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Traumatic Stress-Induced Vulnerability to Addiction: Critical Role of the Dynorphin/Kappa Opioid Receptor System

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Traumatic Stress-Induced Vulnerability to Addiction: Critical Role of the Dynorphin/Kappa Opioid Receptor System

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Substance use disorders (SUD) may emerge from an individual’s attempt to limit negative affective states and symptoms linked to stress. Indeed, SUD is highly comorbid with chronic stress, traumatic stress, or post-traumatic stress disorder (PTSD), and treatments approved for each pathology individually often failed to have a therapeutic efficiency in such comorbid patients. The kappa-opioid receptor (KOR) and its endogenous ligand dynorphin (DYN), seem to play a key role in the occurrence of this comorbidity. The DYN/KOR function is increased either in traumatic stress or during drug use, dependence acquisition and DYN is released during stress. The behavioural effects of stress related to the DYN/KOR system include anxiety, dissociative and depressive symptoms, as well as increased conditioned fear response. Furthermore, the DYN/KOR system is implicated in negative reinforcement after the euphoric effects of a drug of abuse ends. During chronic drug consumption DYN/KOR functions increase and facilitate tolerance and dependence. The drug-seeking behaviour induced by KOR activation can be retrieved either during the development of an addictive behaviour, or during relapse after withdrawal. DYN is known to be one of the most powerful negative modulators of dopamine signalling, notably in brain structures implicated in both reward and fear circuitries. KOR are also acting as inhibitory heteroreceptors on serotonin neurons. Moreover, the DYN/KOR system cross-regulate with corticotropin-releasing factor in the brain. The sexual dimorphism of the DYN/KOR system could be the cause of the gender differences observed in patients with SUD or/and traumatic stress-related pathologies. This review underlies experimental and clinical results emphasizing the DYN/KOR system as common mechanisms shared by SUD or/and traumatic stress-related pathologies, and suggests KOR antagonist as a new pharmacological strategy to treat this comorbidity.
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Traumatic Stress-Induced
Vulnerability to Addiction: Critical Role
of the Dynorphin/Kappa Opioid
Receptor System
Claire Leconte, Raymond Mongeau and Florence Noble *
Université Paris Cité, INSERM, CNRS, T3S, Paris, France
Substance use disorders (SUD) may emerge from an individuals attempt to limit negative
affective states and symptoms linked to stress. Indeed, SUD is highly comorbid with
chronic stress, traumatic stress, or post-traumatic stress disorder (PTSD), and treatments
approved for each pathology individually often failed to have a therapeutic efciency in such
comorbid patients. The kappa-opioid receptor (KOR) and its endogenous ligand
dynorphin (DYN), seem to play a key role in the occurrence of this comorbidity. The
DYN/KOR function is increased either in traumatic stress or during drug use, dependence
acquisition and DYN is released during stress. The behavioural effects of stress related to
the DYN/KOR system include anxiety, dissociative and depressive symptoms, as well as
increased conditioned fear response. Furthermore, the DYN/KOR system is implicated in
negative reinforcement after the euphoric effects of a drug of abuse ends. During chronic
drug consumption DYN/KOR functions increase and facilitate tolerance and dependence.
The drug-seeking behaviour induced by KOR activation can be retrieved either during the
development of an addictive behaviour, or during relapse after withdrawal. DYN is known
to be one of the most powerful negative modulators of dopamine signalling, notably in brain
structures implicated in both reward and fear circuitries. KOR are also acting as inhibitory
heteroreceptors on serotonin neurons. Moreover, the DYN/KOR system cross-regulate
with corticotropin-releasing factor in the brain. The sexual dimorphism of the DYN/KOR
system could be the cause of the gender differences observed in patients with SUD or/and
traumatic stress-related pathologies. This review underlies experimental and clinical results
emphasizing the DYN/KOR system as common mechanisms shared by SUD or/and
traumatic stress-related pathologies, and suggests KOR antagonist as a new
pharmacological strategy to treat this comorbidity.
Keywords: addiction, PTSDposttraumatic stress disorder, traumatic stress disorder, kappa opiate receptor,
dynorphin
INTRODUCTION
Post-traumatic stress disorder (PTSD) and substance use disorders (SUD) are frequently comorbid
(María-Ríos and Morrow, 2020;Hien et al., 2021). Indeed, in a civilian population study, SUD
lifetime prevalence ranges from 25% to 43% in persons with PTSD, compared with 8%25% in the
general population (Jacobsen et al., 2001). This comorbidity is often associated with more severe
Edited by:
Marta Valenza,
Sapienza University of Rome, Italy
Reviewed by:
Eduardo Butelman,
The Rockefeller University,
United States
Charles Chavkin,
University of Washington,
United States
*Correspondence:
Florence Noble
orence.noble@parisdescartes.fr
Specialty section:
This article was submitted to
Translational Pharmacology,
a section of the journal
Frontiers in Pharmacology
Received: 17 January 2022
Accepted: 07 April 2022
Published: 27 April 2022
Citation:
Leconte C, Mongeau R and Noble F
(2022) Traumatic Stress-Induced
Vulnerability to Addiction: Critical Role
of the Dynorphin/Kappa Opioid
Receptor System.
Front. Pharmacol. 13:856672.
doi: 10.3389/fphar.2022.856672
Frontiers in Pharmacology | www.frontiersin.org April 2022 | Volume 13 | Article 8566721
REVIEW
published: 27 April 2022
doi: 10.3389/fphar.2022.856672
clinical proles compared with either diagnosis alone. Among
PTSD patients, the most common SUD is alcoholism: from 24%
of patients in the general population (Mills et al., 2006) to 75% in
combat veterans (Jacobsen et al., 2001), however, cocaine and
heroin use disorders are also highly prevalent (Dworkin et al.,
2018). Moreover, 33% of individuals with an opioid use disorder
have experienced PTSD (Mills et al., 2006), with 92% of heroin
dependent patients exposed to traumatic stress (Mills et al., 2018).
In the last decade, the co-occurrence of PTSD and SUD has been
well documented, although only few studies have investigated the
shared mechanisms. Persons with SUD are all predisposed to
traumatic events exposure (Cottler et al., 1992), and inversely,
PTSD induces vulnerability to SUD (María-Ríos and Morrow,
2020). At the clinical level, several situations are encountered:
PTSD may precede SUD, or inversely, SUD may precede PTSD
(Brady et al., 1998), and when PTSD precedes cocaine use for
example, PTSD symptoms are often more severe (Brady et al.,
1998). The relationship between PTSD and SUD can be explained
in part by the self-medication hypothesis: most patients report
that the use of drugs, such as alcohol or opiates, can reduce stress
symptoms (e.g., insomnia, tachycardia, uncontrolled trembling,
hypervigilance...)(Khantzian, 1985,1997;Volpicelli et al., 1999;
Danovitch, 2016).
Thefactthattherearesomanyneurobiologicaland
biochemical factors implicated in the development of PTSD
and SUD comorbidity makes the treatment of such comorbid
situation difcult to codify. Although exposure therapy (i.e.,
exposure to trauma-related stimuli inducing an effective
extinction of fear memories) is a highly effective treatment
for PTSD alone (Cusack et al., 2016), it appears to be less
effective in the SUD/PTSD comorbidity (Simpson et al., 2017).
Integrated cognitive behavioural therapy of SUD/PTSD patients
began to develop (McGovern et al., 2011,2015;Roberts et al.,
2016), unfortunately, it had no effect on PTSD symptoms.
Concerning pharmacological treatments, diverse medications
were tested with negative results in alcohol use disorders
associated with PTSD (Taylor et al., 2017), with the
exception of two molecules. First, sertraline treatment (a
selective serotonin reuptake inhibitor; SSRI) combined with
cognitive-behavioural therapy reduces both PTSD and
alcohol use disorder severity (Hien et al., 2015). Second,
naltrexone in combination with prolonged exposure therapy
forPTSDdemonstratesabenecial effect 6 months later, for
alcohol drinking outcomes (Foa et al., 2013). Naltrexone, as
naloxone, is a non-selective mu (µ, MOR), delta (δ,DOR),and
kappa (κ, KOR) opioid receptor antagonist, approved for the
treatment of alcohol and opioid use disorders (Sudakin, 2016),
and is actually tested (in co-treatment with buprenorphine), in a
phase 2 clinical trial, to treat alcohol use disorder comorbid with
PTSD (NCT03852628, 2019). Interestingly, the
pharmacological industry was prompted to develop KOR
antagonists to treat stress-induced relapse of cocaine, alcohol,
and tobacco (Carroll and Carlezon, 2013;Banks, 2020). To our
knowledge, a pharmacological strategy aiming selective KOR
antagonism has not yet been explored to treat SUD/PTSD
comorbidity. One goal of the present review is to stimulate
research in this direction.
Although the mechanisms underlying PTSD/SUD association
has been extensively reviewed before (Jacobsen et al., 2001;
María-Ríos and Morrow, 2020), understanding better how
traumatic stress and more generally PTSD can predispose to
SUD would allow to design more effective treatment strategies
aimed specically at patients vulnerable to comorbid psychiatric
disorders. In this review, we thus focus on both preclinical and
clinical research related to the modulation of the KOR system,
and its endogenous ligand dynorphin (DYN), in relation with
stress and addiction. The interest for this topic has been growing
recently (Helal et al., 2017;Karkhanis et al., 2017;Jacobson et al.,
2018;Lanius et al., 2018;Valentino and Volkow, 2018;Beck et al.,
2019;Margolis and Karkhanis, 2019;Tejeda and Bonci, 2019;
Anderson, 2020;Escobar et al., 2020;Nagase and Saitoh, 2020).
We will thus list here some of the most relevant literature on the
DYN/KOR system in pain, dysphoria and psychiatric disorders.
We will pay a special interest to gender differences. It is necessary
to examine in detail the involvement of DYN/KOR in stress-
related behaviours, on the brain circuits mediating fear and the
differential effects of KOR agonists vs antagonists in addiction.
The involvement of KOR in traumatic stress-induced drug
reinstatement is also particularly interesting.
THE DYNORPHIN/KAPPA-OPIOID
RECEPTOR SYSTEM
Beside the hedonic state that often leads to addictive behaviours,
the opioid system is involved in a wide range of physiological
functions. Opioids, mainly non-selective agonists with an
important MOR afnity, induce analgesia, sedation, respiratory
depression, bradycardia, nausea, vomiting, and reduction in
gastric motility (Valentino and Volkow, 2018). Opioid
receptors belong to G-coupled receptors family with the MOR,
DOR, and the KOR subtypes (Valentino and Volkow, 2018), to
which we can add the nociceptin opioid receptor (NOR) subtype
(Pathan and Williams, 2012). Exogenous ligands with agonist
and/or antagonist properties, that are more or less selective, have
been largely investigated (including morphine and heroin as
MOR agonists). Each receptor possesses its own selective
endogenous ligands: endorphin for MOR (with low afnities
to DOR and KOR), enkephalins with a higher DOR afnity,
and the nociceptin/orphanin FQ for NOR. DYN is derived from
pro-dynorphin (PDYN) and is the only endogenous ligand with a
high afnity for KOR. Among specic KOR agonists used in
preclinical research (Banks, 2020), we can cite salvinorin A, the
active principle of Salvia divinorum (Roach and Shenvi, 2018)
and the synthetic analogue U50,488 (Karkhanis et al., 2017).
The DYN/KOR system has a wide distribution in central and
peripheral nervous systems (Chen et al., 2020) and is implicated
in numerous physiological functions: e.g. pain perception,
dysphoria, neuroendocrine regulation, extrapyramidal motor
control, cardiovascular function, respiration, water balance
system (diuresis), temperature regulation and feeding
behaviour (Fallon and Leslie, 1986). Recently, it has also been
shown that KOR activation could decrease the differentiation
process during neurogenesis (Xu et al., 2021), and that dynorphin
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Leconte et al. Kappa in Stress and Addiction
promotes both developmental and stress-induced
oligodendrocyte precursor cell differentiation and myelination
in the striatum (Osso et al., 2021). As other opioid receptors, KOR
mediate peripheral analgesia, by acting on the pain pathway at
primary sensory neurons, the spinal cord and the brainstem
(Figure 1). KOR mediate also central analgesia, at the
amygdala, the parietal cortex and the rostral ventromedial
medulla (Cahill et al., 2014). Although pain treatment using
KOR agonists seems advantageous compared to the clinically
used MOR agonists (no addiction, no respiratory depression),
these agonists are problematic in clinic because of their adverse
effects on mood and sedation. However, some promising mixed
KOR/DOR agonists (Atigari et al., 2021) or KOR biased-agonists
are currently being developed (Valentino and Volkow, 2018).
Opioid receptors are coupled to several signalling pathways,
including Gi/o-protein-dependent signalling and β-arrestin-2-
related signalling (Figure 1). Briey, following an agonist
activation, KOR promotes the Gαsubunit and Gβγ subunits
dissociation. The Gαsubunit interact with various intracellular
downstream effectors, as adenylyl cyclases and cGMP
phosphodiesterase and possess a GTPase intrinsic activity. Gβγ
subunits interact with GRKs, G-protein-coupled phosphoinosite
3 kinase (PI3K) and mitogen-activated protein kinases (MAPK).
In addition, the β-arrestin 2 regulates KOR signalling through
desensitization and internalization, recruiting also MAPK
pathways as p38 stress kinase and extracellular signal-
regulated kinases 1 and 2 (ERK 1/2) (Bruchas and Chavkin,
2010;Faouzi et al., 2020).
Interestingly, differences in KOR trafcking have been noted
for different agonists: dynorphins, U50,488, salvinorin A, TRK-
820, and 3FLB (Jordan et al., 2000;Wang et al., 2005;Chen et al.,
2007). It has been proposed that Gi signalling mediates KOR-
induced analgesia, while the β-arrestin 2-related signalling
mediates dysphoria (Bruchas and Chavkin, 2010). As a matter
of fact, the dysphoric effects of KOR activation required arrestin-
dependent p38αMAPK activation in ventral tegmental area
(VTA) dopaminergic neurons (Ehrich et al., 2015). On the
other hand, some partial KOR agonists, promoting Gi-protein
signalling, are able to induce antinociception without inducing
signicant sedative or dysphoric effects (Brust et al., 2016;Spetea
et al., 2017). These studies, suggests that distinct signalling
pathways inducing differential behavioural and/or
physiological effects could be taken into account to create
biased-agonists which would improve analgesia while reducing
FIGURE 1 | Proposed integrative view of DYN/KOR system main effects and regulations. Dynorphin (DYN) is mainly released by stress and binds to KOR, which
triggers its effects through two signaling pathways: the β-arrestin-2 pathway and the Gi protein signaling pathway. Some compounds can create an imbalance between
these two main effects, such as estradiol at the molecular level that decrease β-arrestin-2 signaling and increase Gi protein signaling (Abraham A. D. et al., 2018),
promoting analgesic effects and decreasing dysphoric effects. Similarly, G-protein biased KOR agonists tend to promote analgesia without dysphoric side effects
(Brust et al., 2016;Spetea et al., 2017) KOR also mediate central and peripheral analgesia, by acting on primary sensory neurons, the spinal cord and the brainstem. In
turn, dysphoric effects are potentially induced through a DA release decrease in the brain by inhibiting the VTA dopaminergic neurons and by an increa sed release of CRF
and HPA axis activation. Stress-induced analgesia is KOR dependent in the case of ine scapable stress. This may somehow be related to dissociative states, following an
emotional shutdown, thought to involve KOR activation, increasing opioid dependent analgesia and producing alterations of mood and perception (Lanius et al., 2018).
CRF, Corticotropin Releasing Factor; DA, dopamine; HPA axis, Hypothalamo-Pituitary-Adrenal axis; KOR, Kappa Opioid Receptor; VTA, ventral Tegmental Area.
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Leconte et al. Kappa in Stress and Addiction
the risk of adverse effects. Similarly, MOR biased agonists have
also been investigated (Faouzi et al., 2020). In 1999, it has been
demonstrated an improved antinociceptive effect of morphine in
β-arrestin2 KO mice (Bohn et al., 1999). However, although MOR
G-protein biased agonist were design in order to enhance and/or
to prolong antinociception and to decrease tolerance, some recent
studies point out controversial results for respiratory depression,
constipation or withdrawal (Hill et al., 2018;Kliewer et al., 2019,
2020). As a matter of fact, G-biased KOR agonists lacking
addictive properties and dysphoric effects could be much more
promising drugs to treat pain (Bruchas and Chavkin, 2010;
Valentino and Volkow, 2018;Faouzi et al., 2020).
Apart from the above effects, the DYN/KOR system is
involved in several psychiatric diseases, including major
depressive disorder (Callaghan et al., 2018;Jacobson et al.,
2018), epilepsy (André et al., 2018), schizophrenia (Clark and
Abi-Dargham, 2019), borderline personality disorder (Anderson,
2020) and addiction (Anderson and Becker, 2017;Norman and
DSouza, 2017;Victorri-Vigneau et al., 2018). It is also involved in
inammatory diseases (Beck et al., 2019;Coffeen and Pellicer,
2019). Indeed, it is known that the DYN/KOR system is
implicated in oxidative stress enzyme activities (Dang et al.,
2018), and in the activation of the hypothalamo-pituitary-
adrenal (HPA) axis that modulate inammation [Figure 1;
(Fuller and Leander, 1984;Song and Takemori, 1992;Bruchas
et al., 2009]. Nevertheless, DYN may also act as an anti-
inammatory compound through the potentiation of
glucocorticoids action, and by promoting brain microglial
polarization toward an anti-inammatory M2 phenotype (Liu
et al., 2020).
Consistently, DYN is released during prolonged or intense
stress (Figure 1) and induces anxiety-like or depression-like
behaviours (Vant Veer and Carlezon, 2013). Interestingly,
because of its dysphoric and aversive effects, the KOR system
was argued to contribute to the negative affective states induced
by pain, driving mood-related pathologies associated with
chronic pain (Cahill et al., 2014). Furthermore, in humans,
KOR agonists could produce a dissociative-like syndrome, a
state occurring during an inescapable traumatic experience
(Lanius et al., 2018). These dysphoric effects are thought to be
the consequence of a dopamine (DA) depletion in the reward and
the fear circuits (Karkhanis et al., 2017;Lanius et al., 2018;
Escobar et al., 2020). KOR have been found to be expressed in
DA neurons of the nucleus accumbens (NAc), the ventral
tegmental area (VTA), the caudate putamen and the
substantia nigra (Chen et al., 2020). Indeed, DYN is known to
be one of the most powerful negative modulators of DA
signalling. It triggers a hyperpolarization in VTA
dopaminergic neurons, decreasing DA release in the NAc, the
basolateral amygdala (BLA), the medial prefrontal cortex
(mPFC), brain structures implicated in both fear and reward
(Karkhanis et al., 2017;Lanius et al., 2018;Escobar et al., 2020).
In contrast to either MOR or DOR agonists that induce a
hedonic state and participate in positive reinforcement, KOR
agonists are generally aversive: their activation leads to anti-
reward effects that trigger negative reinforcement (Fields and
Margolis, 2015;Karkhanis et al., 2017). Furthermore, the DYN/
KOR function is increased during chronic stress or drug
dependence development and leads to drug-seeking (Carroll
and Carlezon, 2013;Karkhanis et al., 2017). This is why some
KOR antagonists seem promising pharmacological strategies in
clinic, to reduce the risk of stress-induced relapse during alcohol
and cocaine withdrawal, smoking as well as for gambling
cessation (Carroll and Carlezon, 2013;Anderson and Becker,
2017;Norman and DSouza, 2017;Victorri-Vigneau et al., 2018;
Banks, 2020;Krystal et al., 2020).
Differences in signalling properties and between selective KOR
antagonists were observed. Prototypical potent and selective KOR
antagonists such as naltrexone-related antagonists
[norbinaltorphimine (nor-BNI), 5-guanidinonaltrindole
(GNTI), ...], or (3R,4R)-dimethyl-4-(3-hydroxyphenyl)
piperidine-based (JDTic), were used in preclinical studies to
dissect properties of the DYN/KOR system. They possess slow
onset and long duration of action that require c-Jun N-terminal
Kinase (JNK) activation (Bruchas and Chavkin, 2010). They also
possess low brain penetration and undesirable side effect, that
made them inadequate for clinical trials (Carroll and Carlezon,
2013;Jacobson et al., 2020). CERC-501, used in phase 1 clinical
trials, does not share nor-BNI or JDTic pharmacological
properties (Carroll and Carlezon, 2013;Jacobson et al., 2020).
Nevertheless, this last compound, a KOR antagonist that have low
afnities for MOR and DOR (Banks, 2020), failed to attenuate
cocaine craving (Reed et al., 2018), or cigarette smoking and
craving (Jones et al., 2020).
Another issue, complicating the therapeutic use of KOR
ligands, concerns gender differences. KOR triggers a sex-
dependent response for both analgesia and dysphoria. The rst
clinical trials on KOR agonists as analgesics were done on men,
consequently, women specic responses to KOR agonists were
largely unknown until years 2000s. Indeed, KOR agonists have
low or inconsistent effects on pain in women and female rodents
although its analgesic efciency could be related to the oestrous
cycle or the sex-dependant MOR/KOR heterodimerization
(Chakrabarti et al., 2010;Lawson et al., 2010;Chartoff and
Mavrikaki, 2015;Abraham A. D. et al., 2018). Similarly, the
efciency of the long-lasting KOR antagonist norBNI is sex-
dependent, probably because of a process induced by oestrogen
regulation of G-protein signalling (Reichard et al., 2020). Indeed,
estradiol is able to modify the G-coupled-protein action of KOR
(Figure 1), decreasing dysphoric effects and enhancing analgesia
(Abraham A. D. et al., 2018). Furthermore, the DYN/KOR system
plays a crucial role on puberty onset and fertility (Navarro et al.,
2009).
POST-TRAUMATIC STRESS DISORDER
AND THE DYNORPHIN/KAPPA-OPIOID
RECEPTOR SYSTEM
PTSD, previously classied as an anxiety disorder (DSM-IV), is
now classied in the DSM-V among trauma- and stressor-
related disorders. PTSD causes signicant impairment in
daily functioning and it develops after direct or indirect
exposure to an acute life-threatening stress. The estimated
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Leconte et al. Kappa in Stress and Addiction
lifetime prevalence of PTSD is near 9% (Kessler, 1995;Roque,
2015). Traumatic events may include war, physical violence,
sexual abuse, accidents, violent crime, epidemic infections or
natural disasters. PTSD includes four major clusters of symptoms
observed several months, and even years, after the trauma: 1) re-
experiencing of the traumatic event through dreams, ashbacks
and intrusive, distressing thoughts; 2) avoidance of trauma
reminders; 3) numbing of emotions, negative alterations in
mood and cognition; and 4) hyperarousal, characterized by
difculties in sleeping and concentrating, irritability, and
hypervigilance (Kessler, 1995;Roque, 2015;María-Ríos and
Morrow, 2020). The criteria to meet PTSD (ICD 10) include
key symptoms that have to last 6 months: ashback, avoidance of
circumstances resembling or associated with the stressor; and
inability to recall some important aspects of the trauma, or
persistent symptoms of increased psychological sensitivity and
arousal. Behavioural PTSD treatments may consist in inducing
extinction of the traumatic memory. Indeed, patients suffering
from PTSD exhibit decient extinction recall along with
dysfunctional activation of the fear extinction network (Maren
et al., 2013;Wicking et al., 2016).
In some studies, PTSD is twice as common in adult women
compared to men (DellOsso et al., 2011;María-Ríos and
Morrow, 2020). This gender difference is already present in
adolescence, with girls having more than three times the odds
of having the disorder compared to boys (McLaughlin et al.,
2013) and may be related to differences in socialization or trauma
exposure. Indeed, traumas most commonly associated with PTSD
are combat exposure and witnessing violence among men and
rape and sexual molestation among women (Kessler, 1995).
Biological sex may also impact PTSD development (Garza and
Jovanovic, 2017). For example, compared to men, women show a
greater reactivity to negative emotional stimuli in key brain
structures of the fear circuit (Stevens and Hamann, 2012). We
will next briey review this fear circuitry to then explore its
modulation by the DYN/KOR system.
Neurocircuitry Involved in Stress and
Post-Traumatic Stress Disorder
Among the most central brain structures of the fear circuit,
there is the hippocampus which is involved in contextual
aspects of fear (the environment) and fear generalization (a
PTSD symptom). The amygdala is involved in both
contextual- and cue-related fear. The lateral (LA) and
basolateral (BLA) nuclei of the amygdala project together
to the central nucleus of the amygdala (CeA) (Johansen et al.,
2011;Izquierdo et al., 2016). The CeA stimulates the
hypothalamus and the periaqueductal gray (PAG) to
induce three main fear responses (Deng et al., 2016;Lanius
et al., 2018): 1) the autonomic response initiated by the lateral
hypothalamus involving sympathetic activation (tachycardia,
increased blood pressure, change in body temperature,
sweating...) preparing the body for physical reactions to
danger; 2) the behavioural ght or ightdefensive
response initiated by the dorsolateral and the ventral PAG
(active defence behaviour, freezing immobility, running,
jumping, aggression); 3) the hormonal stress response,
initiated by the paraventricular nucleus (PVN) of the
hypothalamus.
The PVN projects to the anterior pituitary allowing the release
of the corticotropin-releasing factor (CRF). The anterior
pituitary, induces the adreno-cortico-trophic hormone
(ACTH) secretion that leads to glucocorticoids release
(corticosterone in rodents or cortisol in primates) from the
adrenal cortex. Glucocorticoids receptors within the pituitary,
the hippocampus and the frontal cortex mediate the negative
feedback on hormone release from HPA axis. The ventromedial
prefrontal cortex (vmPFC) is also well located to regulate fear
learning and memory, as both the prelimbic (PL) and infralimbic
(IL) cortices receive extensive projections from the hippocampus
and the BLA, and send projections back to the BLA. It is believed
that PL and IL play opposing roles in the realm of fear learning:
the PL is purported to be necessary for the expression of fear
learning, while the IL is thought to be necessary for extinction
learning (Izquierdo et al., 2016). A last structure worth
mentioning is the bed nucleus of the stria terminalis (BNST)
which is more involved in anxiety-like behaviours than
conditioned fear. It is extensively connected to the PVN, and
would be triggered more by distant or unpredictable threats,
compared to the amygdala which is more about proximal and
imminent dangers (Avery et al., 2016).
PTSD is characterized by an exaggerated fear and a decit in
fear memory extinction, which may be caused by a PFC-
amygdala dysfunction. Most of this mechanism has been
documented in rodent models (Izquierdo et al., 2016), but
recent clinical ndings corroborate them (Åhs et al., 2015;Raij
et al., 2018;Yoshiike et al., 2018;Dunsmoor et al., 2019).
Interestingly, it has been shown that transcranial magnetic
stimulation of the human homologue of IL region of vmPFC
enhances fear memory extinction (Raij et al., 2018). PTSD can
reprogram fear circuitry in adults, in adolescents and in pediatric
PTSD. Several changes in brain structures have been reported,
such as a smaller cerebral gray matter volume (Milani et al., 2017),
smaller PFC areas (Keding and Herringa, 2015) and larger
amygdala (Weems et al., 2015). Furthermore, a prospective
study in adolescents suggests that over-activity within a fear
network, such as within the amygdala, may increase lifetime
vulnerability to develop PTSD after a trauma (McLaughlin et al.,
2014).
Role of Dynorphin/Kappa-Opioid Receptor
System in Stress-Related Disorders
The opioid systems play important roles in regulating the HPA
axis (Figure 2). Although the β-endorphin/MOR system
contributes to decreasing the HPA axis activation after an
acute stress, the DYN/KOR system activates the HPA axis
(Bali et al., 2015). KOR are widely expressed in the central
nervous system, notably in structures reviewed above, and in
the HPA axis that modulate glucocorticoids release (Vant Veer
and Carlezon, 2013;Lanius et al., 2018). Administration of a KOR
agonist is able to induce an increase in corticosterone release in
rodents (Fuller and Leander, 1984), and of cortisol release in
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Leconte et al. Kappa in Stress and Addiction
humans (Ur et al., 1997). Among synthetic opioid agonists, those
targeting KOR are able to stimulate cortisol release activity after
acute administration in primates (Pascoe et al., 2008) and in
humans (Ur et al., 1997). Inversely, the long-acting KOR
antagonist nor-BNI (Allen et al., 2013), or the short-acting
KOR antagonist LY2444296 (Valenza et al., 2017), both reduce
corticosterone release following diverse stressors, chronic cocaine
administration (Valenza et al., 2017) or food restriction (Allen
et al., 2013).
The most widely investigated interactions of KOR with the
HPA axis are those with CRF (Koob et al., 2014;Crowley and
Kash, 2015) a neuropeptide that can also mimic physiological and
behavioural response of stress when administered exogenously
(Hauger et al., 2009;Vant Veer and Carlezon, 2013;Koob et al.,
2014). In the CeA, DYN containing neurons have been
demonstrated to occasionally co-express CRF (Marchant et al.,
2007). DYN and CRF are also co-expressed in the PVN of the
hypothalamus (Roth et al., 1983), and the hypothalamic supra-
optic nucleus (Meister et al., 1990). In addition to this anatomical
overlay between the two peptidergic systems, it has been shown
that the DYN/KOR system is able to inuence CRF expression in
the PVN (Wittmann et al., 2009) and in the CeA (Wittmann et al.,
2009;Negrete et al., 2017), while CRF mRNA was found
decreased in PDYN-KO mice. Inversely, CRF is able to induce
DYN release in the rat striatum (Sirinathsinghji et al., 1989) and
the mouse spinal cord (Song and Takemori, 1992). Beside the
release of stress hormones, the CeA exerts its function on the
ight reactions via the dorsolateral PAG which is directly
modulated by KOR. Systemic administration of Nor-BNI
reduces the ight reaction induced by PAG stimulation.
Furthermore, microinjection of Nor-BNI into the PAG causes
the same panicolytic-like effect (Maraschin et al., 2017). On the
other hand, anxiety behaviour can also result from a KOR
modulation of the BLA to BNST input (Crowley et al., 2016).
The data about the effects of stress and active defense
behaviours in relation to the DYN/KOR system (Figure 2)in
rodents can be found in studies that used models of anxiety- and
depressive-like behaviours (anhedonia, decient grooming,
learned helplessness...). Several studies have shown that
KOR antagonists can prevent the behavioural consequences
of stress (Vant Veer and Carlezon, 2013). Thus, after diverse
stressors (e.g., CRF administration or withdrawal following
repeated administration of drugs of abuse) these antagonists
are able to induce anxiolytic-like effect in the elevated plus maze
(EPM) (Bruchas et al., 2009;Jackson et al., 2010;Valdez and
Harshberger, 2012)andtheopeneld (OF) tests (Wittmann
et al., 2009), and decrease immobility time in the forced swim
test (FST) used to screen antidepressant drugs (Newton et al.,
2002;McLaughlin et al., 2003;Shirayama et al., 2004). Tonic
activation of KOR by DYN does not appear to play a role in
baseline anxiety- or depression-like behaviours. Indeed,
constitutive global PDYN-KO and KOR-KO mice have
similar performances in the EPM and in the sucrose
preference test compared to wild-type animals (Negrete et al.,
2017). However, using conditional KOR-KO mice, a deletion of
KOR in the amygdala results in an increased anxiety-like
behaviour (Crowley et al., 2016).
Several lines of evidence suggest sex differences in the
modulation of depression-related behaviour by DYN/KOR
(Chartoff and Mavrikaki, 2015). It was observed that KOR
FIGURE 2 | Involvement of the DYN/KOR system in response to stress. KOR activation induce an activation of the hypothalamo-pituitary-adrenal axis mainly
through an increase in CRF release by the PVN, participating in the hormonal stres s response (Vant Veer and Carlezon, 2013). The amygdala, the hippocampus and the
PAG are directly modulated by KOR and modulate contextual fear memory, emotional response and the freezing, ght or ight responses to fear. Stress could also
induce dynorphin release and activates KOR in VTA dopaminergic neurons, inducing a decrease of DA release in several brain structures such as, the PFC,the
NAc, the amygdala and the PVN (Karkhanis et al., 2017). After stress or trauma, some interesting processes could be observed: an enhanced function of KOR in VTA,
and NAc, an endogenous opioid withdrawal, or an enhanced negative reinforcement after drug use, that may potentiate the risk of comorbid substance use disorder.
CRF, Corticotropin Releasing Factor; DA, dopamine; KOR, Kappa Opioid Receptor; NAc, Nucleus Accumbens; PAG, periaqueductal gray; PFC, PreFrontal Cortex;
PVN, ParaVentricular Nucleus of the hypothalamus; VTA, Ventral Tegmental Area.
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Leconte et al. Kappa in Stress and Addiction
activation is less dysphoric in female than male rodents (Russell
et al., 2014;Abraham A. D. et al., 2018), but this effect seems to be
highly dependent on the KOR agonist dose used (Robles et al.,
2014). Interestingly, the KOR antagonist norBNI decreases
immobility in the FST in male mice, without modication in
females (Laman-Maharg et al., 2018), while in an intracranial self-
stimulation model, the depressive-like effect of the KOR agonist
U50,488 is weaker in female rats compared to males,
independently of gonadal hormones (Russell et al., 2014).
Concerning conditioned fear memory, decrease expression of
cue-dependent fear and fear-potentiated startle were observed
after a KOR antagonist administration, while it facilitated
extinction of fear in a context-dependent manner (Fanselow
et al., 1991;Knoll et al., 2007;Cole et al., 2011). In contrast,
in another study, mice lacking DYN or mice treated with a KOR
antagonist displayed the opposite effect, an increased contextual
fear and a delayed fear extinction (Bilkei-Gorzo et al., 2012).
Furthermore, the role of KOR in fear conditioning depends on
the brain area. In the NAc, KOR may downregulate attention to
conditioned stimuli that are redundant or non-informative
predictors of shocks (Iordanova et al., 2006). A transient
activation of KOR in the CA3 region of the hippocampus
impairs both the acquisition and the consolidation of
contextual fear-related memory (Daumas et al., 2007), while
KOR antagonism in either the BLA or CeA decreased
conditioned fear in the fear-potentiated startle paradigm
(Knoll et al., 2011). Furthermore, an effective extinction of the
fear potentiated startle is associated with a 67% reduction in KOR
mRNA in the BLA (Knoll et al., 2011). Finally, knockdown of
DYN or CRF signalling in CRF-expressing CeA neurons decrease
the expression of both contextual- and cued-induced conditioned
freezing (Pomrenze et al., 2019).
Therefore, overall, considering data obtained from animal
models of anxiety-, depression-like behaviours, it appears that
activation of the DYN/KOR system is associated with more
anxiety or dysphoria. Although the DYN/KOR system is
clearly implicated in fear memory expression there are
contrasting ndings regarding its exact role.
SUBSTANCE USE DISORDER AND THE
DYNORPHIN/KAPPA-OPIOID RECEPTOR
SYSTEM
Recreational use, or initiation of psychotropic substance use,
generally results in a hedonic state: a pleasant emotional
response, called positive reinforcement (Fields and Margolis,
2015). This reinforcement, which involves activation of the
reward system, could lead to SUD, although this depends on
an individuals vulnerability. To dene drug addiction, the DSM-
V employs the terminology Substance use disorders(SUD) that
takes into account the harmful use(abuse) and the out-of-
control use(dependence) (Norko and Fitch, 2014). SUD are
frequently comorbid with diverse neurologic and psychiatric
disorders, including anxiety, depression (Gómez-Coronado
et al., 2018), schizophrenia (Hunt et al., 2018), borderline
personality (Lee et al., 2015), attention decit/hyperactivity
(Katzman et al., 2017) and PTSD (Jacobsen et al., 2001).
Interestingly, in all the psychiatric pathologies associated with
SUD, there is evidence for involvement of the HPA axis activation
(CRF release), certain neurotransmitter systems (DA, 5-HT,
GABA, and glutamate) and mediators of inammation
(Gómez-Coronado et al., 2018).
In drug addiction, depending on types and stages of SUD,
there are at least two opposite adaptive processes: the rst one is
associated with DA release, while the second one is associated
with suppression of DA release. Indeed, the DA release in the
brain associated with pleasure,as a consequence of drug
administration or its anticipation, causes an altered excitatory/
inhibitory balance. To compensate this imbalance, after drug
metabolization, the suppression of DA release is observed, which
can induce a negative affective state. In a subject developing
addiction, by escalating drug-taking behaviour, the rst process
(hedonic state) is less and less pronounced, while the second
process progressively increases. The later induces anhedonia and
dysphoria, called negative reinforcement. During the dependence
process, the drug-seeking behaviour for the substance is, from the
motivation point of view, much more due to the avoidance of
negative reinforcement than the initial positive reinforcement
(Karkhanis et al., 2017). This negative reinforcement involves,
among others, the DYN/KOR system that has been found to be
up-regulated during addiction (Walker and Koob, 2008).
Neurocircuitry Involved in Reward and
Addiction
The VTA is the key brain structure for mediating the rewarding
effects of a drug through the activation of mesocorticolimbic DA
pathways, while NAc, amygdala, PFC and BNST are major targets
of the VTA dopaminergic neurons (Swanson, 1982). All drugs of
abuse are known to increase DA release in the NAc. This DA
increase is obtained either by inhibition of VTA GABAergic
interneuron projecting to dopaminergic neurons (observed with
MOR agonists and cannabinoids), or by inhibiting DA reuptake
in the NAc through a direct blockade of the DA transporter
(DAT; observed with cocaine). Diverse brain areas could be
involved in SUD, depending of the stage or drug used. For
example, the dorso-medial and lateral striatum, the BLA and
CeA are involved in developed and established complulsive habits
(Lüscher et al., 2020). The locus coeruleus is involved in
withdrawal and relapse in chronic use of psychostimulants
and alcohol (España et al., 2016), but also in withdrawal from
morphine with a pDYN enhanced expression (McClung et al.,
2005). serotoninergic neurons of the raphe nuclei, most known
for their involvement in mood and dysphoria, also play an
important role in addiction most likely in relation with
impulsivity regulation (Kirby et al., 2011).
Circuits of the PFC, involved in fear behaviours, overlap the
circuit that regulates extinction of conditioned responses
associated with drug intake. Projections of the vmPFC
regulate, via glutamate, locomotor drug sensitization, drug-
seeking and drug withdrawal, similarly to fear extinction. On
one hand, the IL cortex not only decreases fear via the CeA, but
also sends excitatory projections to the NAc shell, which
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Leconte et al. Kappa in Stress and Addiction
indirectly inhibit motor responses involved in drug seeking. On
the other hand, the prelimbic (PL) cortex, that is rather excitatory
in conditioned fear, also favours drug seeking. Therefore, IL
favours extinction of addiction, as of fear, and PL favours
expression of acquired addiction behaviours, as conditioned
fear (Peters et al., 2009). Another structure involved in reward
as much as anxiety is the BNST. The latter would be involved in
the negative affective state generated by drug withdrawal.
Together with the NAc and the amygdala, the BNST would be
involved in the generation of dysphoria triggering relapse after a
long period of abstinence (Avery et al., 2016).
The Dynorphin/Kappa-Opioid Receptor
System During Addiction
The mesolimbic and mesocortical DA pathways are central in the
effects of DYN/KOR system in the brain (Vant Veer and
Carlezon, 2013;Tejeda and Bonci, 2019). In the mesolimbic
structures, KOR activation (notably by stress or SUD)
decreases DA release in the BLA, and causes a direct
inhibition of DA neurons ring in the NAc (Karkhanis et al.,
2017). In the VTA, the DYN inhibits DA neurons in two ways: a
direct negative feedback loop following D1 receptor activation,
and indirectly through inactivation of cholinergic interneurons
(Karkhanis et al., 2017). It was initially postulated that activation
of KOR in the VTA induces a decreased of DA release (Dalman
and OMalley, 1999) and glutamate release (Margolis et al., 2005)
that may produce the negative reinforcement effects of KOR
agonists (Bals-Kubik et al., 1993). However, a direct activation of
KOR in NAc, PFC or lateral hypothalamus, could also mediate
such effects (Bals-Kubik et al., 1993;Al-Hasani et al., 2015).
Activation of KOR located on dopaminergic terminals in the PFC
produces a local reduction of DA release and is sufcient by itself
to prevent the conditioned place aversion produced by systemic
U69,593, a KOR agonist (Tejeda et al., 2013).
Several studies suggest that KOR activation in dopaminergic
VTA neurons may disrupt behavioural inhibition (Abraham AD.
et al., 2018). KOR may even inhibit fear memory acquisition in
the hippocampus (Daumas et al., 2007), while generating anxiety-
like responses in the amygdala (Knoll et al., 2011). In the NAc,
while activation of KOR in the ventral part leads to aversion, an
opposite behaviour is reported following KOR activation in the
dorsal part of NAc that drives preference/reward behaviours (Al-
Hasani et al., 2015). Furthermore, the DYN/KOR system reduces
the development of addiction, but may also potentiate
reinstatement after extinction (Vant Veer and Carlezon, 2013;
Karkhanis et al., 2017). The complex and large distribution of
KOR in the VTA and the NAC could explain such discrepancy.
Furthermore, KOR activation in the VTA inhibits both GABA
and DA neurons projecting on the PFC, the NAc and the BLA
(Vant Veer and Carlezon, 2013;Karkhanis et al., 2017).
KOR do not act exclusively on DA neurons to modulate
aversion/dysphoria in the potentiation of drug reward. The
stress-induced DYN release activates KOR in serotonergic
neurons and contributes to reinstate drug seeking (Land et al.,
2009). In a microdialysis study, a KOR agonist decrease local
serotonin (5-HT) efux when infused into the dorsal or median
raphe as well as in the NAc (Tao and Auerbach, 2002). The KOR-
mediated modulation of mood and drug reward probably
involves activation of 5-HT1B receptors in the NAC (Fontaine
et al., 2022) and the antidepressant-like effect of KOR antagonist
could somehow be related to decrease function/density of the
serotonin reuptake transporter, the primary target of SSRIs
(Sundaramurthy et al., 2017).
Effects of Kappa-Opioid Receptor Ligand
Treatments
Arst approach concerning the use of the DYN/KOR system as a
therapeutical target in addiction is to administer agonists during
the acquisition of drug dependence. In preclinical studies, the
conditioned place preference (CPP) test evaluates the drug
reward effect, by associating the drug administration with a
specic environment (Prus et al., 2009). In this model, KOR
agonists would exert a dysphoric effect as they induce place
aversion (Vant Veer and Carlezon, 2013;Cahill et al., 2014;
Margolis and Karkhanis, 2019); i.e., rodents actively avoid a
context previously associated with a KOR agonist. However,
optogenetic studies show that dynorphinergic cell stimulation
creates either aversive (anti-reward) effects when stimulating the
ventral NAc shell, or reward effects when stimulating the dorsal
NAc shell (Al-Hasani et al., 2015). Furthermore, there are gender
effects in this KOR-induced dysphoria: with a low dose of KOR
agonist, female, but not male, mice developed a place aversion,
while with a high dose, male but not female mice developed this
aversion (Robles et al., 2014). Interestingly, if a social defeat stress
is induced before KOR agonist administration, it inhibits the
aversive effect of a low dose of KOR agonist in females, without
modication of the effects induced by a high dose of KOR agonist
in male mice (Laman-Maharg et al., 2017), suggesting that prior
stress modies the dysphoric effect of KOR in females.
Morphine and alcohol are also used to induce CPP, and this
behaviour is blocked by a pre- or co-treatment with U-50,488H or
E-2078, another KOR agonist (Funada et al., 1993;Matsuzawa
et al., 1999). The blockade of morphine-induced CPP by KOR
agonists may result from a reduction of DA release in the NAc
(Funada et al., 1993), since DYN is able to decrease basal and
cocaine-induced rise in striatal DA levels (Zhang et al., 2004).
Similarly, U50,488H administration during alcohol conditioning
inhibits both alcohol-seeking behaviour and alcohol-induced
locomotor activation (Logrip et al., 2009). An increase of
alcohol self-administration was observed following KOR
antagonist treatment in rats during the acquisition phase of a
self-administration behaviour, while KOR agonist administration
was able to reduce self-administration. This effect could be due to
a direct modulation of the reward circuitry (Mitchell et al., 2005).
In the 1990s, it was proposed that KOR agonists could be used to
prevent the initiation of behavioural sensitization and alterations
in mesolimbic DA neurotransmission (Shippenberg and Rea,
1997). However, such DYN effect on early exposure to drug
remain unexploited clinically as KOR agonists would need to be
co-administered with the addictive drug. Inversely, it has been
proposed that stress induced DYN release could produce a
dysphoric state that increase the rewarding valence of
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Leconte et al. Kappa in Stress and Addiction
addictive drugs (McLaughlin et al., 2003,2006), consequently
KOR agonists may thus potentiate addiction development.
The DYN/KOR activation is essential after an early
consumption of drugs to equilibrate brain DA and limit
addictive properties of abuse drugs. In a rat model of heroin
self-administration, DYN expression in the striatum was
enhanced during withdrawal periods but not during acute
administrations (Cappendijk et al., 1999). In another study, it
has been shown that DYN expression is upregulated 324 h after
methamphetamine administration in the dorsal striatum. This
effect is associated with dopaminergic toxicity that creates
oxidative burdens, microgliosis, and pro-apoptotic changes
(Dang et al., 2018). DYN basal expression can also predict the
vulnerability to develop an addictive behaviour. Comparing two
strains of rats, Nylander and colleagues (1995a) have shown that
Lewis rats, that have a higher propensity to self-administer
various drugs of abuse than Fischer rats, display lower basal
DYN levels in the substantia nigra, striatum, VTA and the
pituitary gland. Moreover, chronic morphine treatment and
opiate withdrawal induced different regulations of DYN and
enkephalin in the two strains (Nylander et al., 1995a;1995b).
Other preclinical studies exploiting inter-strain differences in
PDYN genes expression in the NAc, suggest that a high
expression of PDYN may protect against morphine addiction
by limiting drug-induced reward (Gieryk et al., 2010). In addition,
it has been shown that after cocaine withdrawal DYNs action on
GABAergic and glutamatergic neurons is altered in the ventral
palidus, a structure involved in relapse behaviour (Inbar et al.,
2020).
Although KOR agonists could somehow inhibit the positive
reinforcement process during a SUD development (Shippenberg
and Rea, 1997), once dependence and tolerance are established,
the best therapeutic strategy remains KOR antagonists that
reduce the relapse related to withdrawal-induced anxiety. KOR
antagonists are able to alleviates alcohol withdrawal-induced
anxiety and reduce alcohol self-administration in rats (Schank
et al., 2012), conrming role of KOR in stress-induced relapse
after withdrawal. In other words, the DYN/KOR system is
involved in stress-induced vulnerability, not only during
addiction development, but also during the phase of relapse-
risk after drug withdrawal (Karkhanis et al., 2017).
Traumatic Stress Induces Vulnerability to
Addiction
As already mentioned in the Introduction, there is a high
prevalence of SUD/PTSD comorbidity. As in a vicious circle,
the co-occurrence of PTSD and SUD makes an individual
symptoms more severe and more difcult to treat (María-Ríos
and Morrow, 2020). In particular, among SUD patients, the risk
of relapse is strongly enhanced in case of comorbid PTSD
(Norman et al., 2007). Furthermore, during a traumatic event,
both endorphin and DYN levels increase in the brain during the
so-called ght or ight responses (Kavushansky et al., 2013;
Lanius et al., 2018). However, after a trauma, whereas KOR
function may be enhanced in some brain areas such as the
BNST, the NAc, the VTA, in other limbic structures MOR
density is reduced, producing a period of endogenous opioid
withdrawal (Lanius et al., 2018). PTSD patients may counteract
these negative effects by using drugs of abuse (Volpicelli et al.,
1999).
The choice of the drug of abuse selected by PTSD patients
could determine the severity and the nature of PTSD symptoms.
The PTSD-related symptoms clusters could be used in order to
distinguish potential mechanisms underlying those PTSDs
comorbid with SUD (Dworkin et al., 2018). Among the three
symptoms related to PTSD, alcohol use is only associated with
avoidance symptoms (Lane et al., 2019). Cocaine is associated
with hyperarousal symptoms and sedative/hypnotic/anxiolytic
use is associated with numbing of emotions (Dworkin et al.,
2018). Interestingly, opiates, generally MOR agonists, use is
particularly important in comorbid PTSD and SUD
(Danovitch, 2016;Elman and Borsook, 2019), this may result
from the fact that avoidance symptoms (Phifer et al., 2011),
numbing of emotions (Dworkin et al., 2018), and hyperarousal
symptoms are strongly associated with opiates use and misuse
(Dworkin et al., 2018;Takemoto et al., 2020).
Both current and past PTSD periods resulting from non-
combat-related exposures are strong risk factors for opiates
(MOR agonists) use and misuse (Takemoto et al., 2020).
Inversely, among patients treated for heroin dependence, the
prevalence of PTSD has been estimated to 66% (Mills et al., 2018),
suggesting again that self-medication could play a role in this
opioid-use/PTSD comorbidity. Indeed, it is now well documented
in the literature that PTSD is associated with diverse pain
disorders, in civilian patients without injuries (Schwartz et al.,
2006;Phifer et al., 2011) or with a traumatic brain injury (Bryant
et al., 1999), and in war veterans (Wagner et al., 2000). As
illustrated in Figure 3, morphine administered from 1 to 48 h
after trauma, inhibits the trauma-related memory consolidation
FIGURE 3 | The risks and benets of MOR and KOR activation during
and after traumatic events. BNST, Bed Nucleus of the stria terminalis; KOR,
Kappa Opioid Receptor; NAc, Nucleus Accumbens; PTSD, Post Traumatic
Stress Disorder; SUD, Substance Use Disorder; VTA, Ventral Tegmental
Area.
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Leconte et al. Kappa in Stress and Addiction
(Roque, 2015), thus preventing PTSD symptoms, in children
(Saxe et al., 2001) and adults (Schönenberg et al., 2005), notably
by reducing separation-anxiety in children (Saxe, 2006), in a
dose-dependent manner (Bryant et al., 2009).
Opioids can also produce anti-stress effects, notably through
the modulation of both endorphin/MOR and DYN/KOR systems
(Schmidt et al., 2014;Bali et al., 2015). In preclinical studies, it has
been shown that DYN/KOR activation through a chronic stress
(e.g., repeated forced swim test), or through selective agonist
administration signicantly potentiate the magnitude of nicotine
CPP acquisition (Smith et al., 2012). Similarly, KOR activation
induced by repeated forced-swim stress prior to cocaine CPP is
both necessary and sufcient for potentiation of cocaines
reinforcing actions (Schindler et al., 2010). Independently of
associative learning mechanisms, stress may directly enhance
the rewarding value of cocaine by a DYN-dependent
mechanism in the amygdala (Schindler et al., 2010).
The DYN/KOR system activation could also reinstate a reward
memory after extinction of cocaine-induced CPP, suggesting that
KOR is involved in stress-induced vulnerability to addiction by
acting directly on stress-induced neuroplasticity (Land et al.,
2009). Traumatic stress (e.g., brief cold-water swim), leads to a
persistent constitutive activation of KOR and abolish the long-
term potentiation of GABAergic synapses in the VTA, leading to
a reinstatement of cocaine seeking in a rat self-administration
model after behavioural extinction (Polter et al., 2017).
Furthermore, a long-lasting KOR antagonist, suppresses stress-
induced, but not cocaine-recall, reinstatement of cocaine CPP
(Carey et al., 2007). Moreover, a cocaine CPP is reinstated after
either a KOR agonist administration or a chronic social defeat
(Bruchas et al., 2011;Smith et al., 2012). Stress-induced cocaine
CPP reinstatement is inhibited by the antagonist nor-BNI
(Bruchas et al., 2011;Smith et al., 2012), and is absent in
knockout mice lacking the KOR or the PDYN genes
(McLaughlin et al., 2003;Redila and Chavkin, 2008;Land
et al., 2009). Similarly, nor-BNI has been shown to inhibit
stress-induced reinstatement of nicotine-CPP after foot-shocks
(Nygard et al., 2016) or ethanol-CPP after forced swim (Sperling
et al., 2010). This stress-induced DYN/KOR system activation,
involved in drug-seeking behaviour, has been shown to be
dependent on various mechanisms, including a transient rise
in 5-HT transport in the ventral striatum (Bruchas et al., 2011;
Smith et al., 2012), the activation of KORs located in serotonergic
neurons of the dorsal raphe nucleus (Land et al., 2009), a KOR
mediated Gαi signalling pathway within BLA neurons (Nygard
et al., 2016) or an increased noradrenergic neurotransmission in
the locus coeruleus (Al-Hasani et al., 2013). Besides, alcohol-
dependent rodents with an extended period of abstinence
submitted to either a stress (a 20 min immobilization) or
injection of the agonist U50,488, develop an anxiogenic-like
behaviour with a decrease time spent in the open arms in the
EPM. In this model of enhanced responsiveness to stress, nor-
BNI administration inhibits this increase in anxiety (Gillett et al.,
2013).
Finally, again, gender differences could be observed
concerning the PTSD-induced SUD vulnerability, during the
drug dependence acquisition, withdrawal or relapse phases.
Womens risk of addiction increase more rapidly than men
from the initial use to addiction, and this is true for all drugs
of abuse (Brady and Randall, 1999). Trauma history and current
trauma-related symptoms are signicantly associated with
relapse in women, but not men, in chronic and binge alcohol
use (Heffner et al., 2011) or cocaine (Hyman et al., 2008). It was
argued that being a woman and being a previous user of cocaine
or opiates were the strongest predictors of PTSD (Saladin et al.,
1995). Similarly, the use of illicit drugs is strongly associated with
both sexual and physical assault in women (Kilpatrick et al.,
1997). Childhood victimization is higher in alcoholic women
compared with non-alcoholic ones (Miller et al., 1993). There are
also effects of experience and culture on vulnerability to addiction
that can differentially affect males and females (Becker, 2016). At
the preclinical level, the sexually dimorphic balance of drug-
induced DA release in the dorsolateral striatum and the NAc,
could also explain the gender difference (Becker, 2016). The latter
may also result from sexually dimorphic: 1) vulnerability to
opiate addiction dependent from polymorphisms in the PDYN
gene (Clarke et al., 2012), 2) MOR/KOR heterodimerization
(Chakrabarti et al., 2010), or 3) gonadal hormone modulation
by the DYN/KOR system (Eghlidi et al., 2010;Lawson et al.,
2010). Although recently explored in addiction alone (Mitchell
et al., 2005), stress (Robles et al., 2014;Russell et al., 2014;Laman-
Maharg et al., 2017,2018;Abraham A. D. et al., 2018;Williams
and Trainor, 2018) or pain (Chartoff and Mavrikaki, 2015;
Abraham A. D. et al., 2018), there is no experimental research
on the sexually dimorphic effect of DYN/KOR system in
addiction vulnerability triggered by stress. Such information
shall be necessary to explain the great prevalence of SUD/
PTSD comorbid situations in women.
CONCLUSION
As far as PTSD and addiction are concerned, several lines of
evidence indicate that when these disorders are comorbid, their
symptoms are more severe and treatment more difcult than with
either disease alone (Taylor et al., 2017). One strategy put forward
in this review is to use a KOR ligand to treat this comorbidity. For
example, we could envision treating the dysphoric state associated
with drug withdrawal with an antagonist (Carroll and Carlezon,
2013;Banks, 2020) in conjunction with an exposure therapy to
decrease the incidence of PTSD symptoms. Indeed, the activation
of DYN/KOR system is crucial during stress responses, and either
traumatic stress or addiction development increases its function
(Vant Veer and Carlezon, 2013;Karkhanis et al., 2017), leading
to increased risk of SUD in patients that lived traumatic events.
Alternatively, a KOR biased-agonist, averting the β-arrestin 2-
related signalling mediating dysphoria would be advantageous
compared to MOR agonists for pain management and/or
prevention of PTSD development, as such agonist could
prevent dependency (Spetea and Schmidhammer, 2022).
Nevertheless, future pharmacological studies should better
explore gender effects for these KOR ligands, since agonists
have good analgesics properties but inconsistent dysphoric
side effects in women (Chartoff and Mavrikaki, 2015).
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Leconte et al. Kappa in Stress and Addiction
To better understand the addiction to opiates it is essential to
take into consideration the wide distribution of KOR into the
fear/stress circuitry, including the amygdala, the PAG, the frontal
cortex, the hippocampus, the BNST and the HPA axis. KOR
activate the HPA axis (Vant Veer and Carlezon, 2013) and DYN
is often co-expressed with CRF in regions such as the CeA and the
PVN (Crowley and Kash, 2015). In view of these observations, the
therapeutic-like action of KOR antagonists, in animal models of
anxiety as well as in models commonly used to screen
antidepressant drugs, is not surprising (Spetea and
Schmidhammer, 2022). Furthermore, although controversial at
this point, KOR antagonists may effectively reduce associative
fear memories, by acting on some structures involved in
traumatic fear memory formation (Daumas et al., 2007;Cole
et al., 2011;Knoll et al., 2011). Here again, there seems to be
important gender effects in these models.
In the so-called opponent process theory of addiction (Koob
et al., 1989), the DYN/KOR system appears as a crucial element
explaining decrease dopaminergic transmission associated with
dysphoria, contrasting with the initial hedonic
hyperdopaminergic state (Karkhanis et al., 2017). In addition,
brain areas involved in stress, along the HPA axis and the fear
circuit, overlap with those involved in addiction. In particular, the
VTA innervated BNST and NAc regulated by the same vmPFC
PL and IL areas as is the amygdala to regulate extinction. KOR
activation and the hypodopaminergic state associated with
aversion thus involve as much the amygdala as the NAc
(Vant Veer and Carlezon, 2013). Trauma induces a KOR
function increase in the VTA, the NAc and the BNST, that
leads to endogenous opioid withdrawal and enhanced negative
reinforcement after drug consumption. In addition, KOR
dysphoric effect is dose, stress and gender dependent. Despite
these contradictions, we believe that the best pharmacological
strategy remains the development of KOR antagonist to reduce
relapse, withdrawal-induced anxiety and PTSD predisposition.
Acute morphine treatments, can effectively reduce pain in
patients suffering from traumatic stress, and they are initially
benecial whether they are associated with traumatic injury or
not (Saxe et al., 2001;Schönenberg et al., 2005). Surprisingly, a
short-term administration, right after a traumatic event,
decreases the risk to develop PTSD, probably by reducing the
trauma-related memory consolidation (Saxe, 2006). However, on
the other hand, among all the drugs of abuse, opiates and other
MOR agonists, in particular heroin, most commonly trigger the
SUD-PTSD comorbidity, and more obviously in women
(Najavits et al., 1997). The fact that the DYN/KOR system is
directly interacting with the stress axis, the fear and the reward
circuitries may explain this intriguing observation.
General Conclusion
With advances in genetics, molecular biology and
neurobiology, our understanding of the central role of the
DYN/KOR system in the mechanisms of addiction and
traumatic stress progresses. The activation of DYN/KOR
system now appears crucial in stress responses. Traumatic
stress like addiction increase the function of this system. Most
research has been made so far in male preclinical models, and
thus more research on female models is crucially needed, in
view of the gender-dependent differences in DYN/KOR system
and the great prevalence of SUD/PTSD in women. Therapeutic
strategies, targeting the inactivation of KOR are very
promising not only for the treatment of SUD or PTSD
alone, but also for the SUD/PTSD comorbidity.
AUTHOR CONTRIBUTIONS
CL, RM, and FN contributes to the conception of the manuscript.
CL and FN wrote the rst draft of the manuscript with inputs
from RM.
ACKNOWLEDGMENTS
Figures 1,2were using illustrative drawings (brain, cellular
membrane, brainstem, spinal cord, neuron) from servier
medical art database (https://smart.servier.com/). Each gure
was originally edited by the authors.
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