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Stress is natural and belongs to life itself. To sustain it and even grow with it biology invented different mechanisms, since stress resistance is obligatory. These pathways, we surmise, can be activated and learned intentionally, through professional stress management training or 'mind-body medicine', or endogenously and automatically through autoregulation. Since the primary goal of various stress-reducing approaches is corresponding, we expect to find an overlapping physiology and neurobiological principle of stress reduction. These common pathways, as we speculate, involve some of the very same signalling molecules and structures. METHODS: Concepts of stress and stress management are described and then associated with underlying molecular and neurobiological pathways. Evidence is gathered from different sources to substantiate the hypothesis of an overlapping neurobiological principle in stress autoregulation. RESULTS: Stress describes the capacity and mechanisms to sustain and adjust to externally or internally challenging situations. Therefore, organisms can rely on the endogenous ability to self-regulate stress and stressors, i.e., autoregulatory stress management. Stress management usually consists of one to all of the following instruments and activities: behavioral or cognitive, exercise, relaxation and nutritional or food interventions (BERN), including social support and spirituality. These columns can be analyzed for their underlying neurobiological and autoregulatory pathways, thereby revealing a close connection to the brain's pleasure, reward and motivation circuits that are particularly bound to limbic structures and to endogenous dopamine, morphine, and nitric oxide (NO) signalling. Within this work, we demonstrate the existence of opioid, opiate, dopamine and related pathways for each of the selected stress management columns. DISCUSSION: Stress management techniques may possess specific and distinct physiological effects. However, beneficial behaviors and strategies to overcome stress are, as a more general principle, neurobiologically rewarded by pleasure induction, yet positively and physiologically amplified and reinforced, and this seems to work via dopamine, endorphin and morphine release, apart from other messenger molecules. These latter effects are unspecific, however, down-regulatory and clearly stress-reducing by their nature. CONCLUSIONS: There seems to exist a common neurobiological mechanism, i.e., limbic autoregulation, that involves dopamine, morphine and other endogenous signalling molecules, e.g., other opioid receptor agonists, endocannabinoids, oxytocin or serotonin, many of which act via NO release, and this share seems to be of critical importance for the self-regulation and management of stress: stress management is an endogenous potential.
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Neuroendocrinol Lett 2010; 31(1):19–39
R E V I E W
Neuroendocrinology Letters Volume 31 No. 1 2010
The neurobiology of stress management
Tobias E
1,2,3
, George B. S
2,3
1 Division of Integrative Health Promotion, Coburg University of Applied Sciences, Coburg, Germany.
2 Institute for Mind-Body Medicine, Potsdam, Germany.
3 Neuroscience Research Institute, State University of New York, Old Westbury, New York, U.S.A.
Correspondence to: Prof. Dr. Tobias Esch, M.D.
Head, Div. Integrative Health Promotion, Coburg University of Applied Sciences
Friedrich-Streib-Str. 2, D-96450 Coburg, Germany.
Submitted: 2010-01-11 Accepted: 2010-02-02 Published online: 2010-02-17
Key words:
stress; brain; autoregulation; morphine; opioids; oxytocin; dopamine; nitric
oxide; pleasure; reward; relaxation; meditation; exercise; behavior; nutrition;
mind-body medicine
Neuroendocrinol Lett 2010; 31(1):19–39 PMID: 20150886 NEL310110A30 © 2010 Neuroendocrinology Letters www.nel.edu
Abstract
BACKGROUND AND OBJECTIVE: Stress is natural and belongs to life itself. To sus-
tain it and even grow with it biology invented different mechanisms, since stress
resistance is obligatory. These pathways, we surmise, can be activated and learned
intentionally, through professional stress management training or ‘mind-body
medicine, or endogenously and automatically through autoregulation. Since the
primary goal of various stress-reducing approaches is corresponding, we expect to
find an overlapping physiology and neurobiological principle of stress reduction.
These common pathways, as we speculate, involve some of the very same signal-
ling molecules and structures.
METHODS: Concepts of stress and stress manage-
ment are described and then associated with underlying molecular and neurobio-
logical pathways. Evidence is gathered from different sources to substantiate the
hypothesis of an overlapping neurobiological principle in stress autoregulation.
RESULTS: Stress describes the capacity and mechanisms to sustain and adjust to
externally or internally challenging situations. Therefore, organisms can rely on
the endogenous ability to self-regulate stress and stressors, i.e., autoregulatory
stress management. Stress management usually consists of one to all of the fol-
lowing instruments and activities: behavioral or cognitive, exercise, relaxation and
nutritional or food interventions (BERN), including social support and spiritual-
ity. These columns can be analyzed for their underlying neurobiological and auto-
regulatory pathways, thereby revealing a close connection to the brains pleasure,
reward and motivation circuits that are particularly bound to limbic structures
and to endogenous dopamine, morphine, and nitric oxide (NO) signalling. Within
this work, we demonstrate the existence of opioid, opiate, dopamine and related
pathways for each of the selected stress management columns.
DISCUSSION:
Stress management techniques may possess specific and distinct physiological
effects. However, beneficial behaviors and strategies to overcome stress are, as
a more general principle, neurobiologically rewarded by pleasure induction, yet
positively and physiologically amplified and reinforced, and this seems to work
via dopamine, endorphin and morphine release, apart from other messenger mol-
ecules. These latter effects are unspecific, however, down-regulatory and clearly
stress-reducing by their nature.
CONCLUSIONS: There seems to exist a common
neurobiological mechanism, i.e., limbic autoregulation, that involves dopamine,
morphine and other endogenous signalling molecules, e.g., other opioid receptor
agonists, endocannabinoids, oxytocin or serotonin, many of which act via NO
20
Copyright © 2010 Neuroendocrinology Letters ISSN 0172–780X www.nel.edu
Tobias Esch, George B. Stefano
release, and this share seems to be of critical importance
for the self-regulation and management of stress: stress
management is an endogenous potential.
I
S
tress has gained remarkable significance in our
times. Various reasons may account for this.
There is the notion of an acceleration of human
activities, challenges, productivities, and behaviours,
accompanied by increasing levels of noise, pollution
and daily stressors, e.g., having a job or not having a
job, some of these stressors related to over-population
or actual financial crisis [Adler, 2009; Esch, 2002f; Howards, 2000;
Stuckler & Basu 2009]. Whether stress is really and overall
increasing or not, the perception of stress certainly is
[Esch, 2002f; Esch, 2003d; Metz et al. 2009]. Therefore, we see a
surge of stress-related complaints and diseases, many of
them leading to medical interventions and, quite often,
to cost-expensive treatments and disabilities [Adler, 2009;
Croft et al. 2009; Gottholmseder et al. 2009; Rousit et al. 2007].
Hence, the increase in stress awareness may have
created a stress epidemic. Science and medicine have
deliberately examined, or were they forced to face, the
stress phenomenon and its implications for health and
treatment options [Esch, 2002f; Stefano, 2005a]. This science has
led to expanded knowledge on stress and its manage-
ment (stress management (SM)), i.e., pharmaceutical
and especially non-pharmaceutical means as a remedy
[Blumenthal et al. 2005; Ernst et al. 2008; Ernst et al. 2009; Esch, 2003d; Esch
et al. 2003b; Esch & Stefano, 2007b; Esch et al. 2007a; Esch, 2008a; Komaroff,
2001; Michalsen et al. 2005; Schwartz, 1980, Stauder et al. 2009]. New
medical strategies, named, for example, ‘integrativeor
mind-body medicineas well as complementary/alter-
nate medical approaches, were invented particularly to
focus upon our innate self-healing capacities, i.e., self
management, and the autoregulatory capacities that we
all possess to effectively respond to the stressors of daily
life.
Recent research on stress and SM has revealed a
close connection between the clinical features, appear-
ance, and consequences of stress as well as with brain
mechanisms of reward, pleasure and motivation, i.e.,
neurobiology [Esch & Stefano, 2004c]. In particular, limbic
autoregulatory paths in the brain that get activated in
stress and physiological stress response processes have
gained scientific interest [Stefano & Esch, 2005c], and it now
seems time to put theses various findings in a broader
frame and perspective, especially by linking endog-
enous SM capacities (usually involving elements of
positive behaviors, nutrition, exercise, and relaxation
techniques [Esch, 2008a; Esch & Stefano, 2007b; Esch et al. 2006b])
to autoregulatory dopamine, opioid, opiate and nitric
oxide signalling pathways [Stefano & Kream 2009c].
There appears to exist a physiological and neu-
robiological commonalty, at least to a large extent,
between the various self-healing-associated activities
to fight stress, and the endogenous molecular pathways
involved in these very same activities. Our hypothesis
is that, due to biological significance of the stress phe-
nomenon for evolution and survival of the individual
and its species, successful activities to fight stress were
physiologically and genetically conserved and passed
on to following generations, thus accounting for a neu-
robiological overlap in SM strategies. This hypothesis
will be examined further in the following sections.
W
S
tress is a natural, biological and, at times, useful
phenomenon. Stress describes the effects of psy-
chosocial and environmental factors on physi-
cal or mental well-being [Esch, 2003d, Esch et al. 2002a; Esch et al.
2002b; Esch et al. 2002d; Stefano et al. 2005a; Seyle, 1975]. Stressors and
related stress-reactions are distinguished [Esch, 2002f; Esch
et al. 2002a; Esch et al. 2002b; Esch et al. 2002d]. Furthermore, stress
implies a challenge (stimulus) that requires behavioral,
psychological, and physiological changes (adaptations)
to be successfully met, therefore using a state of hyper-
arousal for the initiation of necessary counteracting
reactions [Esch & Stefano, 2002e; Esch et al. 2002c; McEwen, 2009; Stefano
et al. 2005a]. This state of hyperarousal involves physiologi-
cal mechanisms that are known as the stress or fight-or-
flight response, a set of physiological changes that occur
in stressful situations and that prepare the stressed
organism either to fight or to flee. This state of alert-
ness had first been described by Walter Cannon almost
100 years ago [Cannon, 1917; Cannon & Pereira 1924a; Cannon& Querido,
1924b]. Hans Selye, among others, has thereafter refined
the physiological stress concept and its significance for
biology and survival [Seyle, 1975; Seyle, 1973]. Modern con-
cepts and recent studies have eventually associated the
stress theory with human ailments and its neurobiolog-
ical implications [Bakoula et al. 2009; Charmandari et al. 2005; Esch,
2002f; Esch, 2003d; Esch & Stefano, 2007b; Esch et al. 2002a; Esch et al. 2002b;
Esch et al. 2002d; Gould et al. 1997; Gold et al. 2005; McEwen, 1998; McEwen,
2008; McEwen, 2009; Meyer, 2001; Sapolsky, 2003; Sapolsky, 2004; Stefano et
al. 2005a; Stefano et al. 2008c].
Stress occurs when we meet a sudden challenge and
are forced to (re-) act in order to survive, or, less dra-
matically, to endure. When a zebra unexpectedly meets
a lion, its physiology turns towards alarm, i.e., fight
or flight (or eventually ‘freeze, when the challenge is
simply overwhelming, implying a physiological black
out) [Esch, 2008a; Sapolsky, 2004]. Every bodily or mental activ-
ity is now scanned for the usefulness or deleteriousness
in responding to the challenge, the stressor. Beneficial
mechanisms will be enforced, others shut-down. This is
natural and, at times, helpful, though exceptional. Fol-
lowing a successful escape or fight, the body naturally
recovers, the mind relaxes [Esch et al. 2003b; Stefano et al. 2006].
Autoregulatory messengers and signalling molecules
effortlessly enable this rebound or recreational state
[Esch et al. 2009a; Salamon et al. 2006; Stefano et al. 2005d]. However,
problems may occur when stress endures too long, is
too massive or the physiology not fitted to fight a par-
21
Neuroendocrinology Letters Vol. 31 No. 1 2010 Article available online: http://node.nel.edu
The neurobiology of stress management
ticular stressor [Esch, 2003d; Esch & Stefano, 2002e; Esch et al. 2002c;
Stefano & Esch, 2005b; Stefano et al. 2005d]. Or when enough time
for recovery is not allowed. Additionally, on an organic
level, the biochemical response machinery that may
turn off a stress response may be damaged [Fricchione et
al. 1997]. And this seems to be a real human dilemma:
equipped with the very same stress response mecha-
nisms that the zebra fortunately possesses, we usually
dont have to oppose life-threats in forms of lions or
other external enemies in our daily life [Esch, 2002f; Esch,
2003d]. And so we start to think about the stresses and
dangers in the future, the stressors and potentially
stressful situations that might come, or the things that
we encountered in the past, regarded as stressful [Ste-
fano et al. 2005a]. And furthermore, we may start to dwell
about our potentially suboptimal coping and resistance
capacities in the present, thereby diminishing these
very same capacities, causing us self-inflicted stress and
impairment of our defence, i.e., ‘cognitive constipation
[Stefano et al. 2005a]. Finally, an originally useful and help-
ful mechanism may convert to become deleterious,
and stress-related diseases consequently emerge [Esch
et al. 2002a; Esch et al. 2002b; Esch et al. 2002d]. This is the critical
path that underlies much of modern stress and human
stress-related diseases. The good news is that we not
only possess the endogenous capacity to self-inflict
stress and harm, i.e., self-harm, but also to self-manage
it, reduce its impact, be self-efficacious and endog-
enously heal or prevent stress disorders via SM [Fricchione
& Stefano, 2005].
W   
S
ingle cells, even bacteria, already possess physio-
logical stress-attenuating or ‘SOS responsecapa-
bilities [Esch, 1999; Esch, 2003d; Giuliodori et al. 2007]. These
get activated when cells are exposed to stressors and
substantial threats, i.e., alarm signals [Esch, 1999; Foster, 2005;
Galhardo et al. 2007]. In fact, these cellular places of flexibility
and adaptation include actively induced genomic and
gene expression alterations under stress to better ‘cope
with it and improve the cellular environment (‘survival
of the fittest genes’), and this regulatory potential may
be a critical requirement for biological development
and evolution itself [Dusek et al. 2008b; Esch, 1999; Esch, 2003d, Foster,
2005; Galhardo et al. 2007; Giuliodori et al. 2007; Rossano 2007]. Clearly,
stress has given rise to biological progress and survival,
again pointing at the potentially positive characterand
biological necessity of the stress phenomenon, includ-
ing the autoregulatory ability to constructively work
with it for the better of the individual, and the spe-
cies in particular [Esch, 1999; Esch, 2002f; Esch, 2003d; Stefano et al.
2005a]. What is true for the single cell, i.e., that it has an
endogenous creativestress response potential, is also
true for the whole organism, including man [Esch & Stefano
2007b; Stefano et al. 2005a; Stefano et al. 2008c]. Even more, in com-
plex organisms (in comparison to bacteria) these stress
response options are diversified and manifold, e.g., due
to higher integrative states of the nervous system and,
under healthy conditions, a finely tuned neurobiologi-
cal balance, that is, the neurobiology of stress and SM
[Esch & Stefano 2005a, Esch& Stefano 2005b; Stefano & Esch 2005c].
SM builds on innate self-healing capacities [Esch, 2008a;
Stefano & Kream, 2008a; Stefano et al. 2005a; Stefano et al. 2008b; Stefano et
al. 2008c]. Our physiology is prone to regress to balance,
i.e., a physiological or biological regression to the mean,
therefore involving a dynamic autoregulation that leads
to homeostasis or, in case of a state of arousal neces-
sary to reach the required dynamic balance, to allostasis
[Esch, 1999; Esch, 2002f; Esch, 2003d; McEwen, 1998; McEwen, 2008; Stefano
et al. 2005a; Stefano et a1., 2008c]. The character of the balance
finally achieved or secured, whether it is called ‘homeo-
stasisor allostasis, is beyond the scope of this paper,
however, it is the dynamic and potential to always
return to the aspired set-point that is of importance for
our hypothesis on the innate and overlapping biologi-
cal SM capabilities. Usually, this balance or set-point is
reached via dynamic autoregulation, i.e., allostasis or
allostatic stress response pathways [Esch, 1999; Esch, 2003d;
Esch et al. 2003b; McEwen, 1998; Stefano et al. 2005a]. Clearly, at the
bottom of this self-organisational capacity lies our evo-
lutionarily conserved SM potential [Esch, 2002f; eSCh, 2003d;
Rossano, 2007].
To medically or professionally reduce stress, we usu-
ally engage in activities that consist of one to all (or
individual combinations) of the following strategies: a)
behavorial adjustments under stress, including cogni-
tive interventions and mental restructuring (cognitive
behavioral therapy), b) exercise and bodily activities, c)
relaxation techniques, d) nutrition or eating or not
eating/diet and, in general, learning to induce natu-
rally occurring positive chemical messengers in our
body (Fig. 1). Included in this list is the engagement
in, or existence of, sufficient (‘positive’) social support
as well as the belief in something, i.e., spirituality or
connectedness (Fig. 1). These columns of a profes-
sional medical SM have been thoroughly examined,
meanwhile, and their general clinical value appears to
be obvious (e.g., see [Astin et al. 2003; Benson & Casey, 2008; Blu-
menthal et al. 2005; Daubenmier et al. 2007; Dusek & Benson, 2009; Dusek
et al. 2008a; Ernst et al. 2009; Esch, 2002f; Esch & Stefano 2007b; Esch et al.
2003b; Grossmann et al. 2004; Kabat-Zinn et al. 1998; Kabat-Zinn et al. 1992;
Komaroff, 2001; Le Tourneau, 2003; Michalsen et al. 2005; Ornish, 1998; Rich-
ardson & Rothstein, 2008; Schulz et al. 2008; Stefano et al. 2005a]). For
the aim of this work, we will now take a deeper look
into the physiology and neurobiological implications
of these different stress-altering tools and search for
possible commonalties among them. Since all these
techniques potentially reduce stress and are beneficial
in decreasing stress-related ailments and diseases, and
since stress is an almost uniform cellular, bodily and
mental process to ensure survival in a threatening situ-
ation (as described above: challenge or fight-flight), our
speculation is that similar or overlapping neurobiologi-
cal patterns and processes underlie these endogenous
stress-reducing, self-healing strategies. Furthermore,
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Copyright © 2010 Neuroendocrinology Letters ISSN 0172–780X www.nel.edu
Tobias Esch, George B. Stefano
allostasis and adaptation, i.e., adaptive or allostatic
stress responses [Esch 1999; Esch et al. 2003b; McEwen, 1998; Ster-
ling & Eyer, 1988]. Thereby, the goal is to keep balance,
self-organize and maintain autonomy under challenge
and ultimately to survive [Esch, 1999; Esch, 2003d]. When
an organism chooses the right or successful strategy
to fight a stressor and meet the challenge, a boost of
rewarding (and stress-reducing) signalling molecules is
released into the blood through the brains reward and
motivation centres, in the course of the evolving event
or afterwards, to make the individual feel good, become
positively motivated and reinforce (and memorize!) the
beneficial behavior [Esch & Stefano, 2004c; Esch & Stefano, 2005a;
Esch & Stefano, 2005b; Esch & Stefano 2007b; Mantione et al. 2008; Stefano
& Esch, 2005c; Stefano et al. 2001a; Stefano et al. 2007a; Stefano et al. 2008c].
Successful adaptation is thus endogenously rewarded
(see below). As a result of these ongoing processes of
adaptation, over time, allostatic load can accumu-
late, and the overexposure to neural, endocrine, and
immune stress mediators can have adverse effects on
various organ systems, leading to the possible onset or
progression of diseases [Esch et al. 2002a; Esch et al. 2002b; Esch et
al. 2002d; McEwen, 1998]. Hence, profound physiological and
molecular connections between stress and various dis-
ease processes exist [Charmandari et al. 2005; Esch, 2003d; Stefano
et al. 2005a]. Common pathophysiological pathways in
stress-related diseases have been described [Esch & Stefano
2002e; Esch & Stefano, 2007b; Esch et al. 2002c; Esch et al. 2003a; Stefano et
al. 2005a], and they critically involve stress hormone (e.g.,
cortisol, norepinephrin (NE)) and, in particular, NO
activity (see below). Moreover, as noted earlier, stress
may trigger the activation of a damaged or insufficient
biochemical cascade designed to address such normal”
perturbations. In this scenario an individual may
have trouble terminating this response, which, under
these circumstances, will allow for a long and chronic
response sine the terminating processes are not func-
tioning or fully functional [Fricchione et al. 1997].
Two molecules that play a major role in the stress
response are well-known. Each molecule represents
one neurobiological arm of the response, the hypo-
dopamine (DA), endogenous morphine (MO), endo-
cannabinoids and nitric oxide (NO) signalling, as well
as other related cellular and neurobiological messengers
of autoregulation, may critically be involved [Stefano &
Kream 2009].
T   
S
tress has an impact upon the immune, circulatory,
and nervous systems [Esch et al. 2002a; Esch et al. 2002b;
Esch et al. 2002d]. However, the underlying physiol-
ogy reveals high conformance, since the stress phe-
nomenon and its impact are associated with common
stress response pathways [Stefano et al. 2005a; Charmandari et al.
2005]. In fact, stress affects immunological [Esch et al. 2002a],
cardiovascular [Esch et al. 2002b], and neurodegenerative or
mental diseases/disorders [Esch et al. 2002d], and this may
include both positive and negative aspects [Stefano et al.
2005a; Esch et al. 2002a; Esch et al. 2002b; Esch et al. 2002d; Charmandari et
al. 2005]. Stress can either exert ameliorating or deleteri-
ous effects, depending on a multitude of factors (e.g.,
individual, endogenous, or exogenous elements) [Esch,
2002f; Esch, 2003d; Esch et al. 2002a; Esch et al. 2002b; Esch et al. 2002c, Esch
et al. 2002d; Esch et al. 2003b; Jones et al. 2001]. However, clinically,
negative influences of stress upon health and disease
processes seem to predominate [Esch, 2002f; Stefano et al. 2005a;
Esch et al. 2002a; Esch et al. 2002b; Esch et al. 2002d], which may espe-
cially be true in modern societies, where stress-related
health issues and complaints almost have an epidemic
character [Esch, 1999; Esch, 2002f; Esch, 2003d; Jones et al. 2001; Salavecz
et al. 2009; Siegrist & Wahrendorf, 2009; Stefano et al. 2005a]. SM strate-
gies, therefore, are of growing importance and accep-
tance since they address a “basic physiological process
in these societies and countries [Ernst et al. 2009; Esch, 2002f;
Esch, 2003d; Le Tourneau, 2003; Richardson & Rothstein, 2008; Salavecz et al.
2009; Stefano et al. 2005a].
The brain is the central organ of stress and adapta-
tion above normal tissue adaptive responses [McEwen,
2009]. When the brain perceives/senses an experience/
stimulus as stressful, physiological and behavioral
responses (stress responses) are initiated, leading to
Figure 1: The BERN concept of stress
management. The four columns of
professional and integrative i.e.,
multimodal – stress management
programs such as BERN [Esch, 2008a; Esch &
Stefano, 2007b; Esch et al. 2006b; Esch et al. 2009a; Stefano
et al. 2005d] are a) behavior, b) exercise, c)
relaxation, and d) nutrition; two further
columns may be added (if not included,
as above): social support and spirituality;
cognitive behavioral interventions are
critical ingredients i) of the behavioral
column and ii) the underlying therapeutic
model, i.e., mind-body medicine.
23
Neuroendocrinology Letters Vol. 31 No. 1 2010 Article available online: http://node.nel.edu
The neurobiology of stress management
thalamic-pituitary-adrenal (HPA) axis on one side and
the sympathoadrenal medullary (SAM) system on the
other [Negrao et al. 2000]. The molecules are cortisol and
NE/epinephrine [Negrao et al. 2000; Cannon, 1914; McCarty, 1996].
Corticotropin-releasing hormone (CRH) also belongs
in this company of critical molecules, i.e., HPA axis
[Charmandari et al. 2005; Esch et al. 2002a]. More recently, other
molecules with a close connection to the stress neuro-
biology have been detected, e.g., melatonin and mela-
nocyte-stimulating hormone [Brotto et al. 2001; Charmandari et
al. 2005], vasopressin [Charmandari et al. 2005; Esch & Stefano, 2005a;
Esch & Stefano, 2005b; Stefano & Esch, 2005c], oxytocin [Esch & Stefano,
2005a; Esch & Stefano 2005b; Stefano & Esch, 2000c], endocannabi-
noids [Esch, 2005c; Esch et al. 2006; Stefano, 2000e; Stefano et al. 2003],
and endorphins [Charmandari et al. 2005; Esch & Stefano, 2004c; Ste-
fano et al. 2005d; Stefano et al. 2001a]. Furthermore, a connection
of NO with the stress response has been demonstrated,
since this signalling molecule is part of the stress physi-
ology and related disease processes: NO is involved in
immunological, cardiovascular, and neurodegenerative
diseases/mental disorders, associated with stress [Cordel-
lini & Vassilieff, 1998; Esch et al. 2002c; Esch et al. 2003a; Gumusel et al. 2001;
Mantione et al. 2005; Stefano & Esch, 2005b; Stefano et al. 2001a; Stefano
et al. 2001b; Stefano et al. 2005d; Stefano et al. 2008b; Stefano et al. 2009a;
Zhu et al. 2004; Zhu et al. 2005b]. It represents a double-edged
sword, since small quantities produced by constitutive
enzymes may predominantly mediate physiological
or beneficial effects, whereas the expression of induc-
ible NO synthases may lead to larger quantities of NO,
a situation that may be associated with cytotoxic and
detrimental biological effects of NO [Esch et al. 2002c; Esch et
al. 2003a; Stefano et al. 2005a]. These latter NO effects, in par-
ticular, seem to be associated with stress and the nega-
tive side-effects of it.
In addition, stress effects and (patho-) physiologi-
cal consequences are potentially transferred’ not only
within the individual (e.g., systemic interactions
between mind, brain and body [Esch, 2008a; Komaroff, 2001;
Sapolsky, 2004; Stefano et al. 2001a; Stefano et al. 2005a], but also
towards other ‘neighbouring’ cells and organisms, even
those initially not under stress, e.g., by the means of
verbal/non-verbal communication or the exchange of
molecular and physical information [Esch, 1999; Esch, 2003d;
van Wijk et al. 2008a; van Wijk et al. 2008b; Wiegant et al. 1996]. Further-
more, stress mediation and specific impact of stress
hormone activity may be carried over biologically and
conserved beyond generation borders, since parents
and their offspring show stress response commonali-
ties and physiological/neurobiological as well as stress
behavioral coupling [Bakoula et al. 2009; Charmandari et al. 2005;
Chin et al. 2009; Moles et al. 2004]. This transfer of stress con-
sequences via neurobiological, physical, or chemical
coupling can even include genetic alterations, and these
effects may be relatively stable [Chin et al. 2009; Esch, 1999; Meyer
et al. 2001; Wiegant et al. 1996].
Another important element of stressful stimulation
may be the duration or time component of the noxious
or challenging stimulus [Esch & Stefano, 2007b; Fricchione & Stefano,
1994]. A brief physical or mental assaultmay allow an
organism to deal with both an appraised or perceived
stress through various detailed allostatic compensatory
mechanisms [Stefano et al. 2005d]. If the situation were to
continue chronically, the organism might become vul-
nerable, susceptible to the negative aspects of the stress
response, such as in the case of prolonged immune
down-regulation [Esch et al. 2002a, Stefano & Scharrer, 1994; Stefano
et al. 1995c; Stefano et al. 1996a; Stefano et al. 1996b; Stefano et al. 2000d].
Moreover, our physiological and psychological stress
response systems plainly function, or were designed
to do so, over the short-term, i.e., fight or flight, not
for prolonged periods of time [Esch, 2000f]. Given the
signal molecule commonalties and similarities found in
diverse organisms during the course of evolution, not
to mention the common design of animal nervous sys-
tems regardless of phyla [Salzet & Stefano, 1997b; Salzet & Stefano,
1997c; Salzet et al. 1997a; Stefano et al. 1998a; Stefano et al. 1998b; Stefano et
al. 1998c; Stefano et al. 2000b; Stefano et al. 2002; Stefano et al. 2005d; Ste-
fano et al. 2008b; Stefano et al. 2008c], it is not surprising to learn
that they also similarly exhibit stress responses, which
appear to be the same and rapid in implementation [Esch,
2003d; Stefano et al. 2002]
.
Stress, as described above, is natural and at times
very helpful in regard to survival strategies. However,
the underlying physiology can also lead to detrimental
effects. As the stress response is normal, so is the innate
physiology that follows or terminates activated stress
pathways, once initiated in a challenging situation [Esch,
2008b; Esch & Stefano, 2007b]. Under normal conditions, these
SM pathways (see below) follow the same neurobiologi-
cal roads that the stress mechanisms use, e.g., brains
limbic areas and the neuronal stress axes. For activating
this innate autoregulatory healing potential, the brain
even falls back on some of the very same molecules that
account for the initial stress response [Esch & Stefano, 2004c;
Esch et al. 2002c; Mantione et al. 2008; Stefano & Kream, 2008a; Stefano et al.
2008b]. As an example, one can look at what we called
the anticipatory stress response, or ‘love response[Esch
& Stefano, 2005a; Esch & Stefano, 2005b; Stefano & Esch, 2005c; Stefano et
al. 2008c]: in the beginning of an ultimately relaxing and
pleasurable experience, such as falling or being in love,
or executing a relaxation exercise, the body occasion-
ally goes into a short period of stress and physiological
activation, e.g., to screen the environment for potential
challenges or threats, thereby ensuring that it is safe
to relax [Stefano et al. 2008c], or to love [Esch & Stefano, 2005b].
Then, the physiology turns into an innate stress reduc-
tion, i.e., endogenous SM, only by activating additional
stress response mediators or lowering concentrations
of some stress molecules while enhancing others [Esch &
Stefano, 2002e; Esch & Stefano, 2005a; Esch & Stefano, 2005b; Esch & Stefano,
2007b; Esch et al. 2002c; Esch et al. 2003b; Esch et al. 2004a; Esch et al. 2004b;
Esch et al. 2006b; Salamon et al. 2006; Stefano & Esch, 2005c; Stefano et al.
2003; Stefano et al. 2005a; Stefano et al. 2005d; Stefano et al. 2006; Stefano
et al. 2008c].
Chronic stress can impact many physiological sys-
tems given their reliance on common biochemical
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Copyright © 2010 Neuroendocrinology Letters ISSN 0172–780X www.nel.edu
Tobias Esch, George B. Stefano
processes [Esch et al. 2002a; Esch et al. 2002b; Esch et al. 2002d]. In
part, the reason for this may be that at the core of many
disorders one may find a proinflammatory situation
that manifests itself in diverse tissues, differently mask-
ing the commonality [Esch & Stefano, 2002e; Stefano et al. 2005d].
However, it may be the ability to induce relaxation that
breaks the negative impact of chronic stress [Esch et al.
2003b; Stefano et al. 2008c]. Taken together, the acute stress
response is highly protective since it is designed in ani-
mals to meet an immediate challenge. Yet, over time,
initially positive effects can turn into the opposite, i.e.,
chronic stress. The underlying physiology of stress criti-
cally involves neurobiological pathways and circuitries,
such as the central neuronal stress axes or limbic reward
and motivation circuits. Stress mediators and other
effectors that build the neurobiological and molecular
basis of these stress mechanisms are, besides the classi-
cal stress hormones NE and cortisol, for example, DA,
the endocannabinoids and endorphins, oxytocin, vaso-
pressin, NO and, eventually, endogenous MO [Bakoula et al.
2009; Charmandari et al. 2005; Esch & Stefano, 2005b; Gold et al. 2005; Gould et
al. 1997; Kream et al. 2009; McEwen, 1998; McEwen, 2008; Meyer et al. 2001;
Sapolsky, 2003; Sapolsky, 2004; Stefano & Kream, 2009c; Stefano et al. 2005a;
Stefano et al. 2008c].
The general ‘ideaof the stress neurobiology may be
that a stressed organism gets immediate energy supply
and physiological activation for fighting, or taking
flight, while other systems of minor importance for this
primary goal (or even negatively interfering with it) get
shut-down, i.e., down-regulation [Stefano et al. 2005a]. This
differential preference for physiological activation may
even extend into mitochondrial regulation, ultimately
altering energy metabolism [Kream & Stefano, 2009b]. For
example, the experience of pain may call the attention
of a stressed’ individual (e.g., during a fight) towards
the source of this noxious sensation. However, when
the fight is not over, that is, the challenging problem
not solved, it might not be a good idea to put too much
effort and immediate attention into the investigation
of the ache, which makes it thus necessary to have
endogenous pain relieving stress mediators at handto
become released during prolonged stress. This may be
a critical function of the endorphins in stress, as they
are endogenous stress effectors and, additionally, at the
border towards relaxation [Esch & Stefano, 2007b; Salamon et al.
2006], especially cognitively, as they appear in a subse-
quent phase of the stress cycle, consecutively delayed in
comparison to the initial stress hormones (Fig. 2 and 3).
Endorphins are immunobiologically defence-active,
as they act as antibacterial substances themselves and
also trigger proinflammation beyond that [Esch et al. 2002a;
Esch & Stefano, 2002e; Stefano et al. 2001a; Stefano et al. 2005a; Stefano et al.
2005d]. After successfully overcoming the initial threat,
the system, under normal circumstances, endogenously
recovers by involving another set or a different orches-
tration– of autoregulatory molecules, which addition-
Figure 2: Opioid peptides as stress hormones. Stress triggers a release of proenkephalin that gets processed into
enkelytin and Met-enkephalin. This step characterizes opioid peptides as stress hormones at the border to stress
autoregulation, i.e., endogenous stress reduction, since they have the functions of a double-edged sword’: in part,
the opioid peptides/endorphins enable the stressed organism to stay active beyond the normal or physiological
duration of a stress cycle (e.g., ca. 90 minutes max. in humans), by signalling the individual to keep up with
the stress activity (because it might be biologically necessary), while reducing pain and other physiological
companions of a prolonged stress response. In this case, the activated immune response and defence is upheld,
typical signs of stress response activity prevail. However, the opioid peptides already prepare for the relaxing and
recovering part of stress, i.e., stress management, since motivation and behavioral adjustments are positively
influenced; references: [Fricchione & Stefano, 1994; Stefano & Scharrer, 1994; Stefano & Kream, 2008a; Stefano et al. 1996b; Stefano et al. 1998a; Stefano
et al. 2001a; Stefano et al. 2005a; Stefano et al. 2005d].
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The neurobiology of stress management
ally or consequently reward the chosen behavior (i.e.,
strategy), thereby also improving the memorization of
it, further recovering the initially blocked systems and
energy stores, thus, finally, bringing the system back
to normal under inclusion of neurobiological, physi-
ological, and even behavorial adaptations (Fig. 3 and
4). The organism gets the good feeling of ‘having done
the right thing, although, in the immediate phase of the
acute stress response, the conscious cognitive dwelling
upon the stressor/challenge and its possible impact was
blocked, i.e., rational short-cut [Esch & Stefano, 2004c; Esch et al.
2004a; Esch et al. 2004b; Stefano et al. 2005a]. Yet, the innate feeling
good part’ in the late phase of a successfully terminated
stress response leads us to the endogenous autoregula-
tion of stress and its common pathways: the neurobiol-
ogy of SM.
N   
I
n the above section, we looked at underlying prin-
ciples of the stress response and depicted some
of its neurobiological key players, and finally
brought those in line with the idea of an endogenous
autoregulation, i.e., physiological self-care and SM. In
the following section of this report, we will focus upon
the neurobiological commonalties that can be found
between the columns of a professional SM regimen
(Fig. 1: BERN), particularly with regard to the molecu-
lar effectors. For our analysis, we will have a closer look
at endogenous dopaminergic and particularly mor-
phinergic signalling, since this latter opiate alkaloid has
only recently been found in human tissues (e.g., [Atma-
nene et al. 2009; Bilfinger et al. 2002; Boettcher et al. 2005; Fricchione et al.
2008; Olsen et al. 2005; Poeaknapo, 2005; Poeaknapo et al. 2004; Stefano &
Kream, 2009c; Zhu et al. 2005a; Zhu et al. 2007]) and linked to stress
regulation (Fig. 4). Indeed, the catecholamine pathway
may have arisen from endogenous MO biosynthesis,
coupling these signalling processes in an even more
intimate relationship as also made evident by common
enzymes in the synthesis of these chemical messengers
[Mantione et al. 2008; Neri et al. 2008; Stefano & Kream, 2007b; Stefano &
Kream, 2009c]. The results that we now report have, to our
knowledge, not been put into relation to each other so
far, as they have not been linked to an overall neurobio-
logical principle, i.e., stress autoregulation.
Behavior
There exists a high congruency between the different
techniques and approaches towards behavioral stress
reduction (Fig. 1) when it comes to underlying neu-
robiological pathways (see below). Again, we find the
same molecular key players as in stress. In fact, the neu-
robiology of behavioral SM seems to be imbedded in
the brains pleasure, motivation and reward circuitries
[Stefano & Kream, 2007b; Stefano & Kream, 2009c].
Modern science begins to understand pleasure as a
potential component of salutogenesis [Esch & Stefano, 2004c].
Thereby, pleasure is described as a state or feeling of
happiness and satisfaction resulting from an experience
that one enjoys. We and others examined the neuro-
biological factors underlying these reward and pleasure
processes and why they potentially possess a stress-
reducing capability via behavioral adjustments, e.g.,
behavioral SM [Berridge & Kringelbach, 2008; Esch & Stefano, 2004c;
Figure 3: Endogenous stress response management. Stress leads to an activation of opioid peptide influences on
the immune system of the mollusc Mytulis edulis [Hughes et al. 1990; Stefano et al. 1990]. Over time, however, the activity
gets down-regulated by the release of opiate alkaloids, e.g., endogenous morphine, thereby ending the stress
response cycle. When the system goes back to complete normal function, by also terminating the endogenous
stress management or relaxation part (that is, the morphine-related down-regulatory phase), a rebound from
down-regulation may occur, i.e., excitation; further references [Stefano et al. 1998b; Stefano et al. 1998c; Stefano et al. 2002].
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Copyright © 2010 Neuroendocrinology Letters ISSN 0172–780X www.nel.edu
Tobias Esch, George B. Stefano
Esch & Stefano, 2005b; Esch et al. 2004b; Salamon et al. 2005; Stefano & Esch,
2005c; Zhu et al. 2004]. This stress-pleasure-self-regulation, as
the name implies, combines externally stimulating or
challenging activities with internal or endogenous brain
processing, therefore involving dopaminergic signalling
as a core pathway [Berridge & Kringelbach, 2008; Berridge & Robin-
son, 1998; Esch & Stefano, 2004c; Esch et al. 2004b]. Furthermore, the
regulation of attachment behaviors, critical for positive
social support, as this is a major stress-reducing activ-
ity, involves endogenous opioid and opiate as well as
endocannabinoid signalling and, via direct receptor
coupling, NO autoregulation [Esch et al. 2002c; Esch et al. 2006b;
Mahler et al. 2007; Mantione et al. 2008; Moles et al. 2004; Salamon et al.
2005; Stefano, 2000e; Stefano et al. 2001a; Stefano et al. 2003; Stefano et al.
2007a]. Oxytocin, vasopressin and even serotonin, as well
as some stress hormones (e.g., stress catecholamines),
work through this same positive behavioral and moti-
vational mechanism on stress reduction and health
gains [Breard et al. 2007; Chanrion et al. 2007; Esch et al. 2002d; Esch & Ste-
fano, 2005b; Stefano & Esch, 2005c; Stefano et al. 2008c; Salamon et al. 2005;
Umathe et al. 2009; Yu et al. 2008]. The underlying neurobiologi-
cal principle, though ‘deep, appears to be rather simple:
Experiences, activities and behaviors are constantly and
automatically self-evaluated for their health benefits
and stress reduction potential, i.e., stress relief (Fig.
5), and then rewarded by an autoregulatory release of
endogenous ‘pleasure molecules, subsequently enhanc-
ing the biological imprint and memory of the original
behavior as positive and beneficial (e.g., low stress, well-
ness), if given, yet again providing a positive or appeti-
tive motivation to repeat this behavior, at least after the
appetence for that specific activity has been restored
[Esch & Stefano, 2004c]. The down-side of this neurobiologi-
cal circuit is the possibility of addiction for extremely
rewarding activities and behaviors, i.e., motivational
toxicity [Esch & Stefano, 2004c; Mantione et al. 2008; Stefano et al. 2007a].
Importantly, these common signal molecule pathways,
i.e., DA, MO, work in a similar manner as found in
addiction influenced pathways, e.g., nicotine, alcohol,
cocaine [Stefano et al. 2007a].
Pleasurable behaviors can be highly stress-reducing
and/or -protective. This seems to be true for almost
every positive psychology or cognitive behavioral
intervention with the aim of improving health [Berridge
& Kringelbach, 2008; Esch & Stefano, 2004c; Esch et al. 2004b; Esch & Stefano,
2005b; Lee Duckworth et al. 2005; Siegel, 2009; Sin & Lyubomirsky, 2009],
including arts, creativity, and music (e.g., musical heal-
ing [Esch, 2003c; Esch, 2003e; Esch, 2009b]). The reason for this
common healing or stress therapeutic potential may be
that the said behaviors involve the same hardware, that
is, the brains limbic reward and pleasure pathways, for
realizing their beneficial effects [Berridge & Kringelbach, 2008].
In particular, frontal and prefrontal affective regions of
the brain are crucial for the positive validation of indi-
vidual experiences and the consecutive self-regulatory
stress reduction and reward, additionally, by decreas-
ing the amygdaloidal arousal and fearful resistance that
sometimes accompanies stressful encounters, or the
Figure 4: Stress and morphine
autoregulation. The general
neurobiological principle of
autoregulatory stress response
mechanisms, i.e., endogenous stress
management, is to terminate the
initial stress response and recover
the systems, i.e., secondary back-up;
references: [Cannon, 1914; Esch, 2008b; Esch
& Stefano, 2002e; Esch & Stefano, 2007b; Esch et al.
2002a; Esch et al. 2009a; Kream et al. 2009; McCarty
& Gold, 1996; Salamon et al. 2006; Stefano et al.
1995c; Stefano et al. 1996b; Stefano et al. 2005d].
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The neurobiology of stress management
emotional (hyper-) alertness that particularly comes
with unexpected stressful, unfamiliar behaviors or
situations [Esch, 2003d; Esch et al. 2002d; Salamon et al. 2005; Stefano
et al. 2008c]. The frontal parts of the brain and, accord-
ingly, the anterior limbic proportions (the orbitofron-
tal cortex, for example, or the dorsolateral prefrontal
regions) seem to stabilize positive mood, i.e., affectional
stress hardiness, resistance or affective resilience [Berridge
& Kringelbach, 2008; Davidson et al. 2003; Esch & Stefano, 2004c; Esch et al.
2004a; Esch et al. 2004b]. Other regions of critical importance
are the nucleus accumbens, anterior cingulate, the ven-
tral tegmental area, ventral pallidum, or parts of the
insular and brainstem [Berridge, 2003; Berridge & Kringelbach, 2008;
Esch & Stefano, 2004c; Esch et al. 2004b]. Many of these regions are
functionally and anatomically shared between humans
and other animals (Fig. 3 and 5), since the morphin-
ergic and dopaminergic mesostriatal, mesocortical and
especially the mesolimbic pathways and projections,
found in many species, link the different hedonic hot-
spots and motivation areas into an integrated reward
system [Berridge & Kringelbach, 2008; Esch & Stefano, 2004c; Kringelbach,
2005; Panksepp, 2007; Smith & Berridge, 2007; Stefano et al. 2001a].
Taken together, hedonic or pleasurable behaviors
are important ‘ingredients’ of medical SM interven-
tions (Fig. 1). Prima facie, they appear to be accidently
compiled and not behaviorally or even physiologi-
cally linked together, making them possibly appear
not forceful. However, they are clinically effective. We
surmise that this may be due to their common and
powerful neurobiological pathways for self-regulation
and self-efficacy, which underlie numerous health
behaviors. In the end, the stress-ameliorating potential
of these behaviors (that could even include spiritual
practices or engagement in connectedness rituals, etc.
Fig. 1) is related to their general pleasure and happi-
ness potential, which may turn off rational behaviors
that are dwelled on for longer than necessary periods
of time. This potential, and the neuroanatomical ‘hard-
ware behind it, is largely shared among the various
stress-reducing behaviors.
Exercise
Mens sana in corpore sano(a healthy mind in a healthy
body), or more precisely, orandum est, ut sit mens sana
in corpore sanoby Juvenal means that one has to beg
and care for a healthy body for that is the precondition
of a healthy mind and a balanced function of cogni-
tion, and possibly, vice versa. Thus, the idea of an inter-
connection between mind and body with reference to
health, cognition, and exercise is almost 2000 years
old. Physical activity, particularly aerobic exercise, can
improve a number of aspects of cognition and bodily
performance [Hillmann et al. 2008; Stroth et al. 2009; Voelcker-Rehage
et al. 2006]. Every dynamic physical activity, but not static
tasks or sedentary lifestyles, leads to a marked increase
of regional cerebral blood flow [Herholz et al. 1987; Hollmann &
Strueder, 1996; Hollmann & Strueder, 2000a; Hollmann & Strueder, 2000b].
Lack of physical activity, especially among children, is
a major cause of obesity and the early onset, and con-
secutive aggravation in adult life, of many diseases, e.g.,
cardiovascular or metabolic [Ben-Sefer, 2009; Hillmann et al.
2008]. However, there is substantial evidence mounting
up that suggests exercise not only to be highly recom-
mendable for keeping and enhancing physical health,
but also to improve academic and mental performance
running makes smart’ [Hillmann et al. 2008; Stroth et al. 2009; van
Praag et al. 2005; Voelcker-Rehage et al. 2006]. We suggest that this
effect may, in parts, be attributed to the endogenous
stress reduction and protection potential, and a related
neurobiological involvement of limbic portions of the
brain as well as the underlying molecular pathways,
already displayed above. Within this section, we further
scrutinize this hypothesis.
Physical activity is a lifestyle factor that leads to
increased health and stress hardiness throughout life
[Erickson & Kramer, 2008; Esch, 2002f; Hillmann et al. 2008; Hollmann &
Strueder, 1996; Hollmann & Strueder, 2000a; Hollmann & Strueder, 2000b;
Voelcker-Rehage et al. 2006]. It’s good to start early and not give
up this practice while growing up. However, even the
physical and mental decline of the elderly is not com-
pletely inherent or predestined, only reliant on genes
Figure 5: The neurobiology of
stress management – behavioral
adjustments. In addition to molecular
changes during the stress/stress
management cycle of autoregulation,
behavioral adjustments are conducted,
then eventually evaluated and
finally learned (e.g., memorized via
hippocampal/limbic activity in the
brain), when regarded as beneficial.
This molecular-behavioral interaction
marks the integration of cognitive
behavioral changes as the final result
of a physiological stress cascade;
references: [Esch & Stefano, 2004c; Esch & Stefano,
2007b; Esch et al. 2004b; Esch et al. 2009a; McEwen,
2009; Negrao et al. 2000; Sapolsky, 2003; Stefano &
Kream, 2008a; Stefano et al. 2005a; Sterling & Eyer,
1988].
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Tobias Esch, George B. Stefano
or fate, but instead, partly reversible. Yet, these age-
dependent processes can be delayed, some prevented,
compensated, or even reversed, ‘justby starting to get
active again, during old age [Erickson & Kramer, 2008; Hollmann
& Strueder, 2000b; Lazar et al. 2005; van Praag et al. 2005; Voelcker-Rehage et
al. 2006]. The critical aspect for this potential is the life-
long ability of the brain to adjust and adapt, actually on
the molecular level, and this capacity can be trained,
i.e., neuroplasticity [Lazar et al. 2005; Voelcker-Rehage et al. 2006].
A very capable training stimulus therefore seems to be
mild and manageable mental stimulation, e.g., stress or
SM, or mild aerobic exercise [Erickson & Kramer, 2008; Hollmann
& Strueder, 1996; Hollmann & Strueder, 2000b; Lazar et al. 2005; van Praag et
al. 2005]. This neuroplastic effect of exercise therapy also
works with stroke patients, demonstrating it as an effec-
tive life strategy [Gertz et al. 2006; Wolf et al. 2006].
Appropriate lifestyle or purposeful activity interven-
tions can positively influence the reserve capacity of
aging humans and the aging process itself, particularly
with regard to physiological development, cognitive
performance, longevity, as well as the onset and course
of chronic diseases [Hollmann & Strueder, 2000a; Voelcker-Rehage
et al. 2006]. Cognitive development and state are plastic,
i.e., flexible, facilitated by positive behaviors (see above)
and activity, cognitive as well as physical [Voelcker-Rehage
et al. 2006]. Clearly, body and mind are interconnected
[Esch, 2008a; Hollmann & Strueder, 2000b]. For using this capac-
ity, it is important to train cognitive and physical flex-
ibility, likewise, which seems to be true for SM as well
[Esch, 2003d; Stefano et al. 2005a; Stroth et al. 2009; van Donkelaar et al.
2009]. However, the effect of physical activity on cogni-
tive function, particularly – but not exclusively – in the
elderly, turns up to be eminently impressive [Erickson &
Kramer, 2008; Voelcker-Rehage et al. 2006; van Praag et al. 2005].
Physical exercise improves learning. Obviously, this
effect is based upon the enhancement of neurogenesis
in the hippocampus through bodily activity, a brain
area critical for learning and memory, particularly with
regard to the declarative long-term memory, and it is
part of the limbic brain [Esch et al. 2002d; Pollak et al. 2008; van
Praag et al. 2005; van Praag et al. 2008]. Clearly, there exists a posi-
tive neurobiological correlation between running and
neurogenesis [van Praag et al. 2008]. Interestingly, the hip-
pocampus is also extremely sensitive to stress, since
psychosocial or mental stress, in particular, tend to dete-
riorate neurons in the hippocampus, leading to acceler-
ated neurodegeneration and possibly dementia [Esch et al.
2002d; Guarna et al. 2004; McEwen, 2001]. As with stress, aging causes hippo-
campal decline [van Praag et al. 2005]. This negative effect of stress
and aging is potentially counteracted by exercise.
In fact, stress has a direct impact upon the production/
release of brain-derived neurotrophic factor (BDNF),
which itself is strongly linked to the serotonin system
and plays an essential role in mood and memory pro-
cesses [Pollak et al. 2008; van Donkelaar et al. 2009]. More precisely,
stress decreases BDNF levels, particularly in the pre-
frontal cortex where the working memory is located [van
Donkelaar et al. 2009]. Moreover, brain tryptophan levels and
serotonin metabolism correlated positively with BDNF
in both prefrontal cortex and hippocampus in a recent
stress-brain-neurobiology study, again highlighting the
close interconnection and commonality between the
underlying signalling systems [van Donkelaar et al. 2009]. This
appears to be also true for the stress-memory-opioid/
opiate/endogenous MO connection (see below, and
[Esch et al. 2002d; Guarna et al. 2004]), although a rather complex
matter and not fully understood yet.
Stress alters memory performance, and MO inter-
acts with this phenomenon, be it as a primary target
of stress-related memory alteration or, supposedly, as a
secondary back-up player, i.e., autoregulation, follow-
ing a stress-related ‘narrowing’ of the memory focus
and attention concentration with the putative goal of
deleting every memory input that, in the moment of
fight or flight (acute stress), would negatively inter-
fere and not serve the hoped for positive outcome for
the fighting individual: while stressed, new or other
working memory contents are badly learned, that is,
acquired and consolidated [Esch et al. 2002d; Guarna et al. 2004;
Pollak et al. 2008]. However, it seems to be biologically essen-
tial to keep the ‘idea’ of a successful strategy that helped
to fight the stressor in mind, and somehow accessible
afterwards, so that after the fight is over, this success-
ful strategy can become endogenously evaluated and,
if positive, memorized (learned). MO seems to play a
critical role in this process, for example, as a recovery or
secondary back-up molecule (Fig. 4 and 6).
As stated above, exercise enhances learning, func-
tion and neurogenesis in the hippocampus and the
prefrontal cortex, e.g., via BDNF, and this cascade is
negatively influenced by stress [Erickson & Kramer, 2008; McEwen,
2001; Pollak et a., 2008; van Donkelaar et al. 2009; van Praag, 2008]. In fact,
stress and physical activity are counter players [Esch, 2002f;
Esch et al. 2003b; McEwen, 1998; McEwen, 2008; Sapolsky, 2004; Stefano et
al. 2005a], and stress reduction through exercise not only
improves memory functions, hippocampal neurogen-
esis and BDNF levels, but also mood, quality of life, and
overall well-being [Boecker et al. 2008; Esch, 2002f; Esch & Stefano,
2004c; Esch et al. 2002d; Esch et al. 2004b; Pollak et al. 2008]. However,
this seems to apply only to moderate exercise, since
prolonged and strenuous physical activity, for example,
can itself cause stress and proinflammation [Esch & Stefano,
2002e; Esch et al. 2002c; Hollmann & Strueder, 2000b; Rojas Vega et al. 2006b;
Rojas Vega et al. 2006a; Stefano et al. 2001c].
Besides the prefrontal or orbitofrontal and hippo-
campal areas of the brain, there are other regions that
also seem to be of importance in the neurobiological
SM-exercise-cognition relationship, e.g., temporal
cortex, bilateral insula and parainsular cortex, as well
as temporoparietal regions, the amygdala and anterior
cingulate, yet again suggesting region-specific effects
in frontolimbic brain areas that are also involved in the
processing of affective states and mood [Boecker et al. 2008;
Erickson & Kramer, 2008; Hollmann & Strueder, 2000a; Pollak et al. 2008].
Hence, stress reduction, e.g., through exercise, has been
shown to involve serotoninergic, and especially dopa-
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The neurobiology of stress management
minergic and neuropeptidergic signalling in the associ-
ated brain regions [Pollak et al. 2008; Stroth et al. 2009].
DA, for example, seems to be of particular interest here
for spatial memory, concentration and positive mood,
as well as for the general effectiveness of the brain per-
formance, or the reestablishment and safekeeping of a
normal brain function in the course, e.g., of exhausting
(cognitive) tasks [Stroth et al. 2009]. Thus, DA-enhancing
exercises and activities appear to be suitable means to
balance stress on the neurobiological level. Moreover,
these various signalling molecules have to be finely
tuned in challenging tasks, especially while prolonged
or enduring, as suggested in Fig. 6.
The chronology and sequence of stress or stress-
reducing hormone and neurotransmitter release during
exercise not only depends on the actual point in time of
the release, but also on the concentration and half-life,
i.e., kinetic pattern, of the hormone into question. For
example, BDNF and cortisol differ in that they both are
produced, elevated through rampant or strenuous and
exhausting exercise, however, BDNF returns to base
levels instantly after the exercise challenge is over, while
cortisol recovers slower [Rojas Vega et al. 2006b]. Further-
more, the type of exercise is essential, as noted before,
with aerobic and moderate exercise being optimally
suited, in fact crucial, for molecular stress reduction
and health (Fig. 1; also see [Hollmann & Strueder, 2000a; Hollmann
& Strueder, 2000b; Stefano et al. 2001c; Stroth et al. 2009]).
Long-term exercise, such as distant running, can
lead to an euphoric state that is sometimes called ‘run-
ner’s high’ (Fig. 6), enabling the runner to proceed with
the task, though exhausting. The neurochemical cor-
relates of this exercise-induced positive mood change
critically build on opioidergic mechanisms in the
brain, that is, opioid receptor activation, preferentially
in prefrontal and limbic or paralimbic brain structures
[Boecker et al. 2008]. The runners high phenomenon is an
obvious result of autoregulatory opioid signalling. The
opioid peptides (endorphins) beta-endorphin and Met-
enkephalin with its precursor proenkephalin originate
from the anterior pituitary, where proopiomelanocor-
tin (POMC) is produced, again showing the connec-
tion between this signalling system and the central
stress axes, as illustrated. Interestingly, prolactin is
also enhanced during and post-exercise, however, this
latter hormone is a partial DA inhibitor that comes
consecutively (i.e., delayed) after DA release in the
stress-exercise sequence was initiated [Rojas Vega et al. 2006a],
comparable to the endorphins (Fig. 6). Prolactin also
originates from the anterior pituitary. The more pro-
lactin builds up in an exercise, e.g., sexual activity, the
deeper the relaxation and satisfaction later [Rojas Vega et al.
2006a], comparable to the postulated DA-MO sequence
(Fig. 6 and [Esch & Stefano, 2005a; Esch & Stefano, 2005b; Stefano &
Esch, 2005c; Stefano et al. 2007a]). In other words, the greater
the stress (in combination with physical activity and
exhaustion), the deeper the relief and relaxation, i.e.,
endogenous stress reduction and reward (the ‘I did it
component), when successfully solving and overcom-
ing the stressful challenge.
Finally, since DA, endocannabinoids and MO (and
even serotonin see above) exert their effects, in part,
via NO release, it is not surprising to find substantial
constitutive NO activity in exercise [Gertz et al. 2006; Mantione
et al. 2007; Stefano et al. 2001c]. We surmise that this potentially
protective neurobiological signalling molecule plays the
role of an effector for many of the observed phenomena
of autoregulation (Fig. 7). For example, positive results
with exercise therapy in stroke patients are abolished by
the inhibition of NO signalling [Gertz et al. 2006]. Moreover,
Figure 6: The neurobiology of
stress management – running
a marathon. Occurrence of
autoregulatory signalling
molecules over time in enduring
and challenging tasks, including
a subsequent recovery phase,
where the system regenerates
and the benefits of a successful
‘fight or flight are imprinted
and actually gained; speculative,
schematic draft: time/period
around a planned marathon
run; references: [Berridge & Robinson,
1998; Boecker et al. 2008; Breard et al. 2007;
Chanrion et al. 2007; Charmandari et al. 2005;
Esch, 2005c; Esch & Stefano, 2007b; Esch et
al. 2006b; Hillmann et al. 2008; Hollmann &
Strueder, 2000a; Hollmann & Strueder, 2000b;
Mantione et al. 2007; Meyer et al. 2001; Neri
et al. 2008; Pollak et al. 2008; Sapolsky, 2004;
Stefano et al. 2003; Stefano et al. 2005a; Stroth
et al. 2009; van Praag et al. 2008].
30
Copyright © 2010 Neuroendocrinology Letters ISSN 0172–780X www.nel.edu
Tobias Esch, George B. Stefano
NO counteracts NE, that is, cellular stress, on the neu-
ronal level, thereby explaining a self-regulatory anti-
stress capacity of NO-enhancing activities [Esch et al. 2002c;
Esch et al. 2003a; Stefano et al. 2001a]. Taken together, we hypoth-
esize that exercise induces autoregulatory stress reduc-
tion via limbic pleasure and reward pathways, using,
at least in parts, the same neurobiological components
like other SM tools. Positive activities and cognitive
behaviors (‘thoughts’) as well as moderate physical
exercises neurobiologically project on the hypothala-
mus and the pituitary gland, i.e., the central stress axes,
via prefrontal/frontolimbic pathways, thereby inducing
a central vegetative stress reduction, making it possible
to mentally (i.e., self-regulatory, deliberately) influence
stress and autonomous functions throughout the body,
e.g., mind-body medicine. Stress hormones, includ-
ing NE, cortisol and CRH, get reduced, or their effects
antagonized on the receptor level, while DA, opioids
and opiates are endogenously enhanced, that is, their
signalling systems initiated. Serotonin and DA improve
physical endurance capacities and stress hardiness, as
do the endorphins, subsequently, with endogenous MO
presumably playing a role in the recovery phase of stress
and/or strenuous exercise. The latter substances also
improve mood and pain resistance, two critical features
of a successful stress autoregulation. All these effects are
potentially plastic, that is, learnable and modifiable.
Relaxation
We explicitly reported on the neurobiology of relax-
ation, i.e., the relaxation response (RR), a state of physi-
ological hypoarousal opposite to the stress response,
elsewhere, particularly with regard to a DA and MO
involvement, coupled to NO signalling (e.g., see [Dusek
et al. 2006; Esch & Stefano, 2007b; Esch et al. 2003b; Esch et al. 2004a; Esch
et al. 2004b; Mantione et al. 2007; Mantione et al. 2008; Salamon et al. 2006;
Stefano & Esch, 2005b; Stefano et al. 2001a; Stefano et al. 2005a; Stefano et al.
2006, Stefano et al. 2007]). However, the critical facts for our
hypothesis of an overlapping neurobiological principle
for SM processes and autoregulation, including relax-
ation, are these: constitutive NO signalling is critical in
relaxation [Esch et al. 2002c; Salamon et al. 2006; Stefano & Esch, 2005b;
Stefano et al. 2000d; Stefano et al. 2005a; Stefano et al. 2006]. When the
enzyme constitutive NO synthase (cNOS) is stimulated,
e.g., by relaxation induction, NO release occurs for a
short period of time, but this level of NO can exert pro-
found physiological actions for a longer period of time
[de la Torre & Stefano, 2000; Stefano et al. 2000c; Stefano et al. 2000d]. NO
is not only an immune, vascular and neural signalling
molecule, it is also antibacterial, antiviral, scavenges
free radicals, and it down-regulates endothelial and
immunocyte activation and adherence, thus perform-
ing vital physiological activities, including vasodilation,
i.e., blood pressure reduction [Benz, 2002a; Benz, 2002b; Esch et al.
2002c; Esch et al. 2003a; Esch et al. 2003b; Stefano, 1999; Stefano et al. 2000d;
Stefano et al. 2006]. Hence, NO plays the role of an effec-
tor of autoregulation. Novel opiate selective mu opiate
receptor subtypes, namely Mu3 (and Mu4), stimulate
cNOS-derived NO release by MO, thus resulting in the
down-regulation of immune, vascular, gut and neural
tissues [Bilfinger & Stefano, 2000; Liu et al. 1996; Magazine et al. 1996; Man-
tione et al. 2008; Kream & Stefano, 2009b; Stefano & Kream, 2009c; Stefano et
al. 2000a; Stefano et al. 2004; Stefano et al. 1995b; Stefano et al. 2009b].
Individuals who are relaxing experience peripheral
vasodilation, warming of the skin, a decrease in heart
rate and an overwhelming sense of well-being only
when this can occur in a safe and trusted environment.
Counter-intuitively, there may be initial sympathetic
activation in relaxation, i.e., anticipatory stress response
[Stefano et al. 2008c], as noted by NE levels, which initially
go up [Hoffman et al. 1982]. This further appears to be the
case for falling in love and enjoying similar, pleasurable
experiences, since this does, for example, represent the
risk of rejection [Dusek et al. 2008b; Esch & Stefano, 2004c; Marazziti &
Cassano, 2003; Marazziti & Canale, 2004]. Also, it seems appropri-
ate to screenthe environment by enhanced vigilance
and alertness before relaxing, making it safe to slow-
down and focus inwards, introversively. With reference
to the vasodilator peripheral heat-warming processes,
we surmise that this involves NO [Stefano et al. 2001a]. In
regard to the sense of well-being, we can assume that
this process may also involve opioid and opiate receptor
activation by corresponding signalling molecules [Esch &
Stefano, 2004c].
NO has the ability to block a sympathetic response
simply by having its release occur beyond the basal level,
which will lead to vasodilation and peripheral sense of
warmth. Moreover, NO blocks NE effects on the recep-
tor level [Esch et al. 2006b; Stefano et al. 2001a; Stefano et al. 2003]. Its
presence can also explain the paradox of the presence
of NE in plasma while vasodilation is taking place [Hoff-
man et al. 1982]. Recently, we demonstrated that during
the RR NO levels are increased [Dusek et al. 2006; Mantione et
al. 2007], i.e., NO release, further supporting the critical
role of NO in this process. Additionally, endogenous
MO signalling appears to play a role in relaxation: Many
immune processes perpetuate and become embellished
with time by the recruitment of cells, and through ben-
eficial yet sometimes harmful signalling molecules such
as the proinflammatory cytokines [Esch & Stefano, 2002e; Esch
et al. 2002a; Esch et al. 2002c; Esch et al. 2003a; Stefano & Esch, 2005b].
These molecules can all be down-regulated by MO,
which is released following stress or trauma [Stefano et al.
1996b; Stefano et al. 2000d], i.e., autoregulation, specifically via
cNOS-derived NO under certain circumstances. Thus,
MO may help overcome over-stimulated immune, vas-
cular and neural tissues [Stefano et al. 2000d; Stefano et al. 2005d;
Zhu et al. 2005a], particularly in stress, as well as maintain a
basal level of microenvironmental inhibition, prevent-
ing inappropriate excitation from emerging [Stefano et al.
2000c]. Prior to NO release, this process also invokes the
release of NE and opioid peptides.
Relaxation can be cognitively learned, that is, active
induction of the RR [Baron Short et al. 2007; Esch et al. 2002a; Esch
et al. 2002b; Esch et al. 2002d; Stefano et al. 2005a]. This potential is
always endogenously (constitutively) present, and only
31
Neuroendocrinology Letters Vol. 31 No. 1 2010 Article available online: http://node.nel.edu
The neurobiology of stress management
after removing the sympathetic or stress reactions (dis-
inhibition [Stefano et al. 2000a]), does it emerge. It is probably
a critical process that provides for mammalian stress
resistance and longevity, i.e., it is antibiosenescent. The
underlying physiology is, to some extent, similar to
the placebo response since this too involves the brains
neurobiological reward and motivation circuitries and
the very same molecular effectors [Baron Short et al. 2007; de la
Fuente-Fernández et al. 2001; de la Fuente-Fernández et al. 2006; Fricchione &
Stefano, 2005; Fulda & Wetter, 2008; Sher, 2003; Stefano et al. 2001a; Stefano
et al. 2007a]. Relaxation-associated NO possibly indicates
a coupling to endogenous DA and MO release, since
MO, at least in parts, originates from DA through enzy-
matic processing as noted earlier [Dusek et al. 2006; Kream &
Stefano, 2009b; Mantione et al. 2007; Stefano & Kream, 2009c; Stefano et al.
2001a; Stefano et al. 2005d; Stefano et al. 2007a; Zhu et al. 2005b]. Further-
more, relaxation or meditation practices are capable of
slowing-down and decrease the overall brain metabo-
lism, while specific regional parts, e.g., necessary for
autonomous control, attention and concentration, get
activated [Khalsa et al. 2009; Lazar et al. 2000; Newberg et al. 2001].
For example, regular meditation potentially enhances
mood and affect by inducing a left-anterior lateraliza-
tion of brain activity [Davidson et al. 2003]. Thus, relaxation,
meditation and other spiritual practices that incor-
porate some sort of relaxation exercise seem to make
the brain work more effectively, in parts, by improving
neurobiological plasticity, functional resilience and
flexibility, which also includes stress resistance [Davidson
et al. 2003; Esch et al. 2004a; Esch et al. 2004b; Lazar et al. 2005]. This abil-
ity may also represent a critical evolutionary advantage
[Esch, 1999; Esch, 2003d; Rossano, 2007]. Central to our hypothesis
is the significance of NE, NO, DA and MO signalling
in stress and stress autoregulation, including relaxation,
both in the central and peripheral nervous system. We
find that NO and MO control catecholamine processes
on many levels, including synthesis, release and actions.
NO appears to be the physiological converging point of
these said actions [Kream et al. 2007; Kream et al. 2009a; Mantione et al.
2008; Stefano & Kream, 2009c; Stefano & Kream, 2007b].
Nutrition
Food intake is an essential human activity and can
truly be a source of pleasant feelings or sensations,
and stress-reducing, at times, unfortunately’ [Esch & Ste-
fano, 2004c; Esch et al. 2006a]. This vital biological process is
regulated by homeostatic and hedonic systems in the
brain, i.e., limbic reward and motivation circuitries [Ste-
fano & Esch, 2005b; Esch et al. 2004b; Esch et al. 2006a; Kringelbach, 2004].
Positive or appetitive motivation is mediated by neuro-
chemical systems, e.g., within the nucleus accumbens.
Hence, gamma-aminobutyric acid (GABAergic) neu-
rons localized in the accumbens shell directly influence
hypothalamic effector mechanisms for feeding motor
patterns, yet they dont participate in the execution of
more complex food seeking strategies and behaviors
[Kelley et al. 2005]. Opioidergic neurons, i.e., opioid recep-
tor positive (agonistic) neurons, distributed throughout
the nucleus accumbens and caudate-putamen mediate
the hedonic impact of palatable foods (high sugar, high
fat), and these neurons are under modulatory control
of striatal cholinergic interneurons [Esch et al. 2006a; Kelley et
al. 2005]. Opiate alkaloids (e.g., MO) and opioid peptides
(e.g., enkephalin) seem to differ in their ability to act
on nucleus accumbens autoregulation related to palat-
ability and taste [Esch et al. 2006a]. In particular, mu opioid
receptors in the medial shell of the nucleus accum-
bens appear to critically regulate the hedonic impact,
i.e., ‘liking, of sweetness, food and drug rewards [Esch &
Stefano, 2004c; Esch et al. 2004b; Pecina & Berridge, 2005]. Thus, with
regard to the nucleus accumbens, there appears to be a
specific locus responsible for opioidergic amplification
of hedonic impact related to eating/tasting. However,
recent experiments reveal a distinction between opioid
mechanisms for actual food intake and its hedonic
impact [Pecina & Berridge, 2005].
Pleasurable experiences like eating exert calming
effects via release of GABA in the amygdala and other
limbic areas: ‘plenus venter non studet libenter’ – a full
stomach doesn’t like to study, or get stressed [Campbell,
1999; Esch et al. 2004a; Esch et al. 2006a]. Thus, on the neuro-
biological level, pleasure involves autoregulatory sub-
stances that possess calming and anxiolytic capacities,
including GABA or oxytocin, thereby facilitating feel-
ings of well-being and relaxation [Esch & Stefano, 2004c; Esch &
Stefano, 2005b; Esch & Stefano, 2005a; Esch et al. 2004a; Esch et al. 2004b; Ste-
fano & Esch, 2005c; Stefano et al. 2008c]. Endogenous MO, as illus-
trated, acts as a central and peripheral down-regulator,
primary or secondary (i.e., back-up), and its involve-
ment in the neurobiological down-regulation associ-
ated with food and eating behaviors can be assumed
[Esch et al. 2006a]. Even more, MO may play a direct and
specific role in the pleasure-related signalling associ-
ated with eating. MO thereby seems to enhance feeding
(i.e., hunger and subsequent food intake) by increas-
ing the hedonic palatability and pleasantness of food,
e.g., taste [Doyle et al. 1993; Esch et al. 2006a; Pecina & Berridge, 1995].
Yet, enhancement of food palatability may represent a
critical psychological pathway by which opioid agonists
generally induce feeding, i.e., food intake. In fact, such
agonists, for example those selective for the Mu3 and 4
receptors (i.e., opiate alkaloids/endogenous MO [Esch et
al. 2006a; Kelley et al. 2002]), induce a potent increase in food,
sucrose, saccharin, salt, and ethanol intake [Kelley et al.
2002]. This general self-regulatory brain mechanism was
beneficial during evolution for it ensured the consump-
tion of relatively scarce high-energy food sources [Esch et
al. 2006a; Kelley et al. 2002]. Besides MO being found in limbic
tissues and the ventral tegmental area (VTA) of the
brain, it has been localized and coupled to DA signal-
ling in recent times as a MO precursor [Mantione et al. 2008;
Stefano et al. 2007a; Stefano et al. 2008b; Zhu et al. 2005a; Zhu et al. 2005b].
Given the close connection between endogenous DA
and MO biosynthesis, a reward-dependent behavioral
motivation to eat (i.e., appetite) and the actual food-
intake are closely related to DA-MO autoregulation
32
Copyright © 2010 Neuroendocrinology Letters ISSN 0172–780X www.nel.edu
Tobias Esch, George B. Stefano
[Esch & Stefano, 2004c; Esch et al. 2006a; Stefano et al. 2007a]. As noted
earlier, MO via NO release can down-regulate energy
metabolism at the mitochondrial level, complementing
its actions on food intake [Kream & Stefano, 2009b].
Obese individuals seem to suffer a serotonergic and
dopaminergic deficit, e.g., in the midbrain or hypo-
thalamus (e.g., [Tomasi et al. 2009]), and they additionally
show lower activation of the amygdala as a signal of a
full stomach, that is, an impaired control of food intake
(reduced aversion against further ingestion), during
eating [Tomasi et al. 2009]. Thus, they eat more and don’t feel
full or receive the pleasure from it. On the other hand,
hedonic taste reactions are enhanced in MO-treated
more ‘hungry’ animals [Esch et al. 2006a]. Aversive food
reactions remained unchanged, pointing towards a spe-
cific pleasure-relatedness of MO signalling in associa-
tion with eating. Taken together, MO seems to enhance
feeding by increasing the pleasantness of food, which in
return reduces stress (see below).
The hedonic capacity of food is responsive to stress.
Innate neurobiological feedback mechanisms may, this
time, lead to a psychological trap, besides the imme-
diate stress relief or ease coming with eating: Stress,
and chronic stress in particular, leads to elevated glu-
cocorticoid levels in the blood, e.g., cortisol increase,
since these molecules are part of the stress physiol-
ogy (stress hormones) [Esch et al. 2002a; Esch et al. 2002b; Esch et
al. 2002d]. Corticoids exert their functions throughout
the body, including the central nervous system (CNS),
while easily passing the blood-brain-barrier. Together
with insulin, glucocorticoids stimulate a drive for and
ingestion of comfort foods, food that may directly result
in a reduction of CNS stress effects, e.g., in the nucleus
accumbens, through stimulation of the anterior, more
pleasure-related and -stimulated part of this cell group,
thus reducing the impact of the pain- or stress-stimu-
lated, more defensive posterior part: by involving the
pleasure potential of food, eating can be a neurobio-
logical and vital source of stress reduction [Dallmann et al.
2005; Esch & Stefano, 2004c; Esch et al. 2006a]. However, the shift
in caloric intake from simple maintenance foods to a
preference for pleasure-inducingcomfort foods (high
caloric, high fat and/or sugar, low fibre: ‘fast food’)
during chronic stress, e.g., to better cope (i.e., fight or
flight) and then endogenously reduce the initial stress,
together with elevated stress hormones and insulin
during these stress processes, may lead to an overall
elevated energy uptake and reorganization of energy
stores from a peripheral to a more central distribu-
tion, primarily as abdominal fat, which consequently
imposes a health threat itself, i.e., as a result of chronic
stress and the autoregulatory SM attempts: what is good
in the short run can become deleterious in the long, or
too much is too much[Dallmann et al. 2005; Esch et al. 2006a].
This caloric shift appears to reduce the influence of the
chronic stress network on behaviors, autonomic and
neuroendocrine outflow [Dallmann et al. 2005], yet advanta-
geous food capacities to reduce stress may over time be
Figure 7: The common neurobiology of different stress management approaches and healing practices. Different
stress-reducing techniques and practices act via autoregulatory central nervous system (CNS) reward and motivation
circuitries, i.e., they share some parts of their physiology. We surmise that this commonality represents an overlapping
and general (neuro-) biological principle of autoregulation, that is, a self-healing potential. Imbedded in these systems
are various underlying signalling pathways and effector molecules with which the stress management techniques exert
their beneficial results. Many of these signalling mechanisms converge on nitric oxide (NO) as their central and common
effector, i.e., second or third messenger. Thus, NO is critically coupled to the reward physiology and stress self-regulation,
and it can be found and experimentally measured in these very techniques; references: [Berridge & Kringelbach, 2008; Esch, 2008a; Esch
& Stefano, 2004c; Esch & Stefano, 2005b; Esch & Stefano, 2007b; Esch et al. 2004a; Esch et al. 2004b; Esch et al. 2006b; Fricchione & Stefano, 2005; Kream & Stefano, 2009b;
Stefano & Esch, 2005b; Stefano et al. 2003; Stefano et al. 2006; Stefano et al. 2007a].
33
Neuroendocrinology Letters Vol. 31 No. 1 2010 Article available online: http://node.nel.edu
The neurobiology of stress management
far outweighed by the consequences of a presumably
unhealthy fat distribution and elevated blood fat levels,
e.g., in chronic stress [Esch et al. 2002b; Esch et al. 2006a; Stefano et
al. 2005a]. However, dieting as a strategy to reduce body
weight often fails as it causes food cravings, leading to
“bingeing” and weight regain, possibly not only involv-
ing DA but also opiate/opioid regulation [Esch et al. 2006a].
Also, stress resistance and mood may be lowered by
chronic fasting [Esch et al. 2006a].
Taking in and digesting’ negative information can
also interfere with appetite and taste. In other words,
the hedonic capacity of food is responsive to acute
stress and depressive mood swings [Willner & Healy, 1994].
When our mood is low, we seek pleasure, i.e., reward,
self-therapy, as long as biological flexibility, autoregula-
tion and drive still exist [Esch, 2003d; Esch & Stefano, 2004c; Esch et
al. 2004b]. The subsequent neurotransmitter boost, possi-
bly involving serotonin, DA and opioid agonist or MO
signalling, may stimulate or involve food intake as a
supplement’ for low mood swings and thereby, instead
of solving the problem, possibly kicking off a vicious
circle [Esch & Stefano, 2004c; Esch et al. 2006a]. Yes, eating may
buffer against stress, but eating more as a consequence
of chronic stress or depressive episodes may facilitate
overweight which could then increase frustration or
diminish positive and more effective coping strategies
and behavioral problem solving, i.e., appetitive moti-
vation and health promotion [Esch, 2003d; Esch, 2008a; Esch &
Stefano, 2004c; Esch et al. 2006a; Esch et al. 2006b].
Taken together, food intake is an essential biological
activity. Because it is so important, nature has linked
eating to appetitive behavioral motivation, enhanced
motor activity and its underlying neurobiology, includ-
ing pleasure and reward processes [Stefano & Kream, 2007b].
These autoregulatory pathways are located within the
brain, e.g., limbic system, orbitofrontal/frontobasal
structures, nucleus accumbens, VTA etc., and they pro-
mote feelings of wellness and pleasure [Esch & Stefano, 2004c;
Esch et al. 2006a]. In this way, the process of eating itself can
be healthy, e.g., stress reduction via pleasure induction.
Not only what we eat matters, but particularly how we
actually realize it. Palatability, taste, and pleasantness
of food as well as the mindful act of smelling, feeling,
tasting are of major importance, and some of these
functions are critically self-regulated [Ernst et al. 2009; Esch
et al. 2006a]. Thus, all that we like about eating is part of
this important and general hedonic motivational cou-
pled motor system. Pleasure and eating use the same
neurobiological pathways as other hedonic activities,
e.g., love, positive psychology, relaxation, exercise etc.
(Fig. 7), and all these experiences have the capacity to
bring us joy, health and wellness, particularly through
physiological stress reduction, thereby involving the
very same effector systems, such as DA, MO, and the
coupled NO signalling.
D
S
tress is natural and can be helpful. Stress at appro-
priate levels, for example, can improve problem
solving and cognitive function [Huether et al. 1999;
Stefano et al. 2005a; van Praag et al. 2008]. It may act as a trigger
for adaptive modifications, e.g., of the structure and the
function of the brain, and thus serve to adjust, in a self-
optimizing and autoregulative manner, the behavior of
an individual to the ever-changing requirements of its
external world and environments [Esch, 2003d; Huether et al.
1999; Huether, 1996; McEwen, 2009]. In this regard, stress offers
organisms a positive coping strategy, enabling the
organism, so endowed, a greater chance of survival. In
part, this explains why many of the stress components
found at the cellular, tissue and organismic levels in
protists, invertebrates and vertebrates have been pre-
served during the long course of evolution.
Stress can, however, have deleterious effects in all
organisms, and these are related to the dose, form and
duration of stress and its underlying (patho-) physiol-
ogy [Esch et al. 2002a; Esch et al. 2002b; Esch et al. 2002d; Huether et al.
1999; Sachsse et al. 2002; Stefano et al. 2005a]. Accordingly, stress
reduction/termination is an innate protection poten-
tial to ameliorate stress and counteract its dangerous
downside. Hence, SM is natural too, but it has to be
physiologically ‘permitted. The underlying autoregula-
tion involved in stress and SM manifestations shows a
neurobiological overlap (while not denying the specific
parts and shares of SM approaches) pointing towards a
more general neurobiological/life-sustaining principle,
i.e., unspecific or common effects [Esch et al. 2004b; McEwen,
2001; McEwen, 2009]. In this, endogenous SM response path-
ways consist of the same ‘hardwareand chemical mes-
sengers as, for example, the placebo response, namely
the CNS motivation, motor and reward pathways,
located predominantly in the limbic brain [Esch & Stefano,
2004c; McEwen, 2001; McEwen, 2009; Stefano et al. 2001a].
The basic truth appears to be that natural or biologi-
cal and positive activities, i.e., comforting or ‘wellness
interventions in cognitive and higher noncognitive
organisms, serve the goal of survival, appetitive motiva-
tion and health for the individual and the species. These
so endowed organisms are rewarded by an overlapping
pleasure physiology (Fig. 7). The active use of such
self-regulatory potentials may be principally possible,
learnable and trainable, e.g., individually by the use of
mind/body or cognitive behavioral SM techniques [Esch,
2008a; Esch & Stefano, 2007b; Komaroff, 2001], yet these activities
and complementary medicalinterventions (e.g., [Ernst et
al. 2008; Ernst et al. 2009; Esch et al. 2004b; Esch et al. 2007a; Stefano & Esch,
2005b]) via their physiological effects are unconsciously
and automatically self-activated during stress to reduce
it. When used intentionally, we surmise, these activities
may buffer against stress or prevent negative side effects
of it, i.e., chronic stress [Esch, 2002f; Esch, 2003d; Esch, 2008a; Esch
& Stefano, 2007b]. We further speculate that, based on this
34
Copyright © 2010 Neuroendocrinology Letters ISSN 0172–780X www.nel.edu
Tobias Esch, George B. Stefano
knowledge, a novel medical strategy for health, includ-
ing longevity, is at hand.
Nature, as it seems, selected only a handful of
molecular key ‘messenger’ players, many converging
on constitutive NO as their crucial messenger, to trans-
late the stress-reducing potential into the mind and the
body phenomenon [Esch & Stefano, 2007b; Esch et al. 2002c; Esch et
al. 2003a; Stefano & Esch, 2005b]. In part, the building blocks of
these common messengers may be based on their high
level of availability in early life/evolution, i.e., tyrosine,
arginine [Stefano & Kream, 2007b; Stefano & Kream, 2009c]. Hence,
endogenous MO might serve as a central signalling
molecule to realize the necessary down-regulation
following stressful activities and encounters as well as
maintain cell processes in a state of down regulation
whereby they discriminate against excitatory noise.
This hypothesis is supported by the fact that plants
make DA but do not use it as a signal molecule [Stefano &
Kream, 2007b].
Professional SM training, as well as the endogenously
activated intrinsic mechanisms to self-reduce stress (that
possibly can be amplified or conditioned by SM train-
ing), use a broad array of different ways and tools to act
on the neurobiological effector systems and pathways.
Although subsequently converging, physiologically, the
approaches come/start from different sides: SM acts
via strong and broad biological pathways (‘highways’),
consisting, for example, of positive behaviors, exercise,
relaxation, or nutrition (BERN see Fig. 1), includ-
ing social support and spirituality. Because the limbic
system is the critical region in the brain for the neuro-
biological realization of the SM potential, memory pro-
cesses (e.g., hippocampus) and anxiety reduction (e.g.,
amygdala) are coupled to the SM physiology, making
the individual overcome rational hesitance or cogni-
tive dwelling (‘cognitive constipation[Stefano et al. 2005a])
in stress and SM, instead accessing and then memoriz-
ing a successful stress reduction strategy. Here, emotion
may represent the short cut to action whereas too much
cognitive dwelling may lead to inactivity [Stefano & Fricchi-
one, 1995a]. In addition, behavior is constantly evaluated
in the brain and rewarded by motivational circuitries,
when regarded beneficial, thus inducing psycho-behav-
ioral growth and development. Interestingly, growing
older, maturing and going through stressful experiences
as well as incidental stress hormone activity enhance
DA levels also in the amygdala, thereby facilitating the
acknowledgement of the self (self-perception) and self-
regulation, since aversions against what might not be
useful and self-supportive are thus enhanced, at least in
rodents [Barr et al. 2009]. The amygdala, equally, is a critical
region for the stress responses in humans, with a hyper-
active amygdala indicating stress conditions. However,
SM interventions decrease anxiety and perceived stress,
which correlates positively with decreases in right
basolateral amygdala grey matter density [Hölzel et al. 2009].
This too may represent an important biological reason
why stress and the successful solving of an (intended,
adventure-filled) stressful situation by SM activities,
e.g., running, bungee jumping, stage performing, sex
etc. [Esch & Stefano, 2004c; Esch & Stefano, 2005b; Salamon et al. 2005;
Stefano et al. 2008c], can be highly pleasurable, rewarding,
self-efficacious and finally relaxing (Fig. 6).
Beneficial behaviors and strategies to overcome
stress are endogenously rewarded, that is, positively and
physiologically amplified or reinforced, i.e., trained (‘do
it again’), and this happens via DA, endorphin, and MO
release, apart from other messenger molecules. Thus,
to gain the benefits of stress for development, flexibility,
growth, health and survival [Esch, 2002f; Esch, 2003d; Stefano et
al. 2005a], a non-linear and dynamic SM physiology has to
be in place and functioning [Esch, 2003d; Esch & Stefano, 2007b;
Esch et al. 2003b; Stefano & Esch, 2005b], so that, in the end, a full
stress recovery is possible. For this, a physiological self-
regulation capacity is necessary and has to be biologi-
cally possible. At the core of it, as we surmise, lies the
DA-MO-NO autoregulation of SM.
Taken together, autoregulatory signalling messen-
gers have the potential to act as physiological stress
down-regulators, and they exert these effects possibly
via pleasure-related brain pathways. Neurobiologically,
these pathways represent a general or superordinated
principle to terminate activated stress responses, since
the stress physiology, though useful at times, has to be
controlled and stopped in time. Following a stressful
encounter and stress induction, that is, a physiological
stress response initiation, endogenous SM potentials get
activated to subsequently regulate and finally terminate
initial stress, for example, via endogenous relaxation
induction [Esch & Stefano, 2007b; Salamon et al. 2006; Stefano et al.
2006]. If the situation, however, calls for endurance and
prolongation of stress mechanisms, e.g., because the
original stressor or invader is not defeated, endorphins
exemplarily [Stefano et al. 2005d] may serve as means to
down-regulate or decrease the pain or exhaustion that
comes with high or ongoing stress, i.e., fight or flight,
while still up-regulating, for example, the immune
system (e.g., proinflammation). Once the stressful situ-
ation is over, a general down-regulatory mechanism,
including antiinflammation, as well as a secondary
back-up/recovery system has to become activated, and
this, as we surmise, is a key function of endogenous
MO, which also leads to a psychological calming, i.e.,
relaxation and regeneration (psychological and physi-
ological stress recovery see above). Moreover, opiate
as well as DA, oxytocin and endocannabinoid signalling
have now been demonstrated in different health-pro-
moting and self-regulatory techniques, including the
placebo therapy” [de la Fuente-Fernández et al. 2001; de la Fuente-
Fernández et al. 2006; Esch & Stefano, 2004c; Esch & Stefano, 2005b; Esch et
al. 2004b; Esch et al. 2006b; Fricchione & Stefano, 2005; Fulda & Wetter, 2008;
Sher, 2003], which partially works, as we speculate, via the
same DA-MO-NO cascade and therefore will be pre-
dominantly down-regulatory by its nature.
35
Neuroendocrinology Letters Vol. 31 No. 1 2010 Article available online: http://node.nel.edu
The neurobiology of stress management
C
T
here is no doubt that different SM techniques,
as they are explored, have different or specific
physiological effects and components and pos-
sess unique medical properties. Exercise, for example,
exerts its positive effects, e.g., on the cardiovascu-
lar, immune and neural systems, via different initial
pathways than meditation or positive communica-
tion. However, there seems to exist a common neuro-
biological mechanism, i.e., limbic autoregulation, that
involves DA, MO and other endogenous signalling sys-
tems, many of which act through NO release, and this
appears to be of critical importance for the endogenous
self-regulatory system and ability to manage stress as a
useful and potentially health-promoting phenomenon.
Hence, SM techniques at first glance are distinct and
different from each other and then they finally reveal a
joint neurobiology that is profound and effective, which
developed through animalsevolution. We hypothesize
that this common mechanism has a neurobiological
root, which is highly significant since it was conserved
through evolution.
SM builds on an innate self-healing process essen-
tial as an antibiosenescent phenomenon for health
promotion and stress reduction, which offers medical
therapeutic treatment options. Constitutive NO serves
as an effector and converging point for this futuristic
clinical treatment modality. Equally significant are
the target messengers, DA and MO, as invoking novel
counter-intuitive cNOS-derived NO release. These
proposed medical interventions will reduce chronic
stress-induced disorders. This novel approach in physi-
ological stress reduction will also impact biomedical
disorders associated with proinflammatory events.
As stress is natural so is SM (almost like day and
night). However, we must take care to keep this healing
potential in mind and reserve time and space in our
daily routines and stressful lives to let autoregulation
happen and, therefore, function. Otherwise we delay
the ever accumulating stress to deal with the mental
and bodily consequences of a lowered stress-induced
resistance to diseases. Importantly, stress reduction can
be learned, it is neurobiologically rewarding and plea-
surable and one must simply learn to take the first step.
A
We thank Gerd Esch, M.D., for his inspiration, love and
impetus. His great and philanthropical character, exem-
plary medical and human care, and his intellect were
blueprint and motivation to many. We will not forget.
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