Psychoneuroendocrinology 71 (2016) 127–135

Contents lists available at ScienceDirect

Psychoneuroendocrinology
journal homepage: www.elsevier.com/locate/psyneuen

Invited review

Dysfunctional stress responses in chronic pain

Alain Woda a,b , Pascale Picard c , Frédéric Dutheil d,e,f,g,∗
a
Dental faculty, EA 3847, CROC, 11 Boulevard Charles-de-Gaulle, Clermont-Ferrand, France
b
University Hospital of Clermont-Ferrand (CHU), Odontology department, Clermont-Ferrand, France
c
Pain center, University Hospital of Clermont-Ferrand (CHU), Clermont-Ferrand, France
d
Preventive and Occupational Medicine, University Hospital of Clermont-Ferrand (CHU), Clermont-Ferrand, France
e
University Clermont Auvergne, Laboratory of Metabolic Adaptations to Exercise in Physiological and Pathological conditions (AME2P, EA3533),
Clermont-Ferrand, France
f
Australian Catholic University, Faculty of Health, Melbourne, Victoria, Australia
g
CNRS, UMR 6024, Physiological and Psychosocial Stress, LAPSCO, University Clermont Auvergne, Clermont-Ferrand, France

a r t i c l e i n f o a b s t r a c t

Article history: Many dysfunctional and chronic pain conditions overlap. This review describes the different modes of
Received 4 January 2016 chronic deregulation of the adaptive response to stress which may be a common factor for these con-
Received in revised form 6 April 2016 ditions. Several types of dysfunction can be identified within the hypothalamo-pituitary-adrenal axis:
Accepted 18 May 2016
basal hypercortisolism, hyper-reactivity, basal hypocortisolism and hypo-reactivity. Neuroactive steroid
synthesis is another component of the adaptive response to stress. Dehydroepiandrosterone (DHEA) and
Keywords:
its sulfated form DHEA-S, and progesterone and its derivatives are synthetized in cutaneous, nervous,
Acute
and adipose cells. They are neuroactive factors that act locally. They may have a role in the localization
Chronic
Physiopathology
of the symptoms and their levels can vary both in the central nervous system and in the periphery. Per-
Disease sistent changes in neuroactive steroid levels or precursors can induce localized neurodegeneration. The
Autonomic nervous system autonomic nervous system is another component of the stress response. Its dysfunction in chronic stress
Environment responses can be expressed by decreased basal parasympathethic activity, increased basal sympathetic
activity or sympathetic hyporeactivity to a stressful stimulus. The immune and genetic systems also par-
ticipate. The helper-T cells Th1 secrete pro-inflammatory cytokines such as IL-1-␤, IL-2, IL-6, IL-8, IL-12,
IFN-␥, and TNF-␣, whereas Th2 secrete anti-inflammatory cytokines: IL-4, IL-10, IGF-10, IL-13. Chronic
deregulation of the Th1/Th2 balance can occur in favor of anti- or pro-inflammatory direction, locally
or systemically. Individual vulnerability to stress can be due to environmental factors but can also be
genetically influenced. Genetic polymorphisms and epigenetics are the main keys to understanding the
influence of genetics on the response of individuals to constraints.
© 2016 Elsevier Ltd. All rights reserved.

Contents

1. Introduction: dysfunctional pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128

2. The adaptive responses to stimuli . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
2.1. Dysfunctional stress responses mediated by HPA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
2.2. Dysfunctional stress responses mediated by neuroactive steroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
2.3. Effects of steroid dysfunctions on nervous tissues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
2.4. Different dysfunctional stress response modes mediated by ANS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
2.5. Different dysfunctional stress response modes mediated by the immune system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
2.6. Different types of genetic predisposition may promote variability in dysfunctional stress responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
2.7. Interactions between ANS, HPA, neuroactive steroids, the immune system and genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132

∗ Corresponding author at: Preventive and Occupational Medicine, University Hospital of Clermont-Ferrand (CHU), Clermont-Ferrand, France.
E-mail addresses: frederic.dutheil@acu.edu.au, fred dutheil@yahoo.fr (F. Dutheil).

http://dx.doi.org/10.1016/j.psyneuen.2016.05.017
0306-4530/© 2016 Elsevier Ltd. All rights reserved.
128 A. Woda et al. / Psychoneuroendocrinology 71 (2016) 127–135

3. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
Contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132

1. Introduction: dysfunctional pain to the whole organism. Importantly, not only major stressors but
also minor daily events are associated with stress responses (van
Many chronic conditions, with or without pain, are qualified Eck et al., 1996). Permanent adaptation to normal daily activity is
by the terms “functional”, “non-specific” or more appropri- needed, via the physiological stress system. Morbid consequences
ately “dysfunctional”. Among the best known dysfunctional pain can be expected when an individual is affected by chronic stress
conditions are fibromyalgia, some low back pain syndromes, response failure to minor stressors (van Eck et al., 1996; Piazza et al.,
temporo-mandibular disorders, tension-type headache, irritable 2013). The physiological stress response occurs via activation of the
bowel syndrome, complex regional pain syndrome, atypical facial autonomic nervous system (ANS) and the hypothalamo-pituitary-
pain, burning mouth syndrome, and vulvodynia. Although many adrenal (HPA) axis, but in dysfunctional chronic pain conditions five
were identified recently as separate conditions, they have much in domains can be involved: unbalanced ANS, dysfunctional HPA axis
common. They share many symptoms; none have specific clinical (Kadetoff and Kosek, 2010), impaired neuroactive steroid activity,
sign, organic lesion, nor a clearly established etiology and patho- immunological and genetic factors.
physiology (Wessely et al., 1999; Fries et al., 2005; Woda et al.,
2005). The prevalence for almost all of them is significantly higher 2.1. Dysfunctional stress responses mediated by HPA
in women than in men, and they predominantly occur at specific
periods of the female reproductive life. Under normal conditions, HPA activation in response to acute
Dysfunctional pain conditions often develop in a context of anx- physical or psychological stress results in an increase in the cir-
iety and depression (Wessely et al., 1999; Tak and Rosmalen, 2010). culating concentration of corticosteroids, in particular cortisol.
A deregulation of the stress response could be a major etiological HPA axis activation is controlled by a negative feedback sys-
risk factor for chronic pain conditions, either as the primum movens tem in which circulating cortisol inhibits the productions of the
or as a decisive factor in the maintenance of the pain conditions corticotropin-releasing hormone (CRH) and adreno-cortico-tropic
(McBeth et al., 2005; Ablin et al., 2009; Woda et al., 2009). Indeed, hormone (ACTH) via mechanisms involving glucocorticoid recep-
chronic dysfunction of the stress response leads to an inability tors located in the hypothalamus and the pituitary gland. This
to safely adapt to common life events, inducing secondary dis- auto-regulated feedback helps to maintain cortisol levels at the
turbances, particularly in pain control mechanisms (Woda et al., needed concentration within a narrow optimal time window (van
2013). Eck et al., 1996). Deregulation of the adrenal steroid secretions
We will present the different modes of the dysfunctional stress may occur in chronic pathological conditions such as depres-
response, with a focus on various chronic pain syndromes. Vari- sion, anxiety, chronic stress, post-traumatic stress syndrome and
ability of the stress response depends on the type of stimulation, dysfunctional chronic pain conditions (Biondi and Picardi, 1999;
either common or extreme (Biondi and Picardi, 1999), and indi- Heuser and Lammer, 2003; Swaab et al., 2005). Both increased and
vidual genetics and previous interactions with the environment decreased cortisol concentrations with irregular variations in time
(Chapman et al., 2008). These multiple possibilities of interactions have been reported, sometimes in the same pathological condi-
may lead to different forms of dysfunctional pain conditions, whose tion (Kellner et al., 2002a,b; Heuser and Lammer, 2003). Several
basic mechanism is broadly similar i.e. the deregulation of the modes of deregulation can be grouped under two main headings,
response to common life stressors. hypercortisolism, and hypocortisolism.
In hypercortisolism, two different and often associated phenom-
2. The adaptive responses to stimuli ena can be identified, basal hypercortisolism and hyper-reactivity.
Basal hypercortisolism is characterized by a permanent increase in
Since its introduction in the 1930s by Selye (1950), the term cortisol levels, such as in a history of chronic physical or emotional
“stress” has become a commonplace concept whose meaning stressors (Heuser and Lammer, 2003; Tafet and Bernardini, 2003;
remains vague (Heuser and Lammer, 2003). There are three com- Ritsner et al., 2004), and particularly when associated with a his-
monly meanings of the term. The stimulus proper or “stressor”, tory of childhood maltreatment (Jogems-Kosterman et al., 2007),
real or perceived, arises from common life events such as social old age (Van Cauter et al., 1996), melancholic depression (Heuser
interactions requiring mental, emotional or physical activity; they and Lammer, 2003) or a combination of grief and intense chronic
modify the homeostasis equilibrium directly or potentially by anxiety (Biondi and Picardi, 1999). Typically, this form of hyper-
anticipating what may happen (Selye, 1950; McEwen, 2000). In cortisolism is associated with a decrease in circadian variability.
its commonplace, the term “stress” is often viewed as a negative For example, in chronic stress or in older individuals, the normal
concept, although it implies the need to adapt to external and morning peak as evidenced by the cortisol awakening response, is
internal events. The stressor can be real or perceived, pleasant decreased and the normal evening low is blunted (Gotthardt et al.,
(like sport or sexual activities) or unpleasant. All require simi- 1995) probably due to chronic hypersecretion of CRH and a failed
lar adaptive responses whatever their emotional charge or other reset (decreased negative feedback) of the HPA axis. These effects
qualities. The second meaning of “stress” refers to the adaptive have been observed in real life with psychological stressors such as
behavioral or mental responses aimed at addressing the common bereavement, in which permanent changes in the HPA axis occur
life consequences of these stressors, such as increased attention when associated with depressive mood, intense grief or a high level
to perform a mentally demanding task or increased motor activ- of anxiety (Chrousos 2000; Heuser and Lammer, 2003). The most
ity. The third meaning is the physiological responses that trigger widely reported changes in mechanisms are higher plasma corti-
metabolic adaptations at both the systemic and cellular levels. sol levels in combination with decreased negative feedback of the
The metabolic responses allow adequate behavior without harm HPA axis, as evidenced by the dexamethasone test. A lower ACTH
 A. Woda et al. / Psychoneuroendocrinology 71 (2016) 127–135
response to CRH than in normal controls has also been reported
(Biondi and Picardi, 1999). In dysfunctional pain conditions, basal
hypercortisolism has been reported in myofascial pain localized
in the shoulder/neck or masticatory muscle areas (Korszun et al.,
2002; Tosato Jde et al., 2015) and in burning mouth syndrome
(Amenabar et al., 2008; Kim et al., 2012).
Hyper-reactivity is characterized by normal basal cortisol values
combined with excessive behavioral and cortisol responses follow-
ing a common stressful situation (Essex et al., 2002). It has been
particularly described in cases of exposure to maternal stress dur-
ing infancy, which leaves a footprint influencing cortisol response
several years later (Essex et al., 2002). This type of phenomenon
has also been observed in people who have suffered physical or
sexual abuse in childhood (Heim et al., 2000; Rinne et al., 2002)
or traumatic experiences at war (Yehuda 2001). Although patients
with myofascial pain may have normal cortisol levels (Gaab et al.,
2005; Galli et al., 2009; Sjors et al., 2010) or basal hypercortisolism
(Korszun et al., 2002; Tosato Jde et al., 2015), an hyper-reactivity
(Geissler 1985; Jones et al., 1997; Yoshihara et al., 2005) have more
often been reported.
In hypocortisolism, two different, often associated, response
types can again be identified; basal hypocortisolism and hypo-
reactivity characterized by a flattened cortisol rhythm i.e. a
considerable decrease in the nictemeral variability of cortisol lev-
els in spite of a normal basal concentration (Heuser and Lammer,
2003). Again, chronic hypersecretion of hypothalamic CRH and a
failed reset of the HPA system are involved (Chrousos 2000; Heim
et al., 2000; Fries et al., 2005) with the result that there is insuf-
ficient metabolic adaptation to ordinary stress situations (Heuser
and Lammer, 2003). Importantly, cortisol hypofonction depends
on the intensity or duration of stressors (Hansen et al., 2011). It
is thought that hypocortisolism follows a period of repetitive over-
stimulation of the HPA axis with excessive release of cortisol (Tops
et al., 2008). This implies that stress-induced excessive cortisol pro-
duction happens first, followed by hypocortisolism. This sequence
would parallel the clinical history of some patients who experi-
ence prolonged periods of stress before the onset of their symptoms
(Hammaren and Hugoson, 1989; Hakeberg et al., 2003). The mech-
anisms of the process are unknown but downregulation of pituitary
receptors, increased negative feedback sensitivity, reduced hor-
mone synthesis, hormone depletion, and changes in the adrenal
cortex itself have been suggested (Fries et al., 2005; Tyrka et al.,
2008). In post-traumatic stress disorders, lowered basal cortisol
and/or lowered cortisol response to ordinary stress stimuli have
been widely reported together with enhanced negative feedback
control on the HPA axis as evidenced by the dexamethasone test
(Kanter et al., 2001; Mason et al., 2001; Kellner et al., 2002a,b;
Jogems-Kosterman et al., 2007). Basal hypocortisolism associated
with hypo-reactivity has been linked to situations of chronic fatigue
syndrome (Gameiro et al., 2006; Tak and Rosmalen, 2010; Tak
et al., 2011), atypical depression (Mason et al., 2001; Gameiro et al.,
2006), workplace stress (Caplan et al., 1979), burnout (Pruessner
et al., 1999), domestic or work overload in women (Adam et al.,
2006), and prolonged moral harassment (Kudielka and Kern, 2004).
Hypo-reactivity was the most consistent finding for fibromyalgia
(Dadabhoy et al., 2008) and was often associated with a decreased
basal cortisol (Riva et al., 2010; Tak and Rosmalen, 2010). A recent
meta-analysis showed that hypocortisolism was not seen in irrita-
ble bowel syndrome (Tak et al., 2011). Low cortisol levels have also
been reported in patients with low back pain (Sudhaus et al., 2009).
Interestingly, the direction of HPA dysfunction seems to depend on
the spread of muscle pain. Cortisol levels in widespread pain condi-
tions such as fibromyalgia are low but are higher in localized muscle
conditions (Riva et al., 2012). In other experiments, disturbed glu-
cocorticoid receptor function rather than reduced cortisol levels
129
was described as the basis for the core symptoms of fibromyalgia
(Bote et al., 2012; Geiss et al., 2012).
2.2. Dysfunctional stress responses mediated by neuroactive
steroids
Another mode of steroid-based dysfunction can be related to
neuroactive steroids. Vulvodynia and burning mouth syndrome are
characterized by restricted location of the symptoms. This suggests
that the morbid stress response is unlikely to be mediated by the
blood stream hormones alone and could be mediated by neuroac-
tive steroids, which act locally. They are synthesized by nearby
cells (paracrine activity) or even by the same cells (autocrine or
intracrine activities), either peripherally or in the brain.
In healthy individuals, this has the advantage of limiting steroid
activity to a restricted body region (Labrie et al., 2003; Belelli
et al., 2006). Detailed descriptions of the neuroactive steroids can
be found in many reviews (Paul and Purdy, 1992; Baulieu, 1998;
Rupprecht, 2003; Dubrovsky, 2005). Briefly, neuroactive steroids
are synthesized by cutaneous and adipose cells, some neurons,
and glial cells in the central nervous systems and by Schwann
cells in peripheral nervous systems (Baulieu, 1998; Melcangi et al.,
2003; Rupprecht, 2003; Belelli et al., 2006). Their precursors can
be of diverse origin, from either glandular or peripheral tissues.
For instance, estrogens and androgens are neuroactive steroids
when they are synthesized outside endocrine glands and their pre-
cursors include dehydroepiandrosterone (DHEA) and its sulfated
form (DHEA-S). DHEA and DHEA-S are androgenic steroids that
can be synthesized in both adrenal and peripheral tissues. Pro-
gesterone can also be converted into another important group of
neuroactive steroids collectively called the 3␣-reduced neuroactive
steroids. This group includes the 3␣-5␣ tetrahydroprogesterone
(allopregnanolone or THPROG) and the 3␣-5␣ tetrahydrodeoxycor-
ticosterone (THDOC) (Rupprecht, 2003; Belelli and Lambert, 2005).
Neuroactive steroid levels are not static but change dynamically
in a variety of physiological and pathological conditions including
stress, depression, ageing and treatments with antidepressants and
anti-psychotics (Rupprecht, 2003). There are interactions between
intracrine, autocrine, paracrine and endocrine modes of activa-
tion of steroid receptors (Labrie et al., 2003). Finally, the complex
interactions and complementary activities of systemic and local
steroids may induce peripheral and/or central neuropathic vari-
ability. Because blood levels of a steroid do not reflect their
concentrations as neuroactive steroids in a specific location, neu-
roactive steroid levels are technically difficult to assess in humans.
Although hypothetical, their implication is very likely and based
on their ability to explain both the degenerative changes and the
symptom location limited to a restricted anatomical field like in
burning mouth syndrome (Woda et al., 2009).
2.3. Effects of steroid dysfunctions on nervous tissues
Several lines of evidence support the role of systemic and neu-
roactive steroids in neuroregeneration and protection, both in the
central and peripheral nervous systems, while corticosteroids may
have a deleterious effect on the nervous system. Epidemiological
and clinical studies suggest that gonadal steroids protect nervous
tissue against acute nerve or brain injuries or neurological diseases
(Schumacher et al., 2003). In vivo and in vitro animal experiments
have also shown that estradiol or other gonadal steroids such as
progesterone, allopregnanolone and testosterone facilitate nerve
regeneration and offer protection against injuries or degenerative
changes induced by excitotoxic conditions (Azcoitia et al., 2003;
Sayeed et al., 2006).
After injury, locally synthesized pregnenolone metabolites [pro-
gesterone, dihydroprogesterone (DHPROG) and THPROG] reduce
130 A. Woda et al. / Psychoneuroendocrinology 71 (2016) 127–135
damage and promote peripheral and central neurological recovery
in rats (di Michele et al., 2000; Schumacher et al., 2003). The myelin
sheath and Schwann cells seem to be special targets for these pro-
gesterone derivatives, since treatment with progesterone, DHPROG
and THPROG influence the proliferation of Schwann cells and
increase the number of small myelinated fibers in the peripheral
nervous system. This is compensated for by a decreased num-
ber of similar magnitude of unmyelinated axons (Azcoitia et al.,
2003; Melcangi et al., 2003; Melcangi et al., 2005). It is suggested
that neuroactive steroids themselves, or their synthetic receptor
modulators, could offer a therapeutic approach to counteract neu-
rodegenerative events in peripheral nerves (Melcangi et al., 2005).
DHEA and DHEA-S have also been shown to be major neuroprotec-
tive agents (Lapchak and Araujo, 2001; Schumacher et al., 2003).
In fact, low DHEA-S levels seem to contribute to worsening of neu-
rodegenerative diseases in human (Seckl and Olsson, 1995). More
importantly, the local production, in nervous tissues, of the active
metabolites of DHEA may counteract, via a paracrine mechanism,
deleterious effects induced by glucocorticoids (Marklund et al.,
2004).
While adrenal cortisol normally has a positive effect on nervous
tissues (Akama and McEwen, 2005), both low and high levels of
cortisol have been reported to be damaging for the nervous tissues
(Kaufer et al., 2004). For example, both high and low cortisol lev-
els have been shown to predict mortality after a stroke (Marklund
et al., 2004) and a steady increase in glucocorticoid levels caused
degenerative loss or morphological changes of neurons in the hip-
pocampus, the amygdala and the prefrontal brain (McEwen, 2005).
Taken together, the above findings suggest that steroids play a
role in neuroprotection and that persistent changes in their level
are related to neurodegeneration.
2.4. Different dysfunctional stress response modes mediated by
ANS
Under normal conditions, ANS activation in response to an
acute physical or psychological stress consists in a short increase
in the activity of the sympathetic system. It results in release of
norepinephrine by the efferent sympathetic terminals and mostly
epinephrine by the adrenal medulla. Some target organs such as
the myocardial muscle receive dual innervation from the sym-
pathetic and parasympathetic systems, which have often been
presented as exerting a balanced opposing action. In fact, sympa-
thetic and parasympathetic systems should be considered more
complementary than antagonist. The parasympathetic system is
responsible for steadily occurring basal activities such as digestion
or heart beat at rest. Also, the parasympathetic system regulates
tonic activity on a local basis, each organ being monitored and
controlled independently of one another. In contrast, the sympa-
thetic system commands the adaptive responses that threaten the
whole organism. It promotes the release of epinephrine from the
medulla, which can reach vital organs, for example during the fight
or flight response to an emergency situation. The sympathetic sys-
tem allows fast-rising, fast-dissipating, and first-line adaptation
to common daily life events. Both systems have a common com-
mand center in the hypothalamus, which could account for the
dysfunction of the two in dysautonomia. Similarly, training exer-
cise can reinforce simultaneously the two systems, decreasing basal
heart rate and increasing the ability to respond to an acute physical
demand (Nobrega et al., 2014).
Recent evidence strongly suggested the role of ANS in the patho-
genesis of chronic pain (Meeus et al., 2013). The most common
tools to assess ANS are sympathetic skin response, tilt-table test-
ing and overall heart rate variability (HRV) (Martinez-Martinez
et al., 2014). HRV is the variation between two consecutive beats:
the higher the variation, the higher the parasympathetic activity.
Conveniently, HRV can be monitored non-invasively and pain-free
by holter-electrocardiogram. When an acute stimulus occurs, the
normal response is a short-lasting increase in heart rate via sym-
pathetic activation, which is recorded as decreased HRV. However,
some acute overloaded experience can trigger prolonged activa-
tion of the ANS, leading to a long-term decrease in HRV, such as in
post-traumatic syndrome disorders. Importantly, high parasympa-
thetic activity is linked with well-being and greater life expectancy
(Stein and Kleiger, 1999). Some positive environments can improve
in the long term the ANS adaptive response and increase HRV or
other sympathetic markers. This occurs with mindfulness (Mankus
et al., 2013), biofeedback (Francis et al., 2015) and physical train-
ing (Achten and Jeukendrup, 2003; Perini and Veicsteinas, 2003).
However, acute exercise can promote a transient decrease in HRV.
Negative environments such as many types of illness (Marsac
2013), work-related stress (Tonello et al., 2014) and overload train-
ing (Baumert et al., 2006) tend to decrease HRV. Two modes of
impairment of the sympathetic system can be identified in response
to a transient stimulus, hyperactivity and hyporeactivity (Martinez-
Lavin, 2007; Martinez-Martinez et al., 2014). The occurrence of
hyperactivity or hyporeactivity may also depend on whether the
stimulus happens during the day or night (Meeus et al., 2013).
Two recent meta-analysis showed a decreased high-frequency
HRV in chronic pain i.e. a decreased parasympathetic activity. ANS
dysfunctions depend on pain conditions. For example fibromyal-
gia, unlike irritable bowel syndrome, is characterized by greatly
decreased parasympathetic activity (Koenig et al., 2016; Tracy
et al., 2016). Fibromyalgia dysautonomia is also characterized by
a basal hyperactive sympathetic activity with hyporeactivity to
stress (Cohen et al., 2000; Martinez-Lavin, 2007; da Cunha Ribeiro
et al., 2011; Chalaye et al., 2014). This hyporeactivity to stress is
less marked in localized chronic muscle pain (Nilsen et al., 2007).
2.5. Different dysfunctional stress response modes mediated by
the immune system
The immune system is part of the body’s reaction to stress stimu-
lations. Immunological changes are apparent during acute infection
and after acute psychological stress and physical trauma. Although
modest, immunological changes also occur in chronic psychological
stress.
Cytokines are a major factor in the adaptive responses to stress
stimuli (Chapman et al., 2008; Dutheil et al., 2013). The many types
of cytokines can be divided into two groups. One group, secreted
by a first profile of helper-T cells (Th1) is pro-inflammatory and
includes cytokines IL-1-␤, IL-2, IL-6, IL-8, IL-12, IFN-␥, and TNF-␣.
The second group, secreted by a second profile of helper-T cells
(Th2), is anti-inflammatory and includes cytokines IL-4, IL-10, IGF-
10, IL-13. This dual organization offers multiple possibilities of
immune responses ranging from one pole to the other (Elenkov
and Chrousos, 2006). This process is often referred to as the Th1/Th2
balance. Pro-inflammatory Th1 activity is the normal response fol-
lowing acute injury or infection. A special case must be made for
acute infection when chronic symptoms including pain, fatigue and
cognitive changes (Hickie et al., 2006) appear and last after the end
of the acute episode without any chronic ongoing infection (Clauw
and Ablin, 2009). Chronic stress is often considered as inducing a
chronic deregulation of the Th1/Th2 balance in favor of immuno-
suppressive effects (Dhabhar 2000; Sesti-Costa et al., 2012; Ahmad
et al., 2015). Stress hormones (glucocorticoids and catecholamines)
influence the immune response in a more diversified manner
demonstrating the many possible types of stress-induced immuno-
logical responses. These hormones inhibit Th1 pro-inflammatory
responses and induce a Th2 anti-inflammatory shift. In certain local
responses, however, they promote pro-inflammatory cytokine pro-
duction (Dhabhar 2000; Salicru et al., 2007). Such changes in
 A. Woda et al. / Psychoneuroendocrinology 71 (2016) 127–135 131

immunological profile have been observed in the pathogenesis of
chronic diseases including different pain conditions. Interestingly,
opposite profiles have been observed in different chronic pain con-
ditions: pro-inflammatory in fibromyalgia (Sturgill et al., 2014), and
anti-inflammatory in chronic neuropathic pain, low back pain, and
regional pain syndrome (Kaufmann et al., 2007; Luchting et al.,
2015). The immune component of chronic pain pathophysiology
includes microglia and astrocytes activation. Normally, glial activa-
tion is an adaptive defensive mechanism that contributes to handle
acute stress. Glial activation, however, can have deleterious effects
when it is not quickly resolved after the acute stressful event (Pekny
and Pekna, 2014). Glial activation can produce pro-inflammatory
cytokines such as IL-1␤ and TNF-␣. Immunohistochemical studies
have strongly suggested its role in several chronic pain conditions
such as complex regional pain syndrome (Birklein and Schlereth,
2015), HIV-related neuropathic pain, fibromyalgia and chronic low
back pain (Loggia et al., 2015). Glial activation increases the brain
levels of translocator protein, formerly called the peripheral ben-
zodiazepine receptor. Translocator protein is one of the main target
for neuroactive steroids and a marker of glial activation. It is likely
to have a role in dysfunctional pain conditions. Increased brain lev-
els of translocator protein have been observed in low back pain
patients (Loggia et al., 2015).
2.6. Different types of genetic predisposition may promote
variability in dysfunctional stress responses
It was stated in the preceding chapter that a significant number
of individuals will develop one or another dysfunctional syndrome
following different types of acute infections. Some individuals then,
appear to be more vulnerable to the stressing stimulus induced
by infection. Similarly, HPA and ANS may be differently affected
by stress depending on genetic makeup. After an intense acute
and/or chronic stressing stimulus, an underlying genetic predis-
position can be a key factor in producing the switch from a short
and reversible physiological adaptive response to a chronic dys-
functional state of one or several components of the adaptive stress
response system. In the same way that environmental factors are
infinitely diverse there are probably a very large number of pos-
sible variations in the genetic features of an individual in relation
to pain. As stated by Diatchenko et al., 2006 “. . .multiple genetic
pathways and environmental factors interact to produce a diverse
set of idiopathic pain disorders. . .” (Diatchenko et al., 2006). Two
main genetic mechanisms could be at work: polymorphism and
epigenetics. In polymorphism, mutations result in gene differen-
tiation for a single chromosomal locus. Various polymorphisms
of genes coding for monoamine metabolism influence responses
to stress stimulations and pain sensitivity, and/or psychological
profiles. These polymorphisms have been observed in the genes
coding for COMT, D2 dopamine receptor, adrenergic receptor ␤2 ,
serotonin transporter 5-HT, monoamine oxidase A, GABA synthetic
enzyme, and also in the genes coding for glucocorticoid recep-
tor, interleukins 1 ␤ and ␣ and the voltage-gated calcium channel
(Diatchenko et al., 2006; Ablin et al., 2009; Young et al., 2012). Epi-
genetic regulation results in diverse phenotypic expression for a
single genotype. It has recently been shown to play a crucial role in
pain by governing gene expression in response to environmental
cues (Bai et al., 2015). Epigenetic responses have been implicated
in the interaction between stress and pain. Epigenetic regulation
has been observed in the brain area involved in the response of

Fig. 1. Thematic representation of different modes of dysfunctional stress responses. The immune system is schematized by a few ganglions (blue). The hypothalamo-
pituitary-axis (HPA) is schematized by the hypothalamus, pituitary gland and adrenal glands (brown). The main active cells that secrete neuroactive steroids are cutaneous,
nervous, and adipose cells (yellow). The autonomic nervous system (ANS) is represented by the hypothalamus and dorsal spinal cord centers (red). (For interpretation of the
references to colour in this figure legend, the reader is referred to the web version of this article.)
132 A. Woda et al. / Psychoneuroendocrinology 71 (2016) 127–135
the HPA axis to chronic psychogenic stressors (Stankiewicz et al.,
2013). Individual vulnerability to stress may also be affected by psy-
chological profile and previously enhanced pain sensibility, both
of which may be genetically influenced (Bouchard and McGue,
2003; Diatchenko et al., 2013). Among the many genetic factors
that modulate stress tolerance (Trescot and Faynboym, 2014), two
polymorphisms are more particularly involved in the response of
individuals to constraints, the polymorphism of the gene coding for
angiotensin (Montgomery et al., 1999; Thayer et al., 2003), which
is involved in cardiac autonomic responses, and the polymorphism
of serotonin transporter (5-HTT), which influences mood (Hariri
and Weinberger, 2003; McCaffery et al., 2003; Hariri et al., 2006).
Both clinical and experimental pain perception are influenced by
genetic variants (Mogil, 1999; Diatchenko et al., 2005). It can be
expected that genetic testing will explain and predict dysfunctional
pain responses at least in part (Trescot and Faynboym, 2014).
2.7. Interactions between ANS, HPA, neuroactive steroids, the
immune system and genetics
Any dysfunctional state may result from two possible classes of
interactions between the adaptive responses to a stressing stimu-
lus. The first class of interactions falls into each of the categories
of biological responses referred to above (ANS, HPA, neuroactive
steroids, immune system and genetics). Different types of stressing
stimuli may occur simultaneously. Their interactions can trig-
ger different types of response within one category of biological
responses (Biondi and Picardi, 1999). The second class of interac-
tions is between each category. For instance, hypocortisolism in
some patients with stress-related chronic disorders is associated
with an increase in the reactivity of the sympathetic nervous sys-
tem (Yehuda, 2006) and increased catecholamine levels (Fries et al.,
2005). The dissociation between low cortisol levels and increased
sympathetic activity has been related to anxiety, sadness, emo-
tional numbing, and alexithymia (Henry, 1992). A simultaneous
decrease in the responsiveness of both the HPA axis and the sym-
pathetic responses is also one example of the many possibilities
of interactions between HPA axis and sympathetic nervous system
(Tak et al., 2011). Some other examples of these interactions have
been documented (Heuser and Lammers, 2003; Chapman et al.,
2008; Stisi et al., 2008), but it is very likely that many more are
still to be discovered.
Mention must be made of the decision not to deal with the
neurophysiological mechanisms or psychological/behavioral pro-
files in this section. Many patho-physiological mechanisms have
a widely described role in different chronic pain conditions such
as central sensitization, deafferentation associated with impaired
segmental inhibition and modification of the descending controls.
There are also certain psychological/behavioral profiles character-
ized by sensitivity to anxiety, anticipation and avoidance of fear or
harm, catastrophizing ideation, causal attributions for symptoms,
self-efficacy and operant conditioning that can modify the adaptive
biological responses to the life events called stress stimuli (Turk,
2002). Psychological and behavioral profiles may play a large part
in stress-related dysfunctional states but both can be considered
merely as a consequence of the primary dysfunction of the stress
systems (Clauw and Ablin, 2009) (Fig. 1).
3. Conclusions
Large differences exist in the type of deregulation of the physio-
logical response to stress and lead to pathophysiological differences
between pain conditions. There is also much heterogeneity in the
dysfunctions of the HPA-ANS systems observed in patients belong-
ing to the same pain groups. These differences and heterogeneities
may in part explain the differences in the clinical pictures (Clauw
and Ablin., 2009). Complex interactions also occur in chronic pain
conditions not only between the different steroids (Biondi and
Picardi, 1999; Crofford 2002; Zubieta et al., 2003; McEwen and
Kalia, 2010), but also between the HPA axis, ANS and immune
system (Chapman et al., 2008). In addition, genetic determin-
ism influences dysfunctional pain conditions (Buskila et al., 2004;
Zhou et al., 2008). Individual polymorphic variations in genes and
epigenetic variability influence pain sensation and psychological
expression (Mogil, 1999; Zubieta et al., 2003; Diatchenko et al.,
2005; Xiao et al., 2011). When coupled with environmental fac-
tors such as physical or emotional overstimulation, these different
factors interact to produce a phenotype that is vulnerable to the
emergence of dysfunctional pain (Diatchenko et al., 2005). In sum-
mary, while these complex interactions produces large variations
in the clinical picture, the basic mechanism, deregulation of the
response to stress, remains broadly similar.
Contributions
Pr Woda designed the review. Pr Woda and Dr Dutheil drafted
the manuscript. Dr Picard revised the manuscript. All authors
revised and approved the final version submitted for publication.
Funding
None.
Acknowledgement
We are thankful to Mr Jeffrey Watts for his English proof editing.
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