Neuroscience and Biobehavioral Reviews 51 (2015) 138–150
Contents lists available at ScienceDirect
Neuroscience and Biobehavioral Reviews
journal homepage: www.elsevier.com/locate/neubiorev
Review
Stress and opioids: Role of opioids in modulating stress-related
behavior and effect of stress on morphine conditioned place
preference
Anjana Bali, Puneet Kaur Randhawa, Amteshwar Singh Jaggi∗
Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala 147002, India
a r t i c l e i n f o
Article history:
Received 8 April 2014
Received in revised form
24 December 2014
Accepted 31 December 2014
Available online 27 January 2015
Keywords:
Endorphin
Dynorphin
Enkephalin
Stress
Conditioned place preference
a b s t r a c t
Research studies have defined the important role of endogenous opioids in modulating stress-associated
behavior. The release of ␤-endorphins in the amygdala in response to stress helps to cope with a stressor
by inhibiting the over-activation of HPA axis. Administration of mu opioid agonists reduces the risk of
developing post-traumatic stress disorder (PTSD) following a traumatic event by inhibiting fear-related
memory consolidation. Similarly, the release of endogenous enkephalin and nociceptin in the basolateral
amygdala and the nucleus accumbens tends to produce the anti-stress effects. An increase in dynorphin
levels during prolonged exposure to stress may produce learned helplessness, dysphoria and depression.
Stress also influences morphine-induced conditioned place preference (CPP) depending upon the intensity
and duration of the stressor. Acute stress inhibits morphine CPP, while chronic stress potentiates
CPP. The development of dysphoria due to increased dynorphin levels may contribute to chronic stressinduced
potentiation of morphine CPP. The activation of ERK/cyclic AMP responsive element-binding
(CREB) signaling in the mesocorticolimbic area, glucocorticoid receptors in the basolateral amygdala,
and norepinephrine and galanin system in the nucleus accumbens may decrease the acute stress-induced
inhibition of morphine CPP. The increase in dopamine levels in the nucleus accumbens and augmentation
of GABAergic transmission in the median prefrontal cortex may contribute in potentiating morphine
CPP. Stress exposure reinstates the extinct morphine CPP by activating the orexin receptors in the nucleus
accumbens, decreasing the oxytocin levels in the lateral septum and amygdala, and altering the GABAergic
transmission (activation of GABAA and inactivation of GABAB receptors). The present review describes
these varied interactions between opioids and stress along with the possible mechanism.
© 2015 Elsevier Ltd. All rights reserved.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
2. Effect of endorphin/mu opioid agonists on stress-related behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
2.1. Stress and anxiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
2.2. Post-traumatic stress disorder (PTSD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
2.3. Learning and memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
3. Effect of dynorphin system on stress-related anxiety and depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
4. Role of enkephalin in stress and associated behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
5. Role of nociceptin on stress-related behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
6. Influence of gender on stress modulatory role of opioids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
7. Effect of stress on morphine conditioned place preference (CPP)/fear conditioning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
7.1. Stress-induced modulation of morphine conditioned place preference (CPP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
7.2. Effect of stress on morphine CPP reinstatement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
∗ Corresponding author. Tel.: +91 9501016036; fax: +91 0175 2283073.
E-mail addresses: amteshwarjaggi@yahoo.co.in, anjubali.123@gmail.com (A.S. Jaggi).
http://dx.doi.org/10.1016/j.neubiorev.2014.12.018
0149-7634/© 2015 Elsevier Ltd. All rights reserved.
A. Bali et al. / Neuroscience and Biobehavioral Reviews 51 (2015) 138–150 139
7.3. Role of dynorphin system in stress modulatory actions on drug craving/conditioned place preference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
7.4. Effect of stress on other psychoaddictive drugs-induced CPP and reinstatement. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
8. Integrative hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
8.1. Effect of different opioids on stress-related behavior. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
8.2. Effect of stress on drug craving/reward . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
9. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
1. Introduction
“Stress” is a word derived from the Latin word ‘Stringere’ meaning
to draw tight and was popularly used in the 17th century to
mean hardship, strain, adversity or affliction. In modern times,
stress is a buzzword used to describe the physical, emotional,
cognitive and behavioral response to events that are appraised
as threatening and challenging (Cartwright and Cooper, 1997).
The term stress was first employed in a biological context by a
Canadian endocrinologist Hans Selye in 1930s. He defined “stress
as a nonspecific response of the body to any kind of demand
made upon it” (Selye, 1998). Stress is a physical or psychological
stimulus that can produce mental tension or physiological reactions
to produce illness. The changes involved in disturbing the
homeostasis of an organism trigger various changes, including an
alteration in behavior, autonomic function and over-activation of
hypothalamic–pituitary–adrenal (HPA) axis (Bali and Jaggi, 2013,
2014). The ability to cope with a stressor is a crucial determinant
of health and the chemical mediators (stress hormones) play an
important role in promoting stress adaptation. Stress is a predecessor
and is a causative factor for the development of anxiety
and depression. Both anxiety and depression are the result of an
inappropriate adaptation to stress and these have been termed as
‘stress-related disorders’, with a causal role of HPA axis (Bali et al.,
2014).
The endogenous opioids are derived from three independent
genes that give rise to three precursor proteins known as proopiomelanocortin
(POMC), proenkephalin (PENK), and prodynorphin,
and their appropriate processing yields ␤-endorphin, metenkephalin,
leu-enkephalin, dynorphin and nociceptin, respectively.
These peptides and their derivatives exhibit different affinity
and selectivity for the mu-, delta- and kappa-receptors located on
the central and the peripheral neurons, neuroendocrine, immune,
mucosal cells and on many other organ systems (Fig. 1). Two additional
endogenous opioid peptides have been isolated from the
Fig. 1. Endogenous opioids with their precursor molecules and binding receptor
sites.
bovine brain that includes endomorphin-1 and endomorphin-2.
Apart from the analgesic actions of opioids, different opioid agonists
and antagonists have shown therapeutic actions in diverse
diseases of the central nervous system, including depression, stress,
anxiety, epilepsy; gastro-intestinal diseases such as ulceration,
irritable bowel syndrome, diarrhea, postoperative ileus; diseases
of immune system and related inflammatory disorders such as
osteoarthritis and rheumatoid arthritis; and others, including
ischemia-reperfusion injury, alcoholism and obesity/binge eating
(Sauriyal et al., 2011).
Opioids receptors are widely distributed on different components
of the HPA axis such as the hypothalamus, pituitary and
adrenal gland. It has been documented that the POMC fibers originating
in the arcuate nucleus innervate the stress-responsive
hypothalamic nuclei, including the paraventricular nucleus (PVN)
of hypothalamus, median eminence and other limbic structures,
including the septum, bed nucleus of stria terminalis (BNST) and
amygdala (Palkovits, 1987; Steckler et al., 2005; Sauriyal et al.,
2011). Numerous research studies and reviews provide evidence
for the role of the endogenous opioid system in regulating and modulating
the HPA axis, autonomic nervous system and behavioral
responses during stress (Valentino and Bockstaele, 2008). Various
clinical and preclinical studies have documented the critical role of
endogenous as well as exogenous opioids in modulating stress and
stress-associated anxiety, posttraumatic stress disorder (PTSD) and
depression (Nixon et al., 2010; Szczytkowski-Thomson et al., 2013).
Furthermore, stress has also been shown to modulate the response
of opioids, including drug craving and reinstatement of drug of
abuse (Hays et al., 2012; Haghparast et al., 2013). The present article
reviews the role of opioids in modulating stress-associated behavior,
and effect of stress on morphine-induced CPP with the possible
mechanisms.
2. Effect of endorphin/mu opioid agonists on stress-related
behavior
Endorphins (endogenous morphine) are endogenous opioid
peptides that function as neurotransmitters by acting on the mu
receptors. The possible involvement of ␤-endorphin in stressrelated
psychiatric disorders, including depression, PTSD and fear
conditioning has been reported (Merenlender-Wagner et al., 2009).
Specifically, the central endorphinergic neurons originate from two
nuclei, the arcuate nucleus in the posterior hypothalamus and
nucleus tractus solitarius in the brain stem. The endorphinergic
neurons have extensive projections to other brain areas, including
the hippocampus, midbrain and the amygdala, thus, providing
a rich network of POMC fibers throughout the brain, particularly to
regions associated with stress (Palkovits, 1987; Narita and Tseng,
1998).
2.1. Stress and anxiety
Research evidence suggests the key role of ␤-endorphin in
stress-coping behavior (Grisel et al., 2008; Barfield et al., 2010).
Transgenic mice with low ␤-endorphin exhibit increased anxious
behavior and show deficits in coping ability during an inescapable
140 A. Bali et al. / Neuroscience and Biobehavioral Reviews 51 (2015) 138–150
aversive situation, suggesting the anxiolytic actions of endogenous
endorphins (Grisel et al., 2008; Barfield et al., 2010). Mice
with low/no ␤-endorphin have enlarged adrenal glands suggesting
that persistent up-regulation of HPA axis may occur with
the decreased ␤-endorphin levels (Rubinstein et al., 1996). The
reduction in endogenous opioid tone has been linked with the
development of depression (Burnett et al., 1999). Poulin and collaborators
demonstrated that the activation of mu-opioid receptors
in the intercalated nucleus of amygdala modulates the communication
between the basolateral and central amygdala to inhibit
stress-induced fear response (Poulin et al., 2006). A very recent
study has shown that mice with depleted levels of ␤-endorphin
display a stronger aversion to novelty-feeding in response to stress,
suggesting that ␤-endorphin plays a key role in stress coping
behavior (Barfield et al., 2010, 2013). It has been reported that
morphine (1 and 5 mg/kg) attenuates acute restraint stress-induced
anxiety and potentiates adaptation in response to repeated stress
exposure in rats (Joshi et al., 2014; Anand et al., 2012).
Studies have described that genetic differences influence stress
coping behavior that is associated with variation in endogenous
␤-endorphin system (Amir, 1982; Yamada and Nabeshima, 1995;
Sarkar et al., 2007). The response of ␤-endorphin system to acute
stress is heritable and the genetic variations in mu-opioid receptors
mainly contribute to differential stress coping response (Dai
et al., 2005; Schwandt et al., 2011). A recent study examined the
anxious behavior of transgenic mice with varying capacities to synthesize
␤-endorphin in response to stress. The animals with low/no
␤-endorphin displayed a stronger aversion to novelty-suppressed
feeding test following stress exposure. The above findings suggest
that stress induces the release of ␤-endorphin to promote adaptation
at the endocrine and behavioral level, and in the absence of
␤-endorphin, the over-activation of HPA axis may contributes to
maladaptive behavior. Therefore, it is proposed that ␤-endorphins
play an important role in stress-coping behavior and that genotypic
variability in the ␤-endorphin system may contribute to the heritable
differences in stress reactivity and vulnerability (Barfield et al.,
2013).
Stress-induced ␤-endorphin release may be attributed to
increase in CRH secretion that in turn increases the expression
of the POMC gene in the anterior pituitary to produce ACTH and
␤-endorphin (Charmandarie et al., 2005). In turn, ␤-endorphin
attenuates the stress response, including stress-induced nociception
by inhibiting the secretion of CRH through a negative feedback
mechanism (Nakagawasai et al., 1999) (Fig. 2). Curtis et al. described
that both CRH and opioids are involved in fine tuning the LC activity
during stressful conditions. The activation of opioid afferents
tends to restrain the actions of CRH and facilitates the recovery to
pre-stress levels (Curtis et al., 2012).
2.2. Post-traumatic stress disorder (PTSD)
A growing body of literature addresses the important relationship
between morphine and post-traumatic stress (Holbrook
Fig. 2. Role of brain derived ␤-endorphin (mu receptor agonists) in stress adaptation.
Stress enhances the release of CRH from hypothalamus to increase the
expression of the POMC gene in the anterior pituitary that in turn is converted to
ACTH and ␤-endorphin. The latter binds to mu-opioid receptors in the intercalated
nucleus of amygdala to decrease fear response and produce stress adaptation. ␤Endorphin
inhibits the CRH release by a negative feedback mechanism, which may
also contribute in attenuating stress response.
et al., 2010; Nixon et al., 2010; Szczytkowski-Thomson et al.,
2013). Administration of morphine following a traumatic event
reduces the severity of symptoms and the risk of PTSD development
(Bryant et al., 2009; Stoddard et al., 2009). Bryant and collaborators
described that acute administration of morphine inhibits the
development of fear conditioning following a traumatic injury, suggesting
that morphine may be employed as a preventive strategy
to reduce the development of PTSD (Bryant et al., 2009). Nixon and
coworkers documented that morphine reduces the development of
PTSD in children experiencing a traumatic event and the reduction
in PTSD symptoms is positively correlated with morphine dosage
(Nixon et al., 2010). Stoddard and coworkers described a correlation
between the morphine usage and PTSD development in young children
(1–4 years) admitted to pediatric burn center. Treatment with
morphine decreased the development of post-traumatic symptoms,
assessed 3–6 months after the burn event (Stoddard et al.,
2009). A clinical study by Holbrook and collaborators described that
the use of morphine (2–20 mg) in the US military personnel after
a combat injury reduces the risk of PTSD development (Holbrook
et al., 2010). A very recent study has also described a lower prevalence
rate of PTSD in patients with traumatic brain injury who
received intravenous morphine within hours of injury (Melcer et al.,
2014). A recent study documented that the repeated administration
of morphine, but not a single dose, inhibits the enhancement of fear
learning in PTSD model. The authors proposed that administration
of morphine following a traumatic event may obstruct the memory
consolidation and associated fear learning that are necessary
for the development of PTSD (Szczytkowski-Thomson et al., 2013)
(Table 1).
Table 1
Traumatic stress attenuating effects of morphine in experimental and clinical conditions of PTSD.
Sr. No. Intervention Response Reference
1. Morphine Limits fear conditioning after traumatic injury Bryant et al. (2009)
2. Morphine Reduces the development of PTSD in children experiencing a
single traumatic event
Nixon et al. (2010)
3. Morphine Decreased post-traumatic symptoms assessed 3–6 months
after the burn event
Stoddard et al. (2009)
4. Morphine Reduces the risk of subsequent PTSD development in US
military personnel after combat injury
Holbrook et al. (2010)
5. Repeated administration of
morphine (not with single
dose administration)
Inhibits the enhancement in fear learning in another context
suggests that morphine’s mechanism of action is related to
consolidation processes occurring around that time
Szczytkowski-Thomson et al. (2013)
A. Bali et al. / Neuroscience and Biobehavioral Reviews 51 (2015) 138–150 141
2.3. Learning and memory
Research data demonstrates the interactions between stress
and opioids in modulating the learning and memory processes
(Homayoun et al., 2003; Yang et al., 2004). Sanders and collaborators
demonstrated impairment in stress-induced acquisition
of fear learning in mu-opioid receptors deleted mice, suggesting
that activation of these receptors is critical in the fear learning
process (Sanders et al., 2005). Earlier studies had described that
the activation of mu-opioid receptor either by endogenous opioids
or exogenous agonists (morphine) enhances the excitability
of the hippocampal pyramidal cells and dentate gyrus granule
cells by facilitating long term potentiation (LTP) (Simmons and
Chavkin, 1996). However, in contrast to these reports, studies have
also shown that opioids may impair the memory during stressful
conditions. A microinjection of morphine into the amygdala or hippocampus
has been shown to impair stress-induced contextual fear
conditioning (Westbrook et al., 1997). Furthermore, as described
earlier, the ability of morphine to attenuate the development of
PTSD following a traumatic event has been attributed to obstruction
in memory consolidation and fear learning processes (Bryant
et al., 2009; Stoddard et al., 2009; Szczytkowski-Thomson et al.,
2013).
3. Effect of dynorphin system on stress-related anxiety and
depression
The multiple active forms of dynorphin including dynorphin
A, dynorphin B, and ␣/␤-neo-endorphin are produced from
the precursor prodynorphin by an enzyme proproteinconvertase.
Dynorphin A and B are primarily present in the hypothalamus,
medulla, pons, mid-brain, and spinal cord. Dynorphins exert their
effects primarily through G-protein-coupled ␬-opioid receptors, K1
and K2. Although all dynorphin primarily produce their actions by
interacting with ␬ receptors, these peptides also have some affinity
for mu- and ␦-opioid receptors (DOR) (Valentino and Bockstaele,
2008).
Studies have shown that stress induces dynorphin release,
which subsequently activates ␬ receptors in the central nervous
systems to induce anxiety and depression (Hollt et al., 1980; Mague
et al., 2003; McLaughlin et al., 2003; Van’t Veer and Carlezon,
2013). The literature evidences the association between dynorphin
and dysphoria; therefore, the role of dynorphin has also been
investigated in the development of depression. The repeated exposure
of immobilization stress decreases the motivational behavior
in animals and correlate with changes in the dynorphin/␬-opioid
receptor system in the different brain regions (Lucas et al., 2011).
Shirayama and coworkers documented the importance of both
dynorphin A and B in stress-induced depression and reported that
during “learned helplessness”, the levels of dynorphin A and B are
increased in the hippocampus and nucleus accumbens regions. Furthermore,
administration of nor BNI (KOR antagonist) was shown
to promote recovery from the learned helplessness suggesting that
the release of dynorphin is responsible for stress-induced depression
(Shirayama et al., 2004). A single (2 h) or repeated exposures
(2 h × 10 days) of immobilization stress increases the mRNA levels
of ␬-opioid receptors in the striatal and nucleus accumbens regions
of rats. The ␬-opioid receptor related transcriptional changes are
diminished only after a longer recovery period (about 9 days) and
remain unchanged after a shorter recovery period. Consequently, it
is proposed that the prolonged inescapable stress alters the motivational
system to produce learned helplessness and dysphoria,
which is attributed to an increase in dynorphin in the striatal region
(Lucas et al., 2011). Other research studies have also documented
that the activation of dynorphin/␬-opioid receptor system may
Fig. 3. Role of dynorphin system in stress-induced increase in drug craving, reinstatement
of drug of abuse, learned helplessness, dysphoria and depression. Stress
enhances the release of CRH from the hypothalamus that increases the levels of
dynorphin A and B in the locus coeruleus, hippocampus and nucleus accumbens
regions to activate the kappa opioid receptors and trigger the phosphorylation of
CREB which in turn produces learned helplessness, dysphoria and depression. In
amygdala, increased dynorphin levels stimulate p38␣ MAPK, which subsequently
causes the translocation of the serotonin transporter to the synaptic terminals of
serotonergic neurons and decreases the 5HT synaptic availability to produce drug
craving and reinstatement of drug of abuse.
be involved in producing prolonged inescapable stress-induced
depression-like behavior in rodents (Land et al., 2008). Chartoff
and coworkers documented that the antidepressant effects of
desipramine in the swim stress test are accompanied by a decrease
in dynorphin expression and CREB phosphorylation in the nucleus
accumbens, and are independent of the norepinephrine or other
monoaminergic inputs (Chartoff et al., 2009). Research evidence
suggests that stress activates the dynorphin/␬-opioid receptor system
to trigger the intracellular signaling involving the activation of
ERK/CREB pathway (Bruchas and Chavkin, 2010) (Fig. 3).
The activation of the ␬-opioid receptor system in the LC region
is also important in the development of stress-related problems as
an increased gene expression of ␬-opioid receptors has been documented
in this region of Wistar Kyoto rats (a strain particularly
useful for studying stress-related behavior) (Pearson et al., 2006).
It is also suggested that CRH activates the dynorphin/␬-opioid
receptor system in the mouse basolateral amygdala to produce
anxiety-like behavior as pretreatment with ␬-opioid receptor
antagonist (norbinaltorphimine) is reported to block stress/CRHinduced
increase in anxiety (Bruchas et al., 2009). Administration
of KOR antagonist 2-(3,4-dichlorophenyl)-N-methyl-N-[(1S)-
1-(3-isothiocyanatophenyl)-2-(1-pyrrolidinyl) ethyl] acetamide
hydrochloride (DIPPA) produces anxiolytic effects in two different
strains of rats, Wistar Kyoto and Sprague Dawley (Carr and
Lucki, 2010). Furthermore, administration of norbinaltorphimine (a
selective KOR antagonist) prevents stress-induced decline in learning
and memory. Dynorphin gene-disrupted mice do not show the
learning and memory deficits in response to stress exposure, suggesting
that stress-induced activation of kappa opioids receptors is
critical to produce deficits in a novel object recognition test (Carey
et al., 2009).
4. Role of enkephalin in stress and associated behavior
Enkephalin is distributed throughout the limbic system, including
the extended amygdala, cingulate cortex, entorhinal cortex,
septum, hippocampus, and the hypothalamus (Drolet et al., 2001).
The met-enkephalin peptide sequence is coded by the enkephalin
gene; while the sequence of leu-enkephalin peptide is coded by
142 A. Bali et al. / Neuroscience and Biobehavioral Reviews 51 (2015) 138–150
Fig. 4. Adaptogenic and anxiolytic effects of brain-derived enkephalin. Stress
induces increased release ofenkephalin in the amygdala, nucleus accumbens and
hippocampus to produce delta opioid receptor activation and decrease dynorphin
levels in the nucleus accumbens, which are responsible for adaptive and anxiolytic
effects.
both enkephalin and dynorphin genes. The POMC also contains
met-enkephalin sequence on the N-terminus of ␤-endorphin, but
the endorphin peptide is not processed into enkephalin. The latter
demonstrates its action by acting on the delta opioid receptors
(Amir, 1982).
Enkephalin system plays an important role in promoting stress
adaptation in an organism (Van Loon et al., 1990). The decreased
functioning of the enkephalin system produces depression-like
symptoms and accordingly, an increase in enkephalin signaling is
therapeutically explored in the treatment of depression. Chronic
immobilization stress (21 days) has been shown to increase the
expression of enkephalin and delta opioid receptors in the hippocampus
region of rats (Chen et al., 2004). During acute stress
exposure, the reduced activity of soluble enkephalinase in the hippocampus
and membrane enkephalinase in the amygdala increases
the availability and duration of action of enkephalins to produce
anxiolytic actions (Hernández et al., 2009; Kung et al., 2010). Furthermore,
preproenkephalin knockout mice are more sensitive to
traumatic stimuli, and develop more severe anxiety and depressive
symptoms, suggesting the anti-anxiety influence of enkephalin
(Lishmanov et al., 2012). In individuals vulnerable to stress, the
decreased mRNA expression of enkephalin in the posterior basolateral
nucleus of amygdala has been documented. Furthermore,
the specific knockout of enkephalin genes in this region increases
the anxiety-like behavior. Accordingly, the authors suggested that
the enkephalin system in the basolateral nucleus of amygdala
is involved in producing specific neuro-adaptation and resilience
(Bérubé et al., 2014). In another study, the same group of scientists
reported the decrease in mRNA expressions of enkephalin in the
basolateral nucleus of amygdala and an increase in mRNA levels
of dynorphin in the dorsal and media shell of nucleus accumbens
in stress vulnerable rats. It suggests that enkephalin facilitates the
behavioral adaptation in chronic social stress model by opposing
the actions of dynorphin (Bérubé et al., 2013). A very recent study
has documented that the down-regulation of enkephalin in the
nucleus accumbens region triggers the development of anhedonia
in a chronic stress model. The decrease in preproenkephalin
mRNA expression in the nucleus accumbens region is associated
with the development of anxiety in restraint stress-subjected rats
suggesting that the down-regulation of enkephalin in the nucleus
accumbens might underlie the susceptibility to chronic stress
(Poulin et al., 2014) (Fig. 4).
5. Role of nociceptin on stress-related behavior
Nociceptin (orphanin FQ), a relatively newly discovered endogenous
heptadecapeptide, is a 17-amino acid peptide, which shows
structural homology to opioid peptides, particularly to dynorphin
A. Nociceptin/orphaninFQ (N/OFQ)-expressingneurons are present
in the hypothalamus and limbic system to regulate the HPA axis
and stress response (Mollereau et al., 1994; Witkin et al., 2013).
Nociceptin binds to the opioid receptor like-1 receptors (ORL1
receptors), also termed as nociceptin receptors (NOP)/orphanin FQ
receptors, and these receptors lack affinity toward the traditional
opioid receptors (Wick et al., 1994).
Studies have demonstrated the key role of nociceptin in regulating
the stress-associated behavioral and psychological alterations
(Witkin et al., 2013). N/OFQ is essentially an anxiolytic peptide and
plays an important role in stress adaptation. Transgenic mice lacking
the OFQ/N precursor proteins exhibit anxiety-like behaviors
and do not habituate to repeated exposure to stress (Reinscheid
and Civelli, 2002). A number of nociceptin agonists, including
N/OFQ and Ro 64-6198 produce anxiolytic-like effects in the preclinical
models of anxiety (Goeldner et al., 2012; Delaney et al.,
2012). Goeldner and coworkers reported that the N/OFQ peptide
receptor agonists produce dose-dependent anxiolytic effects similar
to benzodiazepine receptor agonists (Goeldner et al., 2012).
Both acute and chronic restraint stress produces time-dependent
changes in the preproN/OFQ transcript expression in the hippocampus,
medio-dorsal forebrain and hypothalamus. Furthermore, acute
and chronic stress induces differential changes in the ppNN/OFQ
expression, with their decreased expression in the central amygdala
in response to acute stressor and increased expression in
the bed nucleus and reticular thalamus in response to a repeated
restraint stressor (Delaney et al., 2012). Injection of N/OFQ in the
central nucleus of amygdala is shown to significantly and selectively
reduce anxiety-like behavior (in the elevated plus maze
test) in restraint rats, suggesting that acute stress activates the
N/OFQ system in this brain region to produce anti-stress effects
(Ciccocioppo et al., 2014). In response to acute restraint stress, the
enhanced expression of N/OFQ in the CA1, CA3, and dentate gyrus
of the hippocampus and rise in the plasma corticosterone levels
has been documented. However, restraint stress failed to increase
the N/OFQ expression in adrenalectomized rats, suggesting that the
increased expression of N/OFQ may be secondary to an increase
in plasma corticosterone in stress-subjected rats (Nativio et al.,
2012).
It has been reported that bilateral microinjections of N/OFQ into
the rat perifornical area of the lateral hypothalamus abolish stressinduced
analgesia and it has been proposed that N/OFQ attenuates
immobilization/restraint stress-induced analgesia via inhibition
of hypocretin/orexin (Hcrt) neurons in the lateral hypothalamus
(Gerashchenko et al., 2011). In response to a single-prolonged stress
(an animal model for PTSD), increased levels of N/OFQ in the CSF
have been correlated with the development of anxiety, hyperalgesia
and allodynia (Zhang et al., 2012). It has been shown that
N/OFQ antagonizes a CRH-induced increase in GABAergic transmission
in the central amygdala in alcohol-dependent rats. Therefore,
it has been hypothesized that nociceptin may produce anxiolytic
effects by inhibiting the actions of CRH (Cruz et al., 2012). In contrast,
Nazzaro and others demonstrated that the potent inhibitory
effects of N/OFQ on the dorsal raphe nuclei are independent of CRH
and GABA (Nazzaro et al., 2009) (Fig. 5).
6. Influence of gender on stress modulatory role of opioids
There have been studies suggesting that ovarian hormones alter
the levels of enkephalin in hippocampal mossy fiber pathway in
A. Bali et al. / Neuroscience and Biobehavioral Reviews 51 (2015) 138–150 143
Fig. 5. Adaptogenic and anxiolytic effects of brain-derived nociceptin. Stress
increases the nociceptin levels directly in the hypothalamus, hippocampus and
medio-dorsal forebrain regions to produce anxiolytic and adaptive effects. The
nociceptin levels are also increased indirectly through increased release of CRH
and corticosterone, which in turn inhibits the CRH release and prevents HPA axis
overactivation by negative feed mechanism. Administration of nociceptin agonists
including N/OFQ and Ro 64-6198 produces anxiolytic-like effects.
females (Torres-Reveron et al., 2008) and dynorphin immunoreactivity
in the hippocampus (Torres-Reveron et al., 2009). The mossy
fiber-CA3 pathway is the most stress vulnerable region in males,
and is rich in opioid peptides and receptors as well as gonadal
steroid receptors (Drake et al., 2007a,b). Ovarian hormones influence
corticotropin releasing factor receptor colocalization with
delta opioid receptors in the CA1 pyramidal cell dendrites (Williams
et al., 2011). Furthermore, ovarian hormones, particularly estrogens,
also alter the mu-opioid receptor binding throughout the
hippocampus. It has been shown that prenatal exposure to morphine
selectively alters the density of mu-opioid receptors in the
hippocampus of adult female (Slamberová et al., 2003). Accordingly,
the studies have shown that gender and fluctuations in
estrogen levels modulate the effects of opioids on stress-associated
behavior. Research data demonstrates that chronic stress differentially
alters the cognitive process in male and females. In contrast
to the impaired cognition in male rats, females exhibit preserved
memory following stress exposure (Bowman et al., 2003; Bowman,
2005). In males, chronic stress impairs learning, decreases LTP,
and produces the atrophy of CA3 pyramidal cell dendrites of
the hippocampus (Magari˜nos et al., 1997; McEwen and Milner,
2007). Conversely, chronic stress neither impairs spatial learning
performance (particularly in the proestrus phase) nor produces
deleterious morphological changes in the hippocampus of females
(Galea et al., 1997; Luine, 2002; McEwen and Milner, 2007). Milner
and collaborators correlated the differential effects of chronic
stress on the memory of females and males to the density and
trafficking of mu-opioid receptors (availability of opioid receptor
pool) in the hippocampal parvalbumin (PARV)-containing GABAergic
interneurons in the hilus of the dentate gyrus of hippocampus.
Results demonstrated that chronic stress differentially decreases
the PARV-labeled cells in males, without any significant effect in
females (Milner et al., 2013). Other studies have described that activation
of mu-opioid receptors in the hippocampus region inhibits
the GABAergic transmission to facilitate LTP and memory formation
(Drake et al., 2007a,b). Accordingly, Milner and colleagues
proposed that the disruption of PARV neurons (having mu-opioid
receptors) following chronic stress may be responsible for memory
deterioration in males. Conversely, the maintenance of PARV
neurons in females during chronic stress may be responsible for
maintenance of LTP and preservation of memory (Milner et al.,
2013). In contrast to chronic stress, acute stress is associated with
higher immunoreactivity of phosphorylated mu opioid receptors
in the dentate gyrus region of hippocampus in males as compared
to females at proestrus and estrus stage (high estrogen stages)
(Gonzales et al., 2011). Milner et al. also demonstrated the differential
effects of acute stress on mu-opioid receptors in males
and females. In males, an increase in mu opioid PARV-labeled cells
was demonstrated in response to acute stress; however, a decrease
in mu opioid PARV-labeled cells was reported in females (Milner
et al., 2013). The same group of workers described the increased
immunoreactivity of phosphorylated dynorphin receptors in the
stratum radiatum of CA2/CA3a of hippocampus in estrus females
(elevated estrogen and progesterone) as compared to proestrus and
diestrus females and males. However, acute immobilization stress
was shown to abolish the increased immunoreactivity of dynorphin
receptors in the estrous cycle phase (Burstein et al., 2013).
Numerous research studies have recognized the positive interfacing
between the endogenous opioid system and sex hormones
on stress reactivity (Allen et al., 2014). Allen and coworkers
demonstrated that estrogen modulates the blood pressure through
endogenous opioids in stressful conditions. It was shown that
stress increases the blood pressure in women taking estrogen
with an intact opioid receptor system and blockade of opioid
receptors with naltrexone decreases blood pressure, suggesting
that estrogen mediates its effects on blood pressure by activating
opioid receptors (Allen et al., 2014). In consistent with the
studies of premenopausal women, the same group of workers
demonstrated the interactions between estrogen and opioids in
postmenopausal women. The postmenopausal women on estrogen
therapy and with intact opioid receptors showed the largest systolic
blood pressure responses to psychological stress, compared
with all other conditions. The interaction between estrogen and
endogenous opioids may be responsible for the sex differences
in opioid effects on stress reactivity in younger premenopausal
women (Allen et al., 2014).
The variation in stress-induced analgesia with fluctuations
in gender-specific hormones also suggests the significance of
opioid-estrogen interactions (Butler and Finn, 2009). The circulating
estrogen influences the pain sensitivity response in a
cold pressor test (opioid-related behavior) during stressful conditions.
Premenopausal women (with higher circulating estrogen)
exhibit decreased pain sensitivity following naltrexone administration
compared to postmenopausal women (with low estrogen),
suggesting that the circulating estrogen influences the actions
of opioids to modulate stress-induced analgesia (al’Absi et al.,
2004). Other studies have also shown the influence of gender
and estrogen on pain-related changes during stress exposure.
Stress-induced analgesia is more profound in males than in
females suggesting that males are more sensitive to stress than
females (Kimoto et al., 2013). It has been reported that kappa
opioid receptor-mediated anti-nociceptive and anti-hyperalgesic
effects are enhanced by exogenous or endogenous estrogen in
the females rats (Lawson et al., 2010). The intensity and unpleasantness
of cold-induced pain following a psychological stress
was shown to be significantly increased in naltrexone administered
women as compared to men (Frew and Drummond, 2007).
Larauche et al. demonstrated that acute and repeated water avoidance
stress-induced visceral analgesia is naloxone-dependent in
females, but naloxone-independent in males (Larauche et al.,
2012). In contrast to acute stress-induced analgesia (CarvalhoCosta
et al., 2014; Ghasemzadeh and Rezayof, 2015), chronic
stresses may contribute to hypersensitivity to pain known as stressinduced
hyperalgesia (Dai and Ma, 2014). As in stress-induced
analgesia, there is also a significant impact of gender on stressinduced
hyperalgesia. Recently, Gamaro et al. studied the influence
of gender on chronic variable stress-induced hyperalgesia and
reported that male rats show a decrease in tail-flick latency, while
females demonstrate an increase in this parameter (Gamaro et al.,
2014).
144 A. Bali et al. / Neuroscience and Biobehavioral Reviews 51 (2015) 138–150
Fig. 6. Stress-induced decline in morphine CPP. Stress increases the mRNA expression
of galanin, GalR1, tyrosine hydroxylase and norepinephrine in nucleus
accumbens to decrease morphine-CPP. Stress induced activation of glucocorticoid
receptors in the basolateral amygdala (BLA) also contribute in decreasing morphine
CPP. Stress increases the ratio of phosphorylated extracellular signal-regulated
kinase (p-ERK) which triggers the phosphorylation of CREB to increase the c-fos
levels in the mesocorticolimbic dopaminergic system. Stress-triggered ERK/CRB
signaling contributes in consolidating the fear memory and decline in morphine
CPP.
7. Effect of stress on morphine conditioned place
preference (CPP)/fear conditioning
7.1. Stress-induced modulation of morphine conditioned place
preference (CPP)
CPP is a type of Pavlovian conditioning, which is employed by
different scientists to measure the motivational effects of addictive
drugs, with reinforcing properties such as morphine. Numerous
studies have demonstrated that stress varying in intensity
and duration inhibits morphine-induced CPP (Papp et al., 1992;
Haghparast et al., 2013). Papp and coworkers demonstrated that
chronic exposure to mild unpredictable stress paired with morphine
suppresses the acquisition of preferences for morphine
without altering picrotoxin or naloxone-induced place aversion.
Thus implying that stress specifically impairs the rewarded behavior
without causing a general impairment of associative learning
(Papp et al., 1992).
Recently, Haghparast and coworkers also demonstrated that the
application of sub-chronic forced swim stress (not acute) decreases
the conditioning scores in morphine CPP tests (Haghparast et al.,
2013). In the same study, the combined application of stress
with morphine was shown to increase the p-ERK/ERK ratio,
p-CREB/CREB ratio, and c-fos levels in the mesocorticolimbic
dopaminergic system. Since both CREB (a transcriptional factor),
and c-fos (immediate early gene), are downstream targets of ERK
(Qi et al., 2008), an increase in p-CREB/CREB ratio, and c-fos levels
during concurrent application of stress and morphine may be
secondary to ERK activation (Haghparast et al., 2013). The authors
proposed that up-regulation of the ERK/CREB pathway in the mesocorticolimbic
region results in memory formation, which in turn
may inhibit morphine-induced place preference during concurrent
stress exposure (Haghparast et al., 2013) (Fig. 6). Other studies have
shown the important role of ERK signaling in memory formation
and inhibition of ERK has been shown to prevent the formation
of long lasting memories of an event including fear (Imbe et al.,
2004; Shiflett and Balleine, 2011). In another recent study, GarcíaCarmona
and coworkers demonstrated the activation of brain stress
system following a morphine-conditioned place preference test in
mice. In this study, an increase in CREB expression in the PVN,
central amygdala and BNST regions; increase in the number of CRH
neurons in the PVN, and enhanced CRH-immunoreactivity fibers
in the nucleus tractus solitarius (NTS) and ventral tegmental area
(VTA) regions was demonstrated following morphine-induced CPP
paradigm. This suggests that exposure to morphine activates the
CREB signaling pathways to increase CRH in the brain stress system
and this signaling may be involved in memorizing the events
during conditioning paradigm (García-Carmona et al., 2013).
Attarzadeh and coworkers demonstrated that physical stress
(forced swim stress) and the administration of corticosterone
reduces the acquisition (but not expression of) morphine-induced
CPP. Furthermore, the blockade of glucocorticoid receptors in the
basolateral amygdala diminishes the inhibitory effects of stress
or corticosterone on acquisition of morphine CPP, suggesting the
involvement of glucocorticoid receptors of the basolateral amygdala
region in modulating morphine CPP during stress exposure
(Attarzadeh-Yazdi et al., 2013). In another study, chronic restraint
stress was shown to impair the formation and facilitate the extinction
of morphine CPP. Furthermore, chronic stress was shown
to increase the mRNA expression of galanin, galanin receptor 1
and tyrosine hydroxylase in the nucleus accumbens. Therefore, it
was proposed that the activation of the galanin system with corresponding
changes in the noradrenergic system may modulate
stress-induced changes in morphine CPP (Zhao et al., 2013).
In contrast to earlier reports of reduction in morphine-induced
CPP during concurrent stress, Li and coworkers demonstrated
that chronic foot-shock exposure (not acute foot shock) or corticosterone
treatment (3 and 5 mg/kg, i.p.) potentiates morphineinduced
CPP. Furthermore, there was a rise in dopamine levels
in the nucleus accumbens region, suggesting that the increase in
dopamine levels in this region may be responsible for potentiating
morphine CPP (Li et al., 2007). Other studies have shown the
differential effect of stress on morphine CPP depending on the controllability
of stressors and it has been shown that inescapable
stress, but not escapable stress, potentiates morphine CPP (Rozeske
et al., 2009). The microinjection of GABAA agonist, muscimol, in
the medial prefrontal cortex led escapable stress to potentiate
morphine CPP similar to that of inescapable stress. On the other
hand, microinjection of GABAA antagonist (picrotoxin) blocked the
potentiating effects of inescapable stress on morphine CPP. Based
on these studies, it may be suggested that during stress exposure,
the inhibition of the medial prefrontal cortex through the
GABA inhibitory neurotransmitter may potentiate stress-induced
morphine CPP and activation of the same brain region through
blockade of GABA neurotransmitter may in turn inhibit morphine
CPP. Accordingly, it is proposed that the medial prefrontal cortex
regulates the differential expression of morphine CPP following
controllable/uncontrollable stress and inactivation of the medial
prefrontal cortex is an important brain event in stress-induced
morphine CPP potentiation (Rozeske et al., 2009). Furthermore,
a recent study by the same group described that prior exposure
to escapable tail shock prevents inescapable shock-induced
potentiation of morphine CPP and anxiety-like behavior in the
form of ‘behavioral immunization’. However, administration of
muscimol in the medial prefrontal cortex was shown to block
behavioral immunization, including non-escapable stress-induced
potentiation of morphine CPP, suggesting that the prior experience
with escapable stress activates the medial prefrontal cortex
and produces long-lasting neural alterations to block inescapableinduced
potentiation of morphine CPP (Rozeske et al., 2012) (Fig. 7).
There are contradictory reports regarding the effect of neonatal
stress on morphine CPP. Exposure of stress in the early life period
(by maternal separation) has been shown to increase the time
spent in morphine-paired compartment in rat offsprings, indicating
that neonatal stress induces the place preference for mu-opioid
receptor agonist (Michaels and Holtzman, 2008). On the contrary,
A. Bali et al. / Neuroscience and Biobehavioral Reviews 51 (2015) 138–150 145
Fig. 7. Inescapable stress and chronic stress-induced potentiation in morphine CPP.
Chronic foot shock stress increases the GABAergic transmission and inactivates the
median prefrontal cortex (mPFC) to potentiate the morphine induced CPP. Administration
of GABA agonist (muscimol) induces mPFC inactivation, whereas GABA
antagonist (picrotoxin) inhibits this process. Inescapable stress-induced increase in
dopamine levels in nucleus accumbens may also contribute in potentiating morphine
CPP.
neonatal exposure to stress/morphine has also been shown to
impair morphine-rewarded CPP (Hays et al., 2012; Boasen et al.,
2009). The latter group of workers supported the ‘stress inoculation
hypothesis’ whereby stressors experienced in early life prepare animals
to tolerate future stress. It was proposed that neonatal stress
induces habituation to subsequent handling and thus reduces their
arousal and stress responsiveness, including craving for morphine
(Hays et al., 2012).
7.2. Effect of stress on morphine CPP reinstatement
Exposure to stress has been shown to reinstate the extinct
morphine CPP and it has been related to drug seeking behavior
or drug relapse. Scientists have investigated the different mechanisms
involved in stress-induced reinstatement of morphine CPP. A
recent study investigated the involvement of orexin in the nucleus
accumbens shell (NAcSh) in stress-induced drug seeking behavior.
The blockade of orexin-1 or orexin-2 receptors in the NAcSh
was shown to significantly attenuate stress-induced morphine CPP
reinstatement without any effect on morphine priming-induced
reinstatement. It suggests that NAcSh is the main brain area
in which orexin participates in stress-induced reinstatement to
morphine-seeking, with no effect on drug priming-induced relapse
of opioid seeking (Qi et al., 2013). During opioid abstinence, the
alterations in oxytocinergic system (decreased oxytocin levels and
increased oxytocin receptor binding) in the lateral septum and
amygdala contribute to the development of anxiety, depression,
and social deficits. Administration of oxytocinergic analog carbetocin
was shown to attenuate the negative emotional consequences
of opioid withdrawal. Furthermore, administration of carbetocin
also prevented stress-induced reinstatement to morphine-seeking
projecting the oxytocinergic system as a possible target for the
treatment of emotional impairment associated with abstinence
(Zanos et al., 2013) (Fig. 8). Very recently, Karimi et al. demonstrated
that the activation of glucocorticoid receptors in the basolateral
amygdala was involved in forced swim stress-induced reinstatement
of extinguished morphine CPP (Karimi et al., 2014).
Li and collaborators described that stress inhibits the 5-HT system
in the dorsal raphe nucleus via CRH-induced stimulation of
GABAergic activity. It was shown that administration of muscimol
(GABAA agonist) in the dorsal raphe nucleus activates the
Fig. 8. Stress-induced reinstatement of extinct morphine CPP. Morphine administration
induces condition place preference behavior and, conditioning without
morphine for prolonged period produces extinction of morphine-CPP. Stress exposure
reinstates morphine CPP through various mechanisms including increased
release of CRH that alters the GABAergic transmission (increases GABAA and
decreases GABAB receptor activation); activates orexin receptors 1 and 2 in nucleus
accumbens and decreases oxytocin in lateral septum and amygdala.
GABAA receptors to reinstate stress-induced morphine CPP, while
bicuculline (GABAA receptor antagonist) attenuates morphine reinstatement
suggesting that GABAA receptors in the dorsal raphe
nucleus predominantly contribute to stress-induced reinstatement
of morphine-CPP (Li et al., 2013). Earlier, Staub and collaborators
described that exposure to morphine sensitizes the 5-HT system in
the dorsal horn neurons to GABAergic inhibitory effects of stress
and CRH (Staub et al., 2012). A recent study examined the role of
GABAB receptors in morphine-induced CPP, extinction and stressinduced
relapse in chronicstress subjected mice. Administration of
baclofen, (GABAB agonist) blocked chronic stress-induced potentiation
of morphine CPP, promoted the extinction, and prevented
stress-induced reinstatement of morphine preference. It was proposed
that stress may inhibit the functioning of GABAB receptors to
reinstate the extinct morphine preference and accordingly, GABAB
receptor-positive modulators may act as anti-addiction agents in
people suffering from chronic stress (Meng et al., 2014).
7.3. Role of dynorphin system in stress modulatory actions on
drug craving/conditioned place preference
Studies have shown the role of dynorphin/␬-opioid receptor
system in drug craving, therefore, ␬-opioid receptor antagonists
have been projected as useful therapeutic agents to reduce stressinduced
drug craving. Recently, Smith and coworkers reported
that repeated forced swim stress activates the dynorphin/␬-opioid
receptor system in the amygdala to potentiate the magnitude of
drug craving and it is suggested that the activation of dynorphin/␬opioid
receptor system in the amygdala may modulate the
rewarding effects of addictive drugs during stressful conditions
(Smith et al., 2012). Studies have demonstrated that the activation
of dynorphin/␬-opioid receptor (KOR) system by repeated
stress exposure/agonist treatment produces place aversion and
reinstates extinguished cocaine place preference behaviors. The
effects of dynorphin are shown to be mediated through stimulation
of p38␣ MAPK, which subsequently cause the translocation of
serotonin transporter to the synaptic terminals of serotonergic neurons
(Lemos et al., 2012). Another study by Schindler and coworkers
extend the above findings using the serotonin transporter knockout
mice and reported that the selective re-expression of serotonin
transporter into the dorsal raphe restores the prodepressive effects
146 A. Bali et al. / Neuroscience and Biobehavioral Reviews 51 (2015) 138–150
of ␬-receptor activation. This suggests that stress-induced activation
of the dynorphin/␬-receptor system produces a transient
increase in serotonin transport that may be responsible for the
stress-induced potentiation of cocaine reward (Schindler et al.,
2012).
A recent study determined the role of the dynorphin/␬receptor
system in regulating anxiety-related behaviors during an
extended period of abstinence from ethanol in animals with a
history of ethanol dependence. The exposure of stress to alcoholdependent
rats enhanced the responsiveness to stress to produce
anxiety-like behavior. Furthermore, administration of ␬-receptor
antagonist, nor-binaltorphimine (nor-BNI), was shown to attenuate
the increased stress responsiveness suggesting that alcohol
withdrawal-associated behavior is regulated (at-least partly) by
dynorphin/␬-opioid receptor system (Gillett et al., 2013). Studies
have also investigated the role of the dynorphin/␬-opioid receptor
system in drug craving during adulthood in neonatal stresssubjected
animals. Michaels and Holtzman studied the effects of
maternal separation, a model of early postnatal stress, on place
conditioning to ␬-opioid receptor agonists in rats. Maternally separated
animals spent significantly more time in the spiradoline
(kappa-opioid agonist)-paired compartment as compared to nonstressed
animals, indicating a place preference to kappa-opioid
agonist in neonatal stress-subjected animals. It indicates that early
postnatal stress induces the significant neuronal changes to affect
the reward value of kappa-opioid agonists in the place preference
conditioning paradigm (Michaels and Holtzman, 2008). Vien and
coworkers reported that neonatal stress increases the activation
of kappa opioid receptors, and combined exposure of neonatal
stress and morphine further enhances the kappa opioid receptor
signaling (Vien et al., 2009). Recently, same group of workers
reported that kappa opioid receptor stimulation increases neonatal
stress-induced cocaine CPP response in adult mice (Hays et al.,
2012).
7.4. Effect of stress on other psychoaddictive drugs-induced CPP
and reinstatement
In addition to morphine CPP, there have been studies
showing that stress influences other psycho-addictive drugsinduced
CPP and reinstatement. Like morphine CPP, acute and
chronic stress produces differential effects on psychoaddictive
drugs-induced CPP. A study by Garcia-Pardo et al. demonstrated
that exposure to acute social defeat stress inhibits
3,4-methylenedioxymethylamphetamine-induced CPP in mice
(García-Pardo et al., 2014); while Smith and collaborators described
that repeated force swim stress potentiates nicotine-induced CPP
(Smith et al., 2012). Furthermore, stress exposure is also suggested
to evoke reinstatement of extinct CPP to addictive drugs. Al-Hasani
et al. described that acute exposure to a stressor potentiates the
reinstatement of cocaine and nicotine-induced CPP (Al-Hasani
et al., 2013). Leão et al. demonstrated that exposure of acute
restraint stress reinstates nicotine-induced CPP in rats after 15 days
of extinction (Leão et al., 2009). Moreover, exposure of acute forced
swim stress has also been shown to evoke reinstatement of cocaine
CPP. Furthermore, CRH 1 receptor antagonist (antalarmin) prevents
stress-induced increase in CRH mRNA in the BNST during reinstatement
of CPP, suggesting that the activation of CRH neurons
induces the reinstatement of cocaine-induced CPP (McReynolds
et al., 2014). A modified force swim test paradigm has also been
shown to reinstate nicotine-induced CPP, 3 days after extinction
(Jackson et al., 2013). A recent study by Bahi and Dreyer also
described that chronic exposure to psychosocial stress exacerbates
reinstatement of ethanol induced CPP (Bahi and Dreyer, 2014).
Accordingly, the role of stress in modulating morphine CPP may
be viewed in a broader context of stress and addiction.
8. Integrative hypothesis
8.1. Effect of different opioids on stress-related behavior
The activation of mu-opioid receptors in the amygdala either by
endogenous endorphin or exogenous morphine is generally associated
with stress coping behavior (Grisel et al., 2008; Barfield
et al., 2010; Rubinstein et al., 1996). Stress-induced release of
CRH triggers the release of endorphin that in turn tends to
inhibit the over-activation of HPA axis (Nakagawasai et al., 1999).
Furthermore, administration of morphine decreases the development
of PTSD following a severe traumatic event (Bryant et al.,
2009; Stoddard et al., 2009) suggesting the anti-stress and beneficial
role of mu-opioid receptors. There are contradictory reports
regarding the role of mu-opioid receptors on learning/memory during
stressful conditions (Sanders et al., 2005; Westbrook et al.,
1997; Bryant et al., 2009). However, careful analysis of these
reports suggests that the differential actions of opioids on the
memory events during stressful conditions are beneficial for an
organism. Results from Sander et al. demonstrating that opioids
are essential for fear learning is based upon the acute
fear learning paradigm in which a single day stressor of moderate
intensity was given to induce learning (Sanders et al.,
2005). In contrast, the reports of opioids-induced impairment
in memory and memory consolidation are derived from chronic
stress or PTSD-based studies (Bryant et al., 2009; Stoddard et al.,
2009; Szczytkowski-Thomson et al., 2013). During acute stress,
endorphins may serve as a general alert mechanism to avoid confounding
effects of stress and hence, endorphins may increase
the fear learning to avoid the stress exposure. On the contrary,
morphine-induced impairment in memory consolidation and associated
fear learning during severe traumatic events or chronic stress
may be to avoid post-stress aversive effects. It is a well-known fact
that the process of memory consolidation is critical in inducing the
post-stress aversive effect following a traumatic event. However,
the hypothesis suggesting the differential role of endorphins/opioid
receptor agonists on learning/memory depending upon the intensity
and duration of stressor needs experimental verification.
An increase in enkephalin and delta opioid receptors in the
basolateral amygdala and nucleus accumbens tends to produce
anti-stress effects (Chen et al., 2004; Hernández et al., 2009; Kung
et al., 2010). Furthermore, in response to acute and chronic stress,
the levels of nociceptin are increased in the hippocampus; hypothalamus
and medio-dorsal fore brain (Delaney et al., 2012) and
the rise in nociceptin tends to produce stress adaptation (Cruz
et al., 2012; Reinscheid and Civelli, 2002). Therefore, during stressful
conditions, the levels of endorphin, enkephalin and nociceptin
are increased that tend to produce stress adaptive and anti-stress
effects. In contrast to other endogenous opioids, the activation of
dynorphin and kappa opioid receptors in the basolateral amygdala,
nucleus accumbens, hippocampus and LC produces depression
(Shirayama et al., 2004; Chartoff et al., 2009). However, published
data reveals that the dynorphin system is primarily activated during
prolonged inescapable stress and accordingly, the activation
of these receptors is critical in inducing the state of ‘dysphoria’
and ‘learned helplessness’ during prolonged stress-induced depression
(Land et al., 2008; Lucas et al., 2011). In consideration of this
evidence, it may be hypothesized that endorphin, enkephalin and
nociceptin are released during the early stages of stress to cope
with a stressor; whereas, during inescapable stress, the levels of
dynorphin may increase to induce a state of anxiety and depression.
8.2. Effect of stress on drug craving/reward
CPP is a technique used in animal studies to evaluate the preferences
for environmental stimuli including drug of abuse and
A. Bali et al. / Neuroscience and Biobehavioral Reviews 51 (2015) 138–150 147
morphine CPP is used to evaluate the addiction potential of such
drugs. Stressors of different intensities and duration modulate
morphine CPP. In general, acute and escapable stressors inhibit
morphine CPP (Papp et al., 1992; Haghparast et al., 2013); while
chronic and inescapable stressors potentiate morphine CPP (Li et al.,
2007; Rozeske et al., 2009). The development of dysphoria during
chronic and inescapable stress may be responsible for morphine
CPP potentiation, which is supported by reports documenting
that the activation of dynorphin system induces drug-craving and
enhances rewarding functions of addictive drugs (Smith et al.,
2012). The activation of the dynorphin system in the amygdala
may potentiate the magnitude of drug craving (Smith et al., 2012)
by stimulating p38␣ MAPK followed by an increased expression of
serotonin transporters on the synaptic terminals of dorsal raphe
(Lemos et al., 2012; Schindler et al., 2012).
Different scientific groups have explored multiple mechanisms
that may be involved in stress-induced inhibition of morphine
CPP. An increased expression of galanin system, tyrosine hydroxylase
and norepinephrine in nucleus accumbens (Zhao et al., 2013);
activation of glucocorticoid receptors in the basolateral amygdala
(Attarzadeh-Yazdi et al., 2013); increased ratio of pERK/ERK and
pCERB/CERB in the mesocorticolimbic area (Haghparast et al., 2013)
and blockade of GABA (inhibitory neurotransmitter) in the median
prefrontal cortex (leading to its activation) may be involved in
stress-induced inhibition of morphine CPP (Rozeske et al., 2009).
On the other hand, chronic stress or inescapable stress-induced
increase in GABAergic neurotransmission leading to the inhibition
of the median prefrontal cortex along with the rise in dopamine
levels in the nucleus accumbens may contribute in potentiating
morphine CPP (Li et al., 2007; Rozeske et al., 2012).
Furthermore, stress also reinstates the extinct morphine CPP
suggesting that stress induces the craving for drugs of abuse (Qi
et al., 2013). Stress exposure may reinstate morphine CPP through
various mechanisms, including increased release of CRH that
alters the GABAergic transmission (increases GABAA and decreases
GABAB receptor activation) (Li et al., 2013; Meng et al., 2014);
activation of orexin receptors 1 and 2 in nucleus accumbens and
decreased oxytocin in lateral septum and amygdala regions (Qi
et al., 2013).
9. Conclusion
Research studies have documented that endogenous opioids
play an important role in regulating the stress response. ␤Endorphins
and mu receptor agonists tend to reduce the stress
response and produce stress adaptation by preventing the overactivation
of the HPA axis. Similarly, brain-derived enkephalin
and nociceptin are also shown to attenuate anxiety and produce
anti-stress effects. In contrast to these findings, a stress-induced
increase in dynorphin levels with subsequent activation of kappa
opioid receptors produces learned helplessness, dysphoria and
depression. Yet stress also influences the response of opioids,
including drug craving, and reinstatement of drug of abuse. Stress
triggered ERK/CREB signaling in the mesocorticolimbic dopaminergic
system; increase in galanin along with norepinephrine in
nucleus accumbens region; and activation of glucocorticoid receptors
in the basolateral amygdala contribute to consolidating the fear
memory and decreasing morphine CPP. Conversely, inescapable
stress-induced increases in dopamine levels in the nucleus
accumbens and chronic stress-induced increases in GABAergic
transmission and inactivation of the median prefrontal cortex contribute
in potentiating morphine-induced CPP. Stress exposure
reinstates the extinct morphine CPP by altering the GABAergic
transmission, activating orexin receptors in the nucleus accumbens
and decreasing oxytocin levels in the lateral septum and
amygdala.
Acknowledgement
The authors are grateful to Department of Pharmaceutical Sciences
and Drug Research, Punjabi University, Patiala, India for
supporting this study and providing technical facilities for the work.
We are also thankful to Dr. Kiran Bali, Clinical Psychologist, Central
Manchester Universities NHS Foundation Trust, UK for editing the
manuscript.
References
al’Absi, M., Wittmers, L.E., Ellestad, D., Nordehn, G., Kim, S.W., Kirschbaum, C., Grant,
J.E., 2004. Sex differences in pain and hypothalamic–pituitary–adrenocortical
responses to opioid blockade. Psychosom. Med. 66 (March–April (2)), 198–206.
Al-Hasani, R., McCall, J.G., Bruchas, M.R., 2013. Exposure to chronic mild stress
prevents kappa opioid-mediated reinstatement of cocaine and nicotine place
preference. Front Pharmacol. 4 (August), 96.
Allen, A.J., McCubbin, J.A., Loveless, J.P., Helfer, S.G., 2014. Effects of estrogen and opioid
blockade on blood pressure reactivity to stress in postmenopausal women.
J. Behav. Med. 37 (February (1)), 94–101.
Amir, S., 1982. Involvement of endogenous opioids with forced swimming-induced
immobility in mice. Physiol. Behav. 28, 249–251.
Anand, R., Gulati, K., Ray, A., 2012. Pharmacological evidence for the role of nitric
oxide in the modulation of stress-induced anxiety by morphine in rats. Eur. J.
Pharmacol. 676 (February (1–3)), 71–74.
Attarzadeh-Yazdi, G., Karimi, S., Azizi, P., Yazdi-Ravandi, S., Hesam, S., Haghparast, A.,
2013. Inhibitory effects of forced swim stress and corticosterone on the acquisition
but not expression of morphine-induced conditioned place preference:
involvement of glucocorticoid receptor in the basolateral amygdala. Behav. Brain
Res. 252 (September), 339–346, http://dx.doi.org/10.1016/j.bbr.2013.06.018
(Epub 2013 June 22).
Bahi, A., Dreyer, J.L., 2014. Chronic psychosocial stress causes delayed extinction and
exacerbates reinstatement of ethanol-induced conditioned place preference in
mice. Psychopharmacology (Berl) 231 (January (2)), 367–377.
Bali, A., Jaggi, A.S., 2013. Angiotensin as stress mediator: role of its receptor and
interrelationships among other stress mediators and receptors. Pharmacol. Res.
76 (October), 49–57, http://dx.doi.org/10.1016/j.phrs.2013.07.004 (Epub 2013
July 24).
Bali, A., Jaggi, A.S., 2014. Multifunctional aspects of allopregnanolone in stress and
related disorders. Prog. Neuropsychopharmacol. Biol. Psychiatry 48 (January),
64–78, http://dx.doi.org/10.1016/j.pnpbp.2013.09.005 (Epub 2013 September
14).
Bali, A., Singh, N., Jaggi, A.S., 2014. Neuropeptides as therapeutic targets to combat
stress-associated behavioral and neuroendocrinological effects. CNS Neurol.
Disord – Drug Targets 13.
Barfield, E.T., Barry, S.M., Hodgin, H.B., Thompson, B.M., Allen, S.S., Grisel, J.E., 2010.
Beta-endorphin mediates behavioral despair and the effect of ethanol on the tail
suspension test in mice. Alcohol Clin. Exp. Res. 34, 1066–1072.
Barfield, E.T., Moser, V.A., Hand, A., Grisel, J.E., 2013. ␤-Endorphin modulates the
effect of stress on novelty-suppressed feeding. Front. Behav. Neurosci. 7, 19.
Bérubé, P., Laforest, S., Bhatnagar, S., Drolet, G., 2013. Enkephalin and dynorphin
mRNA expression are associated with resilience or vulnerability to chronic social
defeat stress. Physiol. Behav. 122, 237–245.
Bérubé, P., Poulin, J.F., Laforest, S., Drolet, G., 2014. Enkephalin knockdown in the
basolateral amygdala reproduces vulnerable anxiety-like responses to chronic
unpredictable stress. Neuropsychopharmacology 39 (5), 1159–1168.
Boasen, J.F., McPherson, R.J., Hays, S.L., Juul, S.E., Gleason, C.A., 2009. Neonatal stress
or morphine treatment alters adult mouse conditioned place preference. Neonatology
95 (3), 230–239.
Bowman, R.E., Beck, K.D., Luine, V.N., 2003. Chronic stress effects on memory: sex differences
in performance and monoaminergic activity. Horm. Behav. 43 (January
(1)), 48–59.
Bowman, R.E., 2005. Stress-induced changes in spatial memory are sexually differentiated
and vary across the lifespan. J. Neuroendocrinol. 17 (August (8)),
526–535.
Bruchas, M.R., Chavkin, C., 2010. Kinase cascades and ligand-directed signaling at
the kappa opioid receptor. Psychopharmacology (Berl.) 210 (2), 137–147.
Bruchas, M.R., Land, B.B., Lemos, J.C., Chavkin, C., 2009. CRF1-R activation of the
dynorphin/kappa opioid system in the mouse basolateral amygdala mediates
anxiety-like behavior. PLoS ONE 4, e8528.
Bryant, R.A., Creamer, M., O’Donnell, M., Silove, D., McFarlane, A.C., 2009. A study
of the protective function of acute morphine administration on subsequent
posttraumatic stress disorder. Biol. Psychiatry 65, 438–440.
Burnett, F.E., Scott, L.V., Weaver, M.G., Medbak, S.H., Dinan, T.G., 1999. The effect
of naloxone on adrenocorticotropin and cortisolrelease: evidence for a reducedresponse
in depression. J. Affect. Disord. 53 (June (3)), 263–268.
Burstein, S.R., Williams, T.J., Lane, D.A., Knudsen, M.G., Pickel, V.M., McEwen, B.S.,
Waters, E.M., Milner, T.A., 2013. The influences of reproductive status and acute
stress on the levels of phosphorylated delta opioid receptor immunoreactivity
in rat hippocampus. Brain Res. 1518 (June), 71–81.
Butler 1, R.K., Finn, D.P., 2009. Stress-induced analgesia. Prog. Neurobiol. 88 (July
(3)), 184–202.
148 A. Bali et al. / Neuroscience and Biobehavioral Reviews 51 (2015) 138–150
Carey, A.N., Lyons, A.M., Shay, C.F., Dunton, O., McLaughlin, J.P., 2009. Endogenous
kappa opioid activation mediates stress-induced deficits in learning and memory.
J. Neurosci. 29 (13), 4293–4300.
Carr, G.V., Lucki, I., 2010. Comparison of the kappa-opioid receptor antagonist DIPPA
in tests of anxiety-like behavior between Wistar Kyoto and Sprague Dawley rats.
Psychopharmacology (Berl.) 210, 295–302.
Cartwright, S., Cooper, C.L., 1997. Managing Workplace Stress. SAGE Publications,
Thousand Oaks, CA.
Carvalho-Costa, P.G., Branco, L.G., Leite-Panissi, C.R., 2014. Acute stress-induced
antinociception is cGMP-dependent but heme oxygenase-independent. Braz. J.
Med. Biol. Res. September (Epub ahead of print).
Charmandarie, Tsigos, C., Chrousos, G., 2005. endocrinology of the stress response.
Annu. Rev. Physiol. 67, 259–284.
Chartoff, E.H., Papadopoulou, M., MacDonald, M.L., Parsegian, A., Potter, D., Konradi,
C., Carlezon, W.A., 2009. Desipramine reduces stress-activated dynorphin
expression and CREB phosphorylation in NAc tissue. Mol. Pharmacol. 75,
704–712.
Chen, J.X., Li, W., Zhao, X., Yang, J.X., Xu, H.Y., Wang, Z.F., Yue, G.X., 2004. Changes
of mRNA expression of enkephalin and prodynorphin in hippocampus of rats
with chronic immobilization stress. World J. Gastroenterol. 10 (September (17)),
2547–2549.
Ciccocioppo, R., de Guglielmo, G., Hansson, A.C., Ubaldi, M., Kallupi, M., Cruz,
M.T., Oleata, C.S., Heilig, M., Roberto, M., 2014. Restraint stress alters
nociceptin/orphanin FQ and CRF systems in the rat central amygdala: significance
for anxiety-like behaviors. J. Neurosci. 34 (January (2)), 363–
372.
Cruz, M.T., Herman, M.A., Kallupi, M., Roberto, M., 2012. Nociceptin/orphanin FQ
blockade of corticotropin-releasing factor-induced gamma-aminobutyric acid
release in central amygdala is enhanced after chronic ethanol exposure. Biol.
Psychiatry 71 (8), 666–676.
Curtis, A.L., Leiser, S.C., Snyder, K., Valentino, R.J., 2012. Predator stress engages
corticotropin-releasing factor and opioid systems to alter the operating mode
of locus coeruleus norepinephrine neurons. Neuropharmacology 62 (March (4)),
1737–1745.
Dai, S., Ma, Z., 2014. BDNF-trkB-KCC2-GABA pathway may be related to chronic
stress-induced hyperalgesia at both the spinal and supraspinal level. Med.
Hypotheses 83 (October (6)), 772–774.
Dai, X., Thavundayil, J., Gianoulakis, C., 2005. Differences in the peripheral levels of
beta-endorphin in response to alcohol and stress as a function of alcohol dependence
and family history of alcoholism. Alcohol Clin. Exp. Res. 29 (November (11)),
1965–1975.
Delaney, G., Dawe, K.L., Hogan, R., Hunjan, T., Roper, J., Hazell, G., Lolait, S.J., Fulford,
A.J., 2012. Role of nociceptin/orphanin FQ and NOP receptors in the response
to acute and repeated restraint stress in rats. J. Neuroendocrinol. 24 (12),
1527–1541.
Drake, C.T., Chavkin, C., Milner, T.A., 2007a. Opioid systems in the dentate gyrus.
Prog. Brain Res. 163, 245–814.
Drake, C.T., Chavkin, C., Milner, T.A., 2007b. Opioid systems in the dentate gyrus.
Prog. Brain Res. 163, 245–263.
Drolet, G., Dumont, E.C., Gosselin, I., Kinkead, R., Laforest, S., Trottier, J.F., 2001. Role
of endogenous opioid system in the regulation of the stress response. Prog.
Neuropsychopharmacol. Biol. Psychiatry 25 (May (4)), 729–741.
Frew, A.K., Drummond, P.D., 2007. Negative affect, pain and sex: the role of endogenous
opioids. Pain 132 (November (Suppl. 1)), S77–S85.
Galea, L.A.M., McEwen, B.S., Tanapat, P., Deak, T., Spencer, R.L., Dhabhar, F.S., 1997.
Sex differences in dendritic atrophy of CA3 pyramidal neurons in response to
chronic restraint stress. Neuroscience 81, 689–697.
Gamaro, G.D., Torres, I.L., Laste, G., Fontella, F.U., Silveira, P.P., Manoli, L.P., Frantz, F.,
Eickhoff, F., Dalmaz, C., 2014. Gender-dependent effect on nociceptive response
induced by chronic variable stress. Physiol. Behav. 135 (August), 44–48.
García-Carmona, J.A., Milanés, M.V., Laorden, M.L., 2013. Brain stress system
response after morphine-conditioned place preference. Int. J. Neuropsychopharmacol.
16 (October (9)), 1999–2011, http://dx.doi.org/10.1017/
S1461145713000588 (Epub 2013 June 10).
García-Pardo, M.P., Rodríguez-Arias, M., Maldonado, C., Manzanedo, C., Mi˜narro, J.,
Aguilar, M.A., 2014. Effects of acute social stress on the conditioned place preference
induced by MDMA in adolescent and adult mice. Behav. Pharmacol. 25
(September (5–6)), 532–546.
Gerashchenko, D., Horvath, T.L., Xie, X.S., 2011. Direct inhibition of hypocretin/orexin
neurons in the lateral hypothalamus by nociceptin/orphanin FQ blocks stressinduced
analgesia in rats. Neuropharmacology 60 (March (4)), 543–549,
http://dx.doi.org/10.1016/j.neuropharm.2010.12.026 (Epub 2010 December
30).
Ghasemzadeh, Z., Rezayof, A., 2015. Ventral hippocampal nicotinic acetylcholine
receptors mediate stress-induced analgesia in mice. Prog. Neuropsychopharmacol.
Biol. Psychiatry 56 (January), 235–242.
Gillett, K., Harshberger, E., Valdez, G.R., 2013. Protracted withdrawal from ethanol
and enhanced responsiveness stress: regulation via the dynorphin/kappa opioid
receptor system. Alcohol 47 (August (5)), 359–365, http://dx.doi.org/
10.1016/j.alcohol.2013.05.001 (Epub 2013 May 31).
Goeldner, C., Spooren, W., Wichmann, J., Prinssen, E.P., 2012. Further characterization
of the prototypical nociceptin/orphanin FQ peptide receptor agonist Ro
64-6198 in rodent models of conflict anxiety and despair. Psychopharmacology
(Berl.) 222 (July (2)), 203–214.
Gonzales, K.L., Chapleau, J.D., Pierce, J.P., Kelter, D.T., Williams, T.J., Torres-Reveron,
A., McEwen, B.S., Waters, E.M., Milner, T.A., 2011. The influences of reproductive
status and acute stress on the levels of phosphorylated mu opioid receptor
immunoreactivity in rat hippocampus. Front. Endocrinol. (Lausanne) 2 (August
(18)).
Grisel, J.E., Bartels, J.L., Allen, S.A., Turgeon, V.L., 2008. Influence of ␤-endorphin on
anxious behavior in mice: interaction with EtOH. Psychopharmacology (Berl.)
200, 105–115.
Haghparast, A., Fatahi, Z., Alamdary, S.Z., Reisi, Z., Khodagholi, F., 2013. Changes in
the levels of p-ERK, p-CREB, and c-fos in rat mesocorticolimbic dopaminergic
system after morphine-induced conditioned place preference: the role of acute
and subchronic stress. Cell. Mol. Neurobiol. (Epub ahead of print).
Hays, S.L., McPherson, R.J., Juul, S.E., Wallace, G., Schindler, A.G., Chavkin, C., Gleason,
C.A., 2012. Long-term effects of neonatal stress on adult conditioned place preference
(CPP) and hippocampal neurogenesis. Behav. Brain Res. 227 (February
(1)), 7–11, http://dx.doi.org/10.1016/j.bbr.2011.10.033 (Epub 2011 October 28).
Hernández, J., Segarra, A.B., Ramírez, M., Banegas, I., de Gasparo, M., Alba, F., Vives,
F., Durán, R., Prieto, I., 2009. Stress influences brain enkephalinase, oxytocinase
and angiotensinase activities: a new hypothesis. Neuropsychobiology 59 (3),
184–189, http://dx.doi.org/10.1159/000219306 (Epub 2009 May 20).
Holbrook, T.L., Galarneau, M.R., Dye, J.L., Quinn, K., Dougherty, A.L., 2010. Morphine
use after combat injury in Iraq and post-traumatic stress disorder. N. Engl. J.
Med. 362, 110–117.
Hollt, V., Haarmann, I., Bovermann, K., Jerlicz, M., Herz, A., 1980. Dynorphin-related
immunoreactive peptides in rat brain and pituitary. Neurosci. Lett. 18, 149–153.
Homayoun, H., Khavandgar, S., Zarrindast, M.R., 2003. Morphine state-dependent
learning: interactions with alpha2-adrenoceptors and acute stress. Behav.
Pharmacol. 14 (February (1)), 41–48.
Imbe, H., Murakami, S., Okamoto, K., Iwai-Liao, Y., Senba, E., 2004. The effects of acute
and chronic restraint stress on activation of ERK in the rostral ventromedial
medulla and locus coeruleus. Pain 112, 361–371.
Jackson, K.J., McLaughlin, J.P., Carroll, F.I., Damaj, M.I., 2013. Effects of the kappa
opioid receptor antagonist, norbinaltorphimine, on stress and drug-induced
reinstatement of nicotine-conditioned place preference in mice. Psychopharmacology
(Berl) 226 (April (4)), 763–768.
Joshi, J.C., Ray, A., Gulati, K., 2014. Differential modulatory effects of morphine on
acute and chronic stress induced neurobehavioral and cellular markers in rats.
Eur. J. Pharmacol. 729 (April), 17–21.
Karimi, S., Attarzadeh-Yazdi, G., Yazdi-Ravandi, S., Hesam, S., Azizi, P., Razavi, Y.,
Haghparast, A., 2014. Forced swim stress but not exogenous corticosterone
could induce the reinstatement of extinguished morphine conditioned place
preference in rats: involvement of glucocorticoid receptors in the basolateral
amygdala. Behav. Brain Res. 264 (May), 43–50.
Kimoto, M., Zeredo, J., Nihei, Z., Yamashita, H., Kaida, K., 2013. Toda sex differences
in antinociceptive effects induced by gravity stress in rats. J. Behav. Brain Sci. 3,
179–187.
Kung, J.C., Chen, T.C., Shyu, B.C., Hsiao, S., Huang, A.C., 2010. Anxiety- and depressivelike
responses and c-fos activity in preproenkephalin knockout mice: oversensitivity
hypothesis of enkephalin deficit-induced posttraumatic stress disorder.
J. Biomed. Sci. 17 (April), 29, http://dx.doi.org/10.1186/1423-0127-17-29.
Land, B.B., Bruchas, M.R., Lemos, J.C., Xu, M., Melief, E.J., Chavkin, C., 2008. The
dysphoric component of stress is encoded by activation of the dynorphin kappaopioid
system. J. Neurosci. 28, 407–414.
Larauche, M., Mulak, A., Kim, Y.S., Labus, J., Million, M., Taché, Y., 2012. Visceral
analgesia induced by acute and repeated water avoidance stress in rats: sex difference
in opioid involvement. Neurogastroenterol. Motil. 24 (November (11)),
1031–1547.
Lawson, K.P., Nag, S., Thompson, A.D., Mokha, S.S., 2010. Sex-specificity and
estrogen-dependence of kappa opioid receptor-mediated antinociception and
antihyperalgesia. Pain 151 (December (3)), 806–815.
Leão, R.M., Cruz, F.C., Planeta, C.S., 2009. Exposure to acute restraint stress reinstates
nicotine-induced place preference in rats. Behav. Pharmacol. 20 (February (1)),
109–113.
Lemos, J.C., Roth, C.A., Messinger, D.I., Gill, H.K., Phillips, P.E., Chavkin, C., 2012.
Repeated stress dysregulates ␬-opioid receptor signaling in the dorsal raphe
through a p38␣ MAPK-dependent mechanism. J. Neurosci. 32 (September (36)),
12325–12336, http://dx.doi.org/10.1523/JNEUROSCI.2053-12.2012.
Li, C., Staub, D.R., Kirby, L.G., 2013. Role of GABAA receptors in dorsal raphe
nucleus in stress-induced reinstatement of morphine-conditioned place preference
in rats. Psychopharmacology (Berl.) 230 (December (4)), 537–545,
http://dx.doi.org/10.1007/s00213-013-3182-x (Epub 2013 June 28).
Li, Y., Li, G.Y., Li, L.J., Wang, C.H., Li, Z.X., Zhang, J.L., Zhang, J., Li, W.H., 2007. Subsequently
enhanced CPP to morphine following chronic but not acute foot-shock
stress associated with corticosterone mechanism in rats. Int. J. Neurosci. 117
(September (9)), 1237–1255.
Lishmanov, Iu B, Maslov, L.N., Naryzhnaia, N.V., Pei, J.M., Kolar, F., Zhang, Y., Portnichenko,
A.G., Wang, N., 2012. Endogenous opioid system as a mediator of acute
and long-term adaptation to stress. Prospects for clinical use of opioid peptides.
Vestn. Ross. Akad. Med. Nauk. 6, 73–82.
Lucas, L.R., Dragisic, T., Duwaerts, C.C., Swiatkowski, M., Suzuki, H., 2011. Effects
of recovery from immobilization stress on striatal preprodynorphin- and
kappa opioid receptor-mRNA levels of the male rat. Physiol. Behav. 104,
972–980.
Luine, V., 2002. Sex differences in chronic stress effects on memory in rats. Stress 5,
205–216.
Magari˜nos, A.M., Verdugo, J.M.G., McEwen, B.S., 1997. Chronic stress alters synaptic
terminal structure in hippocampus. Proc. Natl. Acad. Sci. U. S. A. 94,
14002–14008.
A. Bali et al. / Neuroscience and Biobehavioral Reviews 51 (2015) 138–150 149
Mague, S.D., Pliakas, A.M., Todtenkopf, M.S., Tomasiewicz, H.C., Zhang, Y., Stevens,
W.C., Jones, R.M., Portoghese, P.S., Carlezon, W.A., 2003. Antidepressant-like
effects of kappa-opioid receptor antagonists in the forced swim test in rats. J.
Pharmacol. Exp. Ther. 305, 323–330.
McEwen, B.S., Milner, T.A., 2007. Hippocampal formation: shedding light on the
influence of sex and stress on the brain. Brain Res. Rev 55, 343–355.
McLaughlin, J.P., Marton-Popovici, M., Chavkin, C., 2003. Kappa opioid receptor
antagonism and prodynorphin gene disruption block stress-induced behavioral
responses. J. Neurosci. 23, 5674–5683.
McReynolds, J.R., Vranjkovic, O., Thao, M., Baker, D.A., Makky, K., Lim, Y., Mantsch,
J.R., 2014. Beta-2 adrenergic receptors mediate stress-evoked reinstatement of
cocaine-induced conditioned place preference and increases in CRF mRNA in
the bed nucleus of the stria terminalis in mice. Psychopharmacology (Berl) 231
(October (20)), 3953–3963.
Melcer 1, T., Walker, J., Sechriest 2nd, V.F., Lebedda, M., Quinn, K., Galarneau, M.,
2014. Glasgow Coma Scores, early opioids, and posttraumatic stress disorder
among combat amputees. J. Trauma Stress, http://dx.doi.org/10.1002/jts.21909
(Epub ahead of print).
Meng, S., Quan, W., Qi, X., Su, Z., Yang, S., 2014. Effect of baclofen on
morphine-induced conditioned place preference, extinction, and stress-induced
reinstatement in chronically stressed mice. Psychopharmacology (Berl.) 231
(January (1)), 27–36, http://dx.doi.org/10.1007/s00213-013-3204-8 (Epub 2013
July 28).
Merenlender-Wagner, A., Dikshtein, Y., Yadid, G., 2009. The beta-endorphin role in
stress-related psychiatric disorders. Curr. Drug Targets 10, 1096–1108.
Michaels, C.C., Holtzman, S.G., 2008. Early postnatal stress alters place conditioning
to both mu- and kappa-opioid agonists. J. Pharmacol. Exp. Ther. 325 (April (1)),
313–318.
Milner, T.A., Burstein, S.R., Marrone, G.F., Khalid, S., Gonzalez, A.D., Williams, T.J.,
Schierberl, K.C., Torres-Reveron, A., Gonzales, K.L., McEwen, B.S., Waters, E.M.,
2013. Stress differentially alters mu opioid receptor density and trafficking in
parvalbumin-containing interneurons in the female and male rat hippocampus.
Synapse 67 (November (11)), 757–772.
Mollereau, C., Parmentier, M., Mailleux, P., Butour, J.L., Moisand, C., Chalon,
P., et al., 1994. ORL1, a novel member of the opioid receptor family.
Cloning, functional expression and localization. FEBS Lett. 341, 33–38,
http://dx.doi.org/10.1016/0014-5793(94)80235-1.
Nakagawasai, O., Tadano, T., Tan No, K., Niijima, F., Sakurada, S., Endo, Y., Kisara, K.,
1999. Changes in beta-endorphin and stress-induced analgesia in mice after
exposure to forced walking stress. Methods Find. Exp. Clin. Pharmacol. 21,
471–476.
Narita, M., Tseng, L.F., 1998. Evidence for the existence of the beta-endorphinsensitive
epsilon-opioid receptor in the brain: the mechanisms of
epsilon-mediated antinociception. Jpn. J. Pharmacol. 76 (March (3)),
233–253.
Nativio, P., Pascale, E., Maffei, A., Scaccianoce, S., Passarelli, F., 2012. Effect of stress
on hippocampal nociceptin expression in the rat. Stress 15 (July (4)), 378–384,
http://dx.doi.org/10.3109/10253890.2011.627071 (Epub 2012 January 4).
Nazzaro, C., Marino, S., Barbieri, M., Siniscalchi, A., 2009. Inhibition of serotonin
outflow by nociceptin/orphaninFQ in dorsal raphe nucleus slices from normal
and stressed rats: role of corticotropin releasing factor. Neurochem. Int. 54
(May–June (5–6)), 378–384.
Nixon, R.D., Nehmy, T.J., Ellis, A.A., Ball, S.A., Menne, A., McKinnon, A.C., 2010. Predictors
of posttraumatic stress in children following injury: the influence of
appraisals, heart rate, and morphine use. Behav. Res. Ther. 48, 810–815.
Palkovits, M., 1987. Organization of the stress response at the anatomical level. Prog.
Brain Res. 72, 47–55.
Papp, M., Lappas, S., Muscat, R., Willner, P., 1992. Attenuation of place preference
conditioning but not place aversion conditioning by chronic mild stress. J. Psychopharmacol.
6, 352–356.
Pearson, K.A., Stephen, A., Beck, S.G., Valentino, R.J., 2006. Identifying genes in
monoamine nuclei that may determine stress vulnerability and depressive
behavior in Wistar-Kyoto rats. Neuropsychopharmacology 31, 2449–2461.
Poulin, J.F., Chevalier, B., Laforest, S., Drolet, G., 2006. Enkephalinergic afferents of
the centromedial amygdala in the rat. J. Comp. Neurol. 496, 859–876.
Poulin, J.F., Laforest, S., Drolet, G., 2014. Enkephalin downregulation in the nucleus
accumbens underlies chronic stress-induced anhedonia. Stress 17 (January (1)),
88–96.
Qi, K., Wei, C., Li, Y., Sui, N., 2013. Orexin receptors within the nucleus accumbens
shell mediate the stress but not drug priming-induced reinstatement of morphine
conditioned place preference. Front. Behav. Neurosci. 7 (October), 144,
http://dx.doi.org/10.3389/fnbeh.2013.00144.
Qi, X., Lin, W., Li, J., Li, H., Wang, W., Wang, D., et al., 2008. Fluoxetine increases
the activity of the ERK-CREB signal system and alleviates the depressive-like
behavior in rats exposed to chronic forced swim stress. Neurobiol. Dis. 31 (2),
278–285.
Reinscheid, R.K., Civelli, O., 2002. The orphanin FQ/nociceptin knockout mouse: a
behavioral model for stress responses. Neuropeptides 36 (April–June (2–3)),
72–76.
Rozeske, R.R., Der-Avakian, A., Bland, S.T., Beckley, J.T., Watkins, L.R., Maier, S.F.,
2009. The medial prefrontal cortex regulates the differential expression of
morphine-conditioned place preference following a single exposure to controllable
or uncontrollable stress. Neuropsychopharmacology 34 (March (4)),
834–843, http://dx.doi.org/10.1038/npp.2008.34 (Epub 2008 March 26).
Rozeske, R.R., Der-Avakian, A., Watkins, L.R., Maier, S.F., 2012. Activation of
the medial prefrontal cortex by escapable stress is necessary for protection
against subsequent inescapable stress-induced potentiation of morphine
conditioned place preference. Eur. J. Neurosci. 35 (January (1)), 160–165,
http://dx.doi.org/10.1111/j.1460-9568.2011.07929.x (Epub 2011 November
25).
Rubinstein, M., Mogil, J.S., Japón, M., Chan, E.C., Allen, R.G., Low, M.J., 1996. Absence
of opioid stress-induced analgesia in mice lacking ␤-endorphin by site-directed
mutagenesis. Proc. Natl. Acad. Sci. U. S. A. 93, 3995–4000.
Sanders, M.J., Kieffer, B.L., Fanselow, M.S., 2005. Deletion of the mu opioid receptor
results in impaired acquisition of Pavlovian context fear. Neurobiol. Learn. Mem.
84, 33–41.
Sarkar, D.K., Kuhn, P., Marano, J., Chen, C., Boyadjieva, N., 2007. Alcohol exposure
during the developmental period induces beta-endorphin neuronal death and
causes alteration in the opioid control of stress axis function. Endocrinology 148,
2828–2834.
Sauriyal, D.S., Jaggi, A.S., Singh, N., 2011. Extending pharmacological spectrum
of opioids beyond analgesia: multifunctional aspects in different pathophysiological
states. Neuropeptides 45 (June (3)), 175–188, http://dx.doi.org/
10.1016/j.npep.2010.12.004 (Epub 2011 January 3).
Schindler, A.G., Messinger, D.I., Smith, J.S., Shankar, H., Gustin, R.M., Schattauer, S.S.,
Lemos, J.C., Chavkin, N.W., Hagan, C.E., Neumaier, J.F., Chavkin, C., 2012. Stress
produces aversion and potentiates cocaine reward by releasing endogenous
dynorphins in the ventral striatum to locally stimulate serotonin reuptake. J.
Neurosci. 32 (December (49)), 17582–17596.
Schwandt, M.L., Lindell, S.G., Higley, J.D., Suomi, S.J., Heilig, M., Barr, C.S., 2011.
OPRM1 gene variation influences hypothalamic–pituitary–adrenal axis function
in response to a variety of stressors in rhesus macaques. Psychoneuroendocrinology
36, 1303–1311.
Selye, H., 1998. A syndrome produced by diverse nocuous agents, 1936. J Neuropsychiatry
Clin Neurosci. 10 (Spring (2)), 230–231.
Shiflett, M.W., Balleine, B.W., 2011. Contributions of ERK signaling in the striatum
to instrumental learning and performance. Behav. Brain Res. 218,
240–247.
Shirayama, Y., Ishida, H., Iwata, M., Hazama, G.I., Kawahara, R., Duman, R.S.,
2004. Stress increases dynorphin immunoreactivity in limbic brain regions and
dynorphin antagonism produces antidepressant-like effects. J. Neurochem. 90,
1258–1268.
Simmons, M.L., Chavkin, C., 1996. Endogenous opioid regulation of hippocampal
function. Int. Rev. Neurobiol. 39, 145–196.
Slamberová, R., Rimanóczy, A., Bar, N., Schindler, C.J., Vathy, I., 2003. Density of opioid
receptors in the hippocampus of adult male and female rats is altered by
prenatal morphine exposure and gonadal hormone treatment. Hippocampus
13, 461–471.
Smith, J.S., Schindler, A.G., Martinelli, E., Gustin, R.M., Bruchas, M.R., Chavkin, C.,
2012. Stress-induced activation of the dynorphin/␬-opioid receptor system in
the amygdala potentiates nicotine conditioned place preference. J. Neurosci. 32,
1488–1495.
Staub, D.R., Lunden, J.W., Cathel, A.M., Dolben, E.L., Kirby, L.G., 2012. Morphine
history sensitizes postsynaptic GABA receptors on dorsal raphe serotonin neurons
in a stress-induced relapse model in rats. Psychoneuroendocrinology 37
(June (6)), 859–870, http://dx.doi.org/10.1016/j.psyneuen.2011.10.002 (Epub
2011 November 1).
Stoddard Jr., F.J., Sorrentino, E.A., Ceranoglu, T.A., Saxe, G., Murphy, J.M., Drake, J.E.,
et al., 2009. Preliminary evidence for the effects of morphine on posttraumatic
stress disorder symptoms in one-to four-year-olds with burns. J. Burn Care Res.
30 (5), 836–843.
Szczytkowski-Thomson, J.L., Lebonville, C.L., Lysle, D.T., 2013. Morphine prevents
the development of stress-enhanced fear learning. Pharmacol. Biochem. Behav.
103, 672–677, http://dx.doi.org/10.1016/j.pbb.2012.10.013.
Steckler, T., Kalin, N.H., Reul, J.M.H.M., 2005. Handbook of Stress and the Brain: Part
2: Stress: Integrative and Clinical Aspects. Elsevier, 484 p.
Torres-Reveron, A., Khalid, S., Williams, T.J., Waters, E.M., Drake, C.T., McEwen, B.S.,
Milner, T.A., 2008. Ovarian steroids modulate leu-enkephalin levels and target
leu-enkephalinergic profiles in the female hippocampal mossy fiber pathway.
Brain Res. 1232 (September), 70–84.
Torres-Reveron, A., Khalid, S., Williams, T.J., Waters, E.M., Jacome, L., Luine,
V.N., Drake, C.T., McEwen, B.S., Milner, T.A., 2009. Hippocampal dynorphin
immunoreactivity increases in response to gonadal steroids and is positioned
for direct modulation by ovarian steroid receptors. Neuroscience 159 (March
(1)), 204–216.
Valentino, R.J., Bockstaele, E.V., 2008. Convergent regulation of locus
coeruleus activity as anadaptive response to stress. Eur. J. Pharmacol. 583,
194–203.
Van Loon, G.R., Pierzchala, K., Houdi, A.A., Kvetnansk´y, R., Zeman, P., 1990. Tolerance
and cross-tolerance to stress-induced increases in plasma Met-enkephalin in
rats with adaptively increased resting secretion. Endocrinology 126 (April (4)),
2196–2204.
Van’t Veer, A., Carlezon Jr., W.A., 2013. Role of kappa-opioid receptors in stress
and anxiety-related behavior. Psychopharmacology (Berl.) 229 (October (3)),
435–452.
Vien, T.N., Gleason, C.A., Hays, S.L., McPherson, R.J., Chavkin, C., Juul, S.E., 2009. Effects
of neonatal stress and morphine on kappa opioid receptor signaling. Neonatology
96 (4), 235–243, http://dx.doi.org/10.1159/000220763 (Epub 2009 May
27).
Westbrook, R.F., Good, A.J., Kiernan, M.J., 1997. Microinjection of morphine into the
nucleus accumbens impairs contextual learning in rats. Behav. Neurosci. 111,
996–1013.
150 A. Bali et al. / Neuroscience and Biobehavioral Reviews 51 (2015) 138–150
Wick, M.J., Minnerath, S.R., Lin, X., Elde, R., Law, P.Y., Loh, H.H., 1994. Isolation of
a novel cDNA encoding a putative membrane receptor with high homology to
the cloned mu, delta, and kappa opioid receptors. Brain Res. Mol. Brain Res. 27,
37–44, http://dx.doi.org/10.1016/0169-328X(94)90181-3.
Williams, T.J., Akama, K.T., Knudsen, M.G., McEwen, B.S., Milner, T.A., 2011. Ovarian
hormones influence corticotropin releasing factor receptor colocalization with
delta opioid receptors in CA1 pyramidal cell dendrites. Exp. Neurol. 230 (August
(2)), 186–196.
Witkin, J.M., Statnick, M.A., Rorick-Kehn, L.M., Pintar, J.E., Ansonoff, M., Chen,
Y., Tucker, R.C., Ciccocioppo, R., 2013. The biology of Nociceptin/Orphanin
FQ (N/OFQ) related to obesity, stress, anxiety, mood, and drug dependence.
Pharmacol. Ther., http://dx.doi.org/10.1016/j.pharmthera.2013.10.011
(pii:S0163-7258(13)00216-7, Epub ahead of print).
Yamada, K., Nabeshima, T., 1995. Stress-induced behavioral responses and multiple
opioid systems in the brain. Behav. Brain Res. 67, 133–145.
Yang, Y., Zheng, X., Wang, Y., Cao, J., Dong, Z., Cai, J., Sui, N., Xu, L., 2004. Stress enables
synaptic depression in CA1 synapses by acute and chronic morphine: possible
mechanisms for corticosterone on opiate addiction. J. Neurosci. 24 (March (10)),
2412–2420.
Zanos, P., Georgiou, P., Wright, S.R., Hourani, S.M., Kitchen, I., Winsky-Sommerer,
R., Bailey, A., 2013. The oxytocin analogue carbetocin prevents emotional
impairment and stress-induced reinstatement of opioid-seeking in morphineabstinent
mice. Neuropsychopharmacology, http://dx.doi.org/10.1038/
npp.2013.285 (Epub ahead of print).
Zhang, Y., Gandhi, P.R., Standifer, K.M., 2012. Increased nociceptive sensitivity and
nociceptin/orphanin FQ levels in a rat model of PTSD. Mol. Pain 8 (October),
76.
Zhao, X., Seese, R.R., Yun, K., Peng, T., Wang, Z., 2013. The role of galanin system
in modulating depression, anxiety, and addiction-like behaviors after chronic
restraint stress. Neuroscience 246 (August), 82–93.