986). In humans, the
threshold of the nociceptive withdrawal reflex gradually increases with
the repetition of stress, indicating the analgesic effect of stress through
spinal circuitry. Once again, this analgesic effect could be blocked, or
even reversed, by the administration of naloxone, which produced a
rapid and significant reduction in the reflex threshold below initial
values (Willer et al., 1981). The effects of stress-induced analgesia have
been further examined using brain imaging – these studies have found
that a higher acute stress response (as measured with salivary cortisol)
was associated with a lower brain response to noxious stimulation in
supraspinal regions processing nociception (Vachon-Presseau et al.,
2013a).
Beyond the anti-nociceptive actions of stress mediators, activation
of the HPA also regulates pain by inhibiting inflammation. Cortisol
regulates circulating leukocytes, suppresses immune activity, and limits
the production of pro-inflammatory cytokines and other mediators of
inflammation (Segerstrom and Miller, 2004). The presence of gluco-
corticoids also alters the transcription rates of responsive genes that
modify the messenger RNA of several inflammatory proteins, further
suppressing the immune pro-inflammatory response (De Bosscher et al.,
2000). Stress mediators can therefore exert a regulatory effect over the
pain system via inhibition of nociception both at the level of the spinal
cord and within injured and inflamed tissue. If chronic pain solely de-
pended on these peripheral and spinal factors, one would anticipate
that the stress response generated by recurring pain would inhibit no-
ciception and would in turn relieve the patients’ suffering. Yet, the
phenomenon is actually opposite: higher levels of cortisol have been
associated with higher clinical pain levels (Borsook et al., 2012), a re-
lationship mediated by morphological and functional properties of the
hippocampus (Vachon-Presseau et al., 2013b).
It is clear, then, that the relationship between pain and stress is
neither linear nor unidirectional, and sometimes, it can even seem
contradictory, especially when contrasting acute and chronic states.
However, their association becomes less paradoxical if one considers
the effects of time and context. It is likely that the stress response, in-
itially adaptive when facing acute or sudden challenges in the en-
vironment, can transition into a maladaptive state where homeostasis is
no longer obtained despite the release of stress hormones. In the case of
chronic pain, the body may no longer habituate to a series of multi-
faceted stressors: physical (i.e. pain), psychological (e.g., anxiety to-
ward pain or depressed mood), or socioeconomic (e.g., loss of income).
The term allostatic load has been proposed to refer to this inability to
not only generate an adequate stress response but also the subsequent
failure to shut down this response when it happens (Karatsoreos and
E. Vachon-Presseau
McEwen, 2011; McEwen, 1998a), and it may explain studies showing
how chronic stress can exacerbate chronic pain symptoms, such as
migraines (Borsook et al., 2012).
Fig. 1e represents a schematic illustration of a model summarizing
the maladaptive stress responses in chronic pain. The unpredictable and
uncontrollable nature of persistent pain represents a recurrent stressor
challenging the homeostasis of the organism. The organism facing re-
peated stressors develops a maladaptive stress response once the cor-
ticolimbic system is no longer able to adapt and terminate the stress
response (Borsook et al., 2012). Because elevated levels of stress hor-
mones have deleterious effects on the amygdala, the hippocampus, and
the prefrontal cortex (Arnsten, 2009; Sapolsky, 1985; Sapolsky et al.,
1985, 1990), constant exposure to high levels of stress hormones may in
turn modify this circuitry, regulating the neuroendocrine system in such
a way that suppressing the stress response through the normal feedback
loop becomes impossible. The abnormally high levels of cortisol re-
ported in CBP patients (Vachon-Presseau et al., 2013b) may reflect such
an incapacity. The long-term detrimental effects of stress may also
contribute to other pathological conditions driven by the corticolimbic
circuitry, such as chronic pain.
In summary, the maladaptive stress response is independent from
stress-induced analgesia and the anti-inflammatory properties of stress.
The latter relies on an acute and transient stress response that triggers a
cascade of stress mediators inhibiting pain. In sharp contrast, the ma-
ladaptive stress response is observed with basal measurements of cor-
tisol collected daily without inducing any experimental stressor. Its
sustained effect occurs over months to years and generates long-lasting
plasticity in the corticolimbic system. The distinction between the
phenomena can be particularly appreciated when considering that
chronic pain patients showing abnormally high levels of basal cortisol
are still capable of normal HPA response to an acute stressor and also
show stress-induced analgesia to experimentally induced thermal pain
(Vachon-Presseau et al., 2013a,b). This demonstrates a clear dissocia-
tion between multilevel effects of stress over pain measured within the
same group of patients.
1.6. Vulnerability-resilience to stress
There is a growing literature trying to establish the brain char-
acteristics responsible for making an individual more likely to develop a
given pathology, including those for chronic pain and stress disorders.
Here again, there are similarities between the corticolimbic anatomical
properties that predispose someone to an abnormal stress response and
those predisposing individuals to CBP. For instance, smaller amygdalar
and hippocampal volumes have been shown to be predictive of CBP
development one year after the onset of symptoms (Vachon-Presseau
et al., 2016b). Similarly, hippocampal volume also represents a risk
factor for the development of maladaptative stress responses in both
humans and monkeys (Gilbertson et al., 2002; Lyons et al., 2001;
Vachon-Presseau et al., 2013b). Therefore, it can be hypothesized that
the brain physiology predisposes individuals to developing a mala-
daptive stress response once the individual is facing recurring episodes
of spontaneous pain. As conceptualized in the theoretical model pre-
sented in Fig. 1, the characteristics of the corticolimbic system that
make an individual vulnerable for developing persistent CBP and ab-
normal responses to stress partly overlap, and as such, the two phe-
nomena may be inter-related. In other words, as suggested by Abdallah
and Geha, chronic pain and chronic stress may represent two sides of
the same coin (Abdallah and Geha, 2017).
Besides subcortical circuitry, the importance of the ventromedial
prefrontal cortex (vmPFC) in resilience to stress has been highlighted in
a recent study conducted in humans. Sinha et al elegantly demonstrated
that cortisol response to highly aversive images was associated with a
diminution of brain activation in the vmPFC and higher brain activation
in the ventral striatum, right amygdala, right hippocampus, and hy-
pothalamus (Sinha et al., 2016). The authors further demonstrated that
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Progress in Neuropsychopharmacology & Biological Psychiatry xxx (xxxx) xxx–xxx
the initial deactivation of the vmPFC during the stressful condition was
followed by a return to normal levels of activation in later runs of
emotion images, indicating that the initial disruption due to stress was
reversed as a person habituated to the stressor. These results show the
flexibility in vmPFC responses during stress and may reflect an in-
dividual’s capacity to cope with the situation. Therefore, the vmPFC has
been proposed to be a central locus in controlling behavior when facing
stress and may potentially act as a key element in determining resi-
lience to stress.
The vmPFC is a brain region with a massive number of connections
with other regions of the limbic system, areas that are also involved in
generating affective appraisals used to guide decision making (Roy
et al., 2012). According to the somatic marker hypothesis (Damasio,
1996), the vmPFC is a key region in making choices. Patients suffering
from lesions to the vmPFC showed persisting behaviors in gambling
tasks and demonstrated an inability to learn from previous mistakes
related to risk-taking (Bechara et al., 2005). Similarly, CBP patients
have also shown aberrances in gambling preferences associated with
loss-aversion, where CBP patients are more sensitive to potential
monetary gains no matter how large an accompanying monetary loss
was (Apkarian et al., 2004; Berger et al., 2014). These behavioral al-
terations are associated with changes in the modularity of the NAc,
which showed an overall disconnection with frontal regions and an
increase in connections with subcortical regions (Berger et al., 2014).
Therefore, the vmPFC represents a region acting not only as a stress
regulator, but also as a general integrator of somatic and affective in-
formation that enables it to generate emotions and drive behaviors. The
functional coupling of this structure with other limbic regions can po-
tentially determine resilience to maladaptive stress responses if patients
end up facing recurring episodes of pain.
1.7. Comorbidity: depression, chronic pain and maladaptive stress responses
Depression is a highly comorbid condition in patients suffering from
chronic pain (Bair et al., 2003), as patients reporting multiple pain
symptoms are 3–5 times more likely to be clinically depressed com-
pared to patients without pain (Von Korff et al., 1988), and patients
with depression are 2 times more likely to experience CBP (Croft et al.,
1995). Furthermore, headache, abdominal pain, joint pain, and chest
pain are more frequently reported by patients with depression in pri-
mary care settings (Kroenke et al., 1994). A longitudinal cohort study
revealed that depressive and distress symptoms actually predict the
incidence of low back pain, neck-shoulder pain, and other muscu-
loskeletal morbidity (Leino and Magni, 1993). Because chronic pain is
tightly linked with comorbid depression, it is plausible that mood dis-
orders actually contribute to the maladaptive stress responses observed
in chronic pain patients (and vice versa).
Major depression (MD) is one of the most common psychiatric
conditions and its potential monoamine, hormonal, or inflammatory
origins have been extensively studied (Zunszain et al., 2011). It has
been suggested that hyperactivity of the HPA axis—reflected in ele-
vated basal levels of cortisol and increase cortisol response to acute
stressors—and immune resistance to glucocorticoids may be the roots of
major depression. The neurotoxic effect of stress hormones induces
plasticity and reduced neurogenesis in limbic regions such as the hip-
pocampus that potentially contribute to depressive symptoms (Lee
et al., 2002). Hence, patients suffering from depression display smaller
hippocampal volume compared to heathy controls (Videbech and
Ravnkilde, 2004), and the same corticolimbic circuitry presented in
Fig. 1a plays a role for vulnerability or resilience in mood disorders
(Russo and Nestler, 2013). There are therefore several similarities be-
tween the theoretical models of stress in chronic pain and stress in
depression.
Some have even suggested that major depression represents the
actual mediator between higher levels of cortisol and chronic pain in
women suffering from fibromyalgia (Wingenfeld et al., 2010).
E. Vachon-Presseau
However, the relationship between depressive mood and abnormally
high levels of basal cortisol was not replicated in CBP patients (Vachon-
Presseau et al., 2013b). Furthermore, most of the brain imaging studies
performed in chronic pain patients usually have exclusion criteria to
rule out potential confounds related to depression. Therefore, although
depression and chronic pain are highly comorbid and governed by si-
milar corticolimbic circuitry, it remains unclear if the maladaptive
stress responses are specific to pain chronification or to potential co-
morbid conditions such as depression.
1.8. Conclusion, limitations, and future directions
In this review, the role of the corticolimbic circuitry in chronic pain
and regulation of the stress response was presented. It was demon-
strated that stress hormones can change both the structure and the
function of this circuitry, in turn significantly impacting the normal
performance of the HPA axis and associated behaviors. The review also
showed that abnormally high levels of basal stress hormones have been
implicated in chronic pain patients, indicating maladaptive stress re-
sponses, and that this reaction may be responsible for the plasticity
observed in the mPFC, amygdala, and hippocampus of chronic pain
patients.
There are numerous limitations that should be acknowledged when
referring to the current theoretical framework presented in Fig. 1. First,
the extent of the overlap between stress and chronic pain remains an
open question, as some sub-components of the corticolimbic circuitry
may be specific for stress regulation, while others represent risk factors
for chronic pain. Furthermore, this model is probably not a one-size-
fits-all model applying to all chronic pain conditions, as different
chronic pain conditions yield different stress responses and each has
their own brain anatomical abnormalities (Baliki et al., 2011). Most of
the model is built from CBP patients, which show abnormal cortico-
limbic brain circuitry and abnormally high levels of basal cortisol.
Meanwhile, others have proposed a similar theoretical framework in
patients suffering from migraines (Borsook et al., 2012). Additionally,
OA pain intensity has been associated with elevated levels of cortisol
(Carlesso et al., 2016), and cortisol/dehydroepiandrosterone ratio in
females suffering from TMJ was associated with pain intensity, pain
disability, and depression (Jo et al., 2016). The clinical portrait may
however be different for other types of chronic pain such as fi-
bromyalgia or chronic fatigue syndrome, where lower levels of basal
cortisol and a blunted cortisol response to acute stressors were observed
(Romano et al., 2015; Wingenfeld et al., 2008). Finally, the impact of
stress hormones in other complex conditions such as pelvic pain, irri-
table bowel syndrome, CRPS, or burning mouth syndrome showed
conflicting results (Patacchioli et al., 2001; Wingenfeld et al., 2008) or
remains poorly understood. Therefore, the model presented in this re-
view may be specific to certain pain conditions such as CBP, migraine,
and perhaps OA and TMJ, and may not generalize to all chronic pain
conditions.
One remaining question that has yet to be addressed by the pain
community is the extent to which stress reduction programs are clini-
cally useful in the prevention and treatment of chronic pain. Several
studies have demonstrated that practicing mindfulness meditation
(Grant and Rainville, 2009; Zeidan et al., 2011) or yoga (Villemure
et al., 2015) can decrease pain sensitivity and increase pain tolerance.
Interestingly, these findings suggest that the beneficial effects of these
techniques are mediated by anatomical properties of brain regions in-
cluding the anterior cingulate cortex, parahippocampal gyrus, and in-
sula (Grant et al., 2010, 2013; Villemure et al., 2014). However, these
studies were performed in healthy individuals facing experimental pain
administered in the settings of a laboratory. The translation of these
findings to chronic pain patients remains speculative and evidence
showing the effectiveness of stress reduction programs to prevent ma-
ladaptive stress responses in early stages of pain chronification remains
to be demonstrated. If such programs would prove to prevent
6
Progress in Neuropsychopharmacology & Biological Psychiatry xxx (xxxx) xxx–xxx
maladaptive stress and associated brain plasticity in networks ampli-
fying chronic pain, they could provide a useful treatment at minimal
cost with minimal side effects. Further studies are necessary to fully
address this open question.
Funding
EVP is receiving post-doctoral award from the Fonds de Recherche
du Québec – Santé (FRQS).
Acknowledgements
I would like to thank Pierre Rainville for his feedback on the
manuscript. I would also like to thank Sara Berger and Jacob Vogel for
their edits on the manuscript.
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