Anxiety disorders are the most common and prevalent forms of psychiatric disease, although the biological basis of anxiety is not well understood. The dynorphin/κ opioid receptor system is widely distributed in the central nervous system and has been shown to play a critical role in modulating mood and emotional behaviors. In the present review, we summarize current literature relating to the role played by the dynorphin/κ opioid receptor system in anxiety and κ opioid receptor antagonists as potential therapeutic agents for the treatment of anxiety disorders.
Anxiety is a recognized symptom of various anxiety disorders, with more than 3.6 million individuals in European countries suffering an anxiety disorder at some point in their lifetime1. The clinical anxiety disorders recognized in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) include the following: generalized anxiety disorder, obsessive compulsive disorder, panic disorder, acute and chronic posttraumatic stress disorder, and various phobias, including agoraphobia, social phobia, and specific phobia (eg, fear of flying)2. Anxiety disorders, commonly occurring with depression and drug abuse, can be triggered or promoted by stress3,4. The most widely used therapeutic agents for the treatment of anxiety disorders include selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, benzodiazepine anxiolytic and NMDA receptor modulators5. However, currently available anxiety disorder modulators are inadequate for patients because of the existence of “nonresponders” or unwanted side effects, such as ataxia, drowsiness, and impairment of cognition6,7,8. Increasing evidence indicates that the dynorphin/κ opioid receptor system plays an important role in the regulation of anxiety disorders. In this review, we describe existing data from pre-clinical studies using animal models to present an overview of the dynorphin/κ opioid receptor system in anxiety.
The dynorphin/κ opioid receptor system
κ Opioid receptors belong to the rhodopsin sub-family of the G protein-coupled receptor (GPCR) family. In the brain, κ opioid receptors are present primarily in the claustrum, cortex, hypothalamus, endopiriform nucleus, nucleus accumbens, caudate putamen, and substantial nigra9,10,11. Stimulation of κ opioid receptors results in the dissociation of G proteins into Gα and Gβγ subunits, in turn affecting a variety of effectors including adenylyl cyclase, potassium/calcium channels, phospholipase C and the p42/44 mitogen-activated protein kinase pathway12. Activation of the κ opioid receptor in vivo produces various effects, including analgesia/antinociception, psychomimesis, dysphoria/aversion, diuresis, antipruritic and blockade of psychostimulant effects12. In contrast, the activation of μ opioid receptors is known to induce euphoria and mediates positive reinforcement. Previous studies have demonstrated that κ opioid receptor agonists functionally attenuate cocaine-induced behavioral sensitization13,14, place preference14,15, and self-administration16,17. These inhibitory effects of κ opioid receptor agonists on cocaine-induced abuse-related behaviors are achieved potentially through the inhibition of dopamine release from dopaminergic neurons18,19.
Dynorphin peptides, potent endogenous κ opioid receptor ligands20, consist of dynorphin A (Dyn A), dynorphin A(1-8), dynorphin B (Dyn B), α-neoendorphin (α-Neo), β-neoendorphin (β-Neo), leumorphin, and big dynorphin (Big Dyn, which contains both Dyn A and Dyn B)21 and have been found to modulate neuronal excitability and to regulate nociception, motivation, cognitive function and stress-induced mood disorders22.
Rodent models of anxiety
The validity of anxiety models rests on three criteria: face validity, predictive validity and construct validity2. In the anxiolytic drug discovery field, the most commonly used rodent models include elevated plus-maze (EPM), light/dark box, social interaction, Vogel conflict, open field, ultrasonic distress vocalization, conditioned fear, Geller-Seifter conflict and stress-induced hyperthermia2. Among these, EPM, light/dark box and open field have been main stay tests for many years. The details of these models and their uses in anxiety have been previously described2,23. Pharmacological data involving different anxiety models are often inconsistent across studies. For example, mice with ablation of κ opioid receptors from brain dopamine neurons displayed anxiolytic effects in the open field and light/dark box tests but not in the EPM test24. This discrepant result may be due to genetic and environmental influences25. Therefore, it will be important to use multiple tests to obtain a broad understanding of the molecular mechanisms of anxiety and to develop new medications for the treatment of anxiety disorders.
Role of the dynorphin/κ opioid receptor system in anxiety
Chronic stress may lead to anxiety and depression4. Moderate to high levels of dynorphin mRNA and κ opioid receptors are expressed in regions of the brain that are stress-related in rodents, including the hypothalamic paraventricular nucleus (PVN), amygdala (AMY), hippocampus (Hip) and bed nucleus of the stria terminalis (BNST)11,26,27, and stress exposure has been shown to increase endogenous dynorphin levels28. A growing body of evidence reveals that the dynorphin/κ opioid receptor system plays an important role in stress29,30,31.
κ Opioid receptor agonists and antagonists
Human studies show that selective κ opioid receptor agonists produce dysphoria, anxiety and abnormal behavior along with psychotomimesis at higher doses29. The benzomorphan κ opioid receptor agonist MR2033 elicited dose-dependent dysphoric and psychotomimetic effects, which were antagonized by naloxone29. This was consistent with work demonstrating that salvinorin A, a highly selective κ opioid receptor agonist, caused a certain degree of anxiety according to the state-trait anxiety inventory-S, a 20-item self-rating scale32.
However, κ opioid receptor agonists exert biphasic effects on anxiety in rodents. Increasing evidence shows that selective κ opioid receptor agonists produce anxiety-like behaviors in the EPM test33,34,35,36,37,38,39. These findings were further supported by findings that anxiolytic effects are produced by deficiencies in the κ opioid receptor system in mice. Mice lacking prodynorphin displayed increased anxiolytic parameters of explorative behavior in the open field as well as EPM and light-dark tests38. Ablation of κ opioid receptors from brain dopamine neurons produced reduced anxiety-like behaviors in the open field and light-dark tests but not in the EPM test40. In addition, intra-amygdala microinjection of dynorphin A increased anxiety-like behavior in the light-dark test41. However, inconsistent with these observations is the finding that the κ opioid receptor agonist U50488 significantly increased time spent in open arms during the EPM test42,43. This is consistent with work demonstrating that U69593 and salvinorin A both produced anxiolytic effects in rodents44,45. Microinjection of U69593 into the infralimbic cortex reduced anxiety-like behavior in the EPM test46. Kuzmin et al (2006) showed that big dynorphin, a prodynorphin-derived precursor peptide, induced anxiolytic-like behavior in mice in the EPM test47. Whereas, deletion of the prodynorphin gene increased anxiety-like behaviors in the EPM and light-dark tests48. Similarly, ablation of prodynorphin showed increased anxiety-like behaviors in zero-maze and startle-response tests49. It must be noted that some lines of constitutive κ opioid receptor knockout (KO) mice did not display altered anxiety-like behaviors50,51. Discrepancies among these studies may be due to, but are not limited to, the use of specific genetic constructs for generating mutant mice, experimental paradigms, size of the apparatus, intensity of illumination, test conditions, animal strains, and lab specific basal stress levels. Although with these limitations and variables, the findings clearly demonstrate that the dynorphin/κ opioid receptor system is involved in anxiety-related behavior33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,49,50,51 (see Table 1 for a summary of current literature), but it is difficult to define the exact role of κ opioid receptor signaling because both anxiolytic- and anxiogenic-like effects are reported with κ opioid receptor agonists. Indeed, THC, a CB1 receptor agonist, microinjected at low doses in the prefrontal cortex and ventral hippocampus induced an anxiolytic-like response, while high doses caused an anxiogenic reaction52. Considering that κ opioid receptors are widely expressed in the central nervous system11, it is not surprising that specific brain regions (ie, prefrontal cortex, amygdala and hypothalamus) may have opposite and complementary roles in the regulation of anxiety by κ opioid receptors. Further studies are clearly needed to understand the mechanism involved in biphasic effects induced by κ opioid receptor agonists.
Although κ opioid receptor agonists present conflicting profiles in mood disorders, the administration of κ opioid receptor antagonists have been shown to exert consistent anxiolytic effects in different animal models34,37,38,39,53,54,55,56,57,58,59,60 (see Table 2 for a summary of the current literature). The κ opioid receptor antagonists nor-BNI and JDTic increased open arm exploration in EPM tests and decreased conditioned fear in the fear-potentiated startle paradigm55,60. Similarly, DIPPA produced anxiolytic-like effects in both novelty-induced hypophagia and defensive burying tests57. In addition, it was demonstrated that animals treated with GNTi displayed increased open arm exploration in the EPM test and increased center area exploration in the open field test38. Together, these studies suggest that κ opioid receptor antagonists may be particularly effective for the treatment of anxiety disorders61,62.
Link between the dynorphin/κ opioid receptor system and corticotrophin-released factor
The neuropeptide corticotrophin-release factor (CRF) plays a critical role in the stress response by its regulation of the hypothalamic-pituitary axis (HPA) and subsequent adrenocorticosteroid release63. CRF and dynorphin are co-expressed in the hypothalamus64,65 and central amygdala66,67. CRF causes dynorphin release68,69 and dynorphin-dependent κ opioid receptor activation in several anxiety-related brain regions30. Land et al (2008) reported that CRF-induced anxiety-like behaviors were blocked by a κ opioid receptor antagonist30. Recent work further showed that the anxiogenic-like effects of CRF were triggered by CRF1-R activation of the dynorphin/κ opioid receptor system59. These results reveal a connection between CRF and the dynorphin/κ opioid receptor system70 and support that the CRF-induced dynorphin/κ opioid receptor-dependent pathway is involved in the modulation of anxiety-like behaviors62.
Brain regions involved in κ opioid receptor-mediated anxiety
The mesocorticolimbic dopamine (DA) system originates in the ventral tegmental area (VTA) and projects to the amygdala, BNST, nucleus accumbens, prefrontal cortex, and hippocampus40,71. κ Opioid receptors are located on both the cell bodies and terminals of mosocorticolimbic DA neurons72,73. Activation of κ opioid receptors leads to the inhibition of DA neurons in the VTA74 and decreases DA release in regions that receive VTA input75,76. κ Opioid receptor agonists produce dysphoria, anhedonia and depressive-like effects, which are partially mediated by decreased function of the mesocorticolimbic DA system76,77. Recently, two lines of mice with mutations in the κ opioid receptor system were generated24. One is a constitutive κ opioid receptor knockout (KOR−/−), the other is a conditional knockout (DAT-KORlox/lox) in which κ opioid receptors are lacking in DA-containing neurons. Behavioral characterization demonstrated that DAT-KORlox/lox mice displayed reduced anxiety-like behaviors in the open field and light/dark box tests. These findings suggest that the activation of κ opioid receptors in the mesocorticolimbic DA system plays a key role in anxiety.
The amygdala, a target of VTA dopamine neurons, is critical for anxiety-related responses. Knoll et al (2011) found that the microinjection of κ opioid receptor antagonist into the basolateral amygdala (BLA) produced anxiolytic-like responses in the EPM test55. The importance of the amygdala in anxiety has also been confirmed by other researchers who report that stress- or CRF-induced anxiety is mediated by dynorphin release in the BLA, which can be blocked by a local injection of the κ opioid receptor antagonist norBNI59.
The dorsal raphe nucleus (DRN), the primary source of serotonin that sends projections to multiple forebrain limbic regions, is critical for regulating affective states and stress78. Land et al (2009) demonstrated that the aversive properties of κ opioid receptor activation was encoded by DRN to NAc serotonergic projections because κ opioid receptor KO mice failed to develop κ opioid receptor agonist U50488-induced CPA; however, lentivirus expression of κ opioid receptors in the DRN restored the aversive response79, whereas lentivirus expression of mutated κ opioid receptors that were unable to activate p38 MAPK in the DRN did not restore the aversive response. In addition to mediating the dysphoric responses of stress, p38 MAPK activation within the DRN has also been found to contribute to depressive-like and drug-seeking behaviors80.
The locus coeruleus (LC) is one of the primary sources of norepinephrine (NE) in the forebrain81. Dynorphin and κ opioid receptors are coexpressed within the LC on noradrenergic (NA) neurons67,82,83,84,85. Previous reports have shown that both stress and CRF engage in LC NA cell firing86,87. Ai-Hasani et al (2013) first reported that κ opioid receptors within the LC NA nuclei modulate the reinstatement of cocaine place preference through a noradrenergic mechanism88. Because the LC-NE system is a critical stress response system81, κ opioid receptor pathway interactions with the NA system may influence κ opioid receptor-mediated aversion and anxiety-like behaviors. Evidence supports a model in which the dynorphin/κ opioid receptor system and CRF coordinate in stress-induced anxiety behaviors. κ Opioid receptors and CRF are co-expressed in the hypothalamus64 and central amygdala65. Both stress and CRF cause dynorphin-dependent κ opioid receptor activation in the BLA, nucleus accumbens, dorsal raphe and hippocampus30. Recent evidence indicates that κ opioid receptors are expressed on the terminal of amygdala inputs to BNST89, a brain region strongly involved in fear and anxiety90. Thus, there is a considerable possibility that the dynorphin/κ opioid receptor system within these regions may play a role in anxiety.
Various stress paradigms differentially influence κ opioid receptor-induced responses
Previous studies implicate stress activation of the κ opioid receptor in increased anxiety-like behaviors, dysphoric responses, and potentiation of drug seeking behaviors29,30,31,38,76,91. It has been reported that acute stress activates the hypothalamic-pituitary-adrenal (HPA) axis and influences amygdala CRF gene expression, which is a key mediator of the stress response61. Acute stress has also been found to affect κ opioid receptor activation in the BLA and κ opioid receptor transcription in the PVN of the hypothalamus55,59. Using an acute swim stress method, Bruchas et al (2009) demonstrated that CRF1-R activation of the dynorphin/κ opioid receptor system in the BLA mediates anxiety-like behaviors59. Moreover, recent work demonstrates that single acute swim stress-induced cocaine seeking reinstatement occurred via κ opioid receptor activation88. Similar to acute stress, repeated exposure to stress also results in dynorphin release and subsequent κ opioid receptor activation92. Following repeated swim stress, κ opioid receptor mRNA expression was regulated in a region-specific manner in the brain93. In recent reports, exposure to repeated stress resulted in the dysregulation of κ receptor signaling in the DRN through a p38 MAPK-dependent mechanism92. In this study, repeated swim stress significantly reduced κ opioid receptor-mediated G-protein gated inwardly rectifying potassium channel currents in serotonergic neurons post-synaptically, without affecting pre-synaptic excitatory transmission92. The functional consequences of repeated stress exposure on κ opioid receptor-dependent behaviors have not been well investigated; however, several studies reveal that repeated swim stress-induced activation of the dynorphin/κ opioid receptor system potentiates nicotine conditioned place preference35 and cocaine rewarding effects94. Chronic mild stress is a widely used animal model for inducing anxiety-like behavior; however, the significance of κ opioid receptors in chronic mild stress is unclear. Recently, Ai-Hasani et al (2013) compared different types of exposure to stress (acute, sub-chronic, and chronic) to study the impact on κ opioid receptor-induced reinstatement95. They found that following an acute swim stress, the activation of κ opioid receptors potentiated cocaine reinstatement; however, repeated swim stress and chronic mild stress blocked κ opioid receptor-induced cocaine or nicotine reinstatement. These findings indicate that various types of stress paradigms affect dynorphin/κ opioid receptor system-mediated reinstatement. Although these studies do not definitively prove that stress types differentially influence κ opioid receptor-mediated affective states, they do provide the basis for further investigation.
Ligand-directed signaling at the κ opioid receptor
Numerous studies support that GPCRs exist in multiple conformation states. Agonists can initiate distinct receptor conformations that produce distinct signaling cascades to mediate various behavioral effects. This concept is referred to as ligand-directed signaling or biased agonism96. It has been recognized that biased μ opioid receptor agonists may be promising analgesics with less abuse potential, whereas biased κ opioid receptor agonists can be used for the treatment of pain and other disorders with less risk of convulsions97. Ligand-directed signaling at the κ opioid receptor also has important implications because the activation of the κ opioid receptor produces analgesia with a low risk of addiction or dysphoria, unlike the action of the μ opioid receptor, which induces euphoria62. κ Opioid receptor agonists activate a variety of kinase cascades including ERK1/2, JNKs, PKC, and p38 MAPKs62. The link between κ opioid receptor ligand-selective signaling cascades and in vivo responses has not been fully characterized, but recent behavioral studies demonstrate that arrestin-dependent p38 activation is selectively involved in dysphoria induced by κ opioid receptor activation, whereas Gβγ-dependent signaling underlies analgesic responses. Bruchas et al (2006) found that κ opioid receptors activate the p38 MAPK pathway through a GRK3- and arrestin-dependent mechanism98. κ Opioid receptor activation of the p38 MAPK pathway in the DRN, a serotonergic nucleus, is important for κ opioid receptor agonist U50488-induced conditioned place aversion and stress-induced reinstatement of drug seeking79. Further selective inactivation of p38 signaling in serotonergic neurons of the DRN blocked defeat-induced social aversion79. Therefore, arrestin-dependent p38 activation is required for κ opioid receptor-mediated dysphoric and proaddictive effects. Together, these findings demonstrate that κ opioid receptor agonist-biased signaling exerts behavioral consequences. From a therapeutic perspective, signaling pathway-selective κ opioid receptor agonists may have clinical applications for the treatment of mood disorders. In contrast to κ opioid receptor agonists, κ opioid receptor antagonists such as norBNI, GNTI and JDTic have long durations of action and cause κ opioid receptor inactivation through a c-Jun N-terminal kinase (JNK)-dependent signaling cascade; the underlying mechanisms need to be elucidated99.
The dynorphin/κ opioid receptor system has a wide range of biological effects, including affecting mood disorders, cognition and reward. Activation of the κ opioid receptor by agonists may have biphasic effects in anxiety-like behaviors. These inconsistent findings require further study to examine the underlying mechanism of the dynorphin/κ opioid receptor system in the neurobiology of anxiety. Another view based on preclinical studies is that κ opioid receptor antagonists produce profoundly consistent anxiolytic effects in animal behavioral models, although solid evidence from clinical studies is lacking. It is not fully understood how the κ opioid receptor blockade will eventually affect behavior. Answering this question may provide insights into the mechanism of anxiety. So far, the available κ opioid receptor antagonists have an extremely long duration of action. If shorter acting agents become available and are effective, κ opioid receptor antagonists may have therapeutic potential for the treatment of anxiety disorders.
Wittchen HU, Jacobi F . Size and burden of mental disorders in Europe —a critical review and appraisal of 27 studies. Eur Neuropsychopharmacol 2005; 15: 357–76.
American Psychiatric Association (US). Diagnostic and statistical manual of mental disorders, 5th ed: DSM-V®. Arlington, VA: American Psychiatric Association; 2013.
van Praag HM . Can stress cause depression? Prog Neuro-Psychoph 2004; 28: 891–907.
Chiba S, Numakawa T, Ninomiya M, Richards MC, Wakabayashi C, Kunugi H . Chronic restraint stress causes anxiety- and depression-like behaviors, downregulates glucocorticoid receptor expression, and attenuates glutamate release induced by brain-derived neurotrophic factor in the prefrontal cortex. Prog Neuropsychopharmacol Biol Psychiatry 2012; 39: 112–9.
Farb DH, Ratner MH . Targeting the modulation of neural circuitry for the treatment of anxiety disorders. Pharmacol Rev 2014; 66: 1002–32.
Ravindran LN, Stein MB . The pharmacologic treatment of anxiety disorders: a review of progress. J Clin Psychiatry 2010; 71: 839–54.
Venlafaxine. Prescribing information. Pfizer/Wyeth Pharmaceuticals, Inc, Philadelphia 2012.
Allgulander C, Bandelow B, Hollander E, Montgomery SA, Nutt DJ, Okasha A, et al. WCA recommendations for the long-term treatment of generalized anxiety disorder. CNS Spectr 2003; 8: 53–61.
Mansour A, Khachaturian H, Lewis ME, Akil H, Watson SJ . Autoradiographic differentiation of mu, delta, and kappa opioid receptors in the rat forebrain and midbrain. J Neurosci 1987; 7: 2445–64.
Mansour A, Khachaturian H, Lewis ME, Akil H, Watson SJ . Anatomy of CNS opioid receptors. Trends Neurosci 1988; 11: 308–14.
Wang YJ, Rasakham K, Huang P, Chudnovskaya D, Cowan A, Liu-Chen LY . Sex difference in kappa opioid receptor (KOPR)-mediated behaviors and brain region KOPR level and KOPR-mediated guanosine 5′-O-(3-35S]thiotriphosphate) binding in the guinea pig. J Pharmacol Exp Ther 2011; 339: 438–50.
Liu-Chen LY . Agonist-induced regulation and trafficking of kappa opioid receptors. Life Sci 2004; 75: 511–36.
Ukai M, Mizutani M, Kameyama T . Opioid peptides selective for receptor types modulate cocaine-induced behavioral responses in mice. Nihon Shinkei SeishinYakurigaku Zasshi 1994; 14: 153–9. Japanese.
Crawford CA, McDougall SA, Bolanos CA, Hall S, Berger SP . The effects of the kappa agonist U-50,488 on cocaine-induced conditioned and unconditioned behaviors and Fos immunoreactivity. Psychopharmacol (Berl) 1995; 120: 392–9.
Shippenberg TS, LeFevour A, Heidbreder C . kappa-Opioid receptor agonists prevent sensitization to the conditioned rewarding effects of cocaine. J Pharmacol Exp Ther 1996; 276: 545–54.
Mello NK, Negus SS . Effects of kappa opioid agonists on cocaine- and food-maintained responding by rhesus monkeys. J Pharmacol Exp Ther 1998; 286: 812–24.
Schenk S, Partridge B, Shippenberg TS . U69593, a kappa-opioid agonist, decreases cocaine self-administration and decreases cocaine-produced drug-seeking. Psychopharmacol (Berl) 1999; 144: 339–46.
Di Chiara G, Imperato A . Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci U S A 1988; 85: 5274–8.
Maisonneuve IM, Archer S, Glick SD . U50,488, a kappa opioid receptor agonist, attenuates cocaine-induced increases in extracellular dopamine in the nucleus accumbens of rats. Neurosci Lett 1994; 181: 57–60.
Chavkin C, James IF, Goldstein A . Dynorphin is a specific endogenous ligand of the kappa opioid receptor. Science 1982; 215: 413–5.
Schwarzer C . 30 years of dynorphins—new insights on their functions in neuropsychiatric diseases. Pharmacol Ther 2009; 123: 353–70.
Tejeda HA, Shippenberg TS, Henriksson R . The dynorphin/κ-opioid receptor system and its role in psychiatric disorders. Cell Mol Life Sci 2012; 69: 857–96.
Ramos A . Animal models of anxiety: do I need multiple tests? Trends Pharmacol Sci 2008; 29: 493–8.
Van't Veer A, Bechtholt AJ, Onvani S, Potter D, Wang YJ, Liu-Chen LY, et al. Ablation of kappa-opioid receptors from brain dopamine neurons has anxiolytic-like effects and enhances cocaine-induced plasticity. Neuropsychopharmacology 2013; 38: 1585–97.
Wahlsten D, Bachmanov A, Finn DA, Crabbe JC . Stability of inbred mouse strain differences in behavior and brain size between laboratories and across decades. Proc Natl Acad Sci U S A 2006; 103: 16364–9.
Lin S, Boey D, Lee N, Schwarzer C, Sainsbury A, Herzog H . Distribution of prodynorphin mRNA and its interaction with the NPY system in the mouse brain. Neuropeptides 2006; 40: 115–23.
Morris BJ, Haarmann I, Kempter B, Hollt V, Herz A . Localization of prodynorphin messenger RNA in rat brain by in situ hybridization using a synthetic oligonucleotide probe. Neurosci Lett 1986; 69: 104–8.
Nabeshima T, Katoh A, Wada M, Kameyama T . Stress-induced changes in brain Met-enkephalin, Leu-enkephalin and dynorphin concentrations. Life Sci 1992; 51: 211–7.
Pfeiffer A, Brantl V, Herz A, Emrich HM . Psychotomimesis mediated by kappa opiate receptors. Science 1986; 233: 774–6.
Land BB, Bruchas MR, Lemos JC, Xu M, Melief EJ, Chavkin C . The dysphoric component of stress is encoded by activation of the dynorphin κ-opioid system. J Neurosci 2008; 28: 407–14.
McLaughlin JP, Marton-Popovici M, Chavkin C . Kappa opioid receptor antagonism and prodynorphin gene disruption block stress-induced behavioral responses. J Neurosci 2003; 23: 5674–83.
Gonzalez D, Riba J, Bouso JC, Gomez-Jarabo G, Barbanoj MJ . Pattern of use and subjective effects of Salvia divinorum among recreational users. Drug Alcohol Depend 2006; 85: 157–62.
Gillett K, Harshberger E, Valdez GR . Protracted withdrawal from ethanol and enhanced responsiveness stress: regulation via the dynorphin/kappa opioid receptor system. Alcohol 2013; 47: 359–65.
Valdez GR, Harshberger E . Kappa opioid regulation of anxiety-like behavior during acute ethanol withdrawal. Pharmacol Biochem Beha 2012; 102: 44–7.
Smith JS, Schindler AG, Martinelli E, Gustin RM, Bruchas MR, Chavkin C . Stress-induced activation of the dynorphin/κ-opioid receptor system in the amygdala potentiates nicotine conditioned place preference. J Neurosci 2012; 32: 1488–95.
Vunck SA, Snider SE, van den Oord EJCG, Beardsley PM . The kappa opioid receptor agonist, U50,488, exacerbates conditioned fear in mice. FASEB J 2011; 25: 617–20.
Harshberger E . Kappa opioid regulation of stress-related behavior. McNair Scholars J 2010; 14: 63–7.
Wittmann W, Schunk E, Rosskothen I, Gaburro S, Singewald N, Herzog H, et al. Prodynorphin-derived peptides are critical modulators of anxiety and regulate neurochemistry and corticosterone. Neuropsychopharmacology 2009; 34: 775–85.
Wiley MD, Poveromo LB, Antapasis J, Herrera CM, Bolanos Guzman CA . Kappa-opioid system regulates the long-lasting behavioral adaptations induced by early-life exposure to methylphenidate. Neuropsychopharmacology 2009; 34: 1339–50.
Van't Veer A, Carlezon WA Jr . Role of kappa-opioid receptors in stress and anxiety-related behavior. Psychopharmacology 2013; 229: 435–52.
Narita M, Kaneko C, Miyoshi K, Nagumo Y, Kuzumaki N, Nakajima M, et al. Chronic pain induces anxiety with concomitant changes in opioidergic function in the amygdala. Neuropsychopharmacology 2006; 31: 739–75.
Kudryavtsevaa NN, Gerritsb MAFM, Avgustinovicha DF, Tenditnika MV, Van Ree JM . Modulation of anxiety-related behaviors by μ- and κ-opioid receptor agonists depends on the social status of mice. Peptides 2004; 25: 1355–63.
Kudryavtseva NN, Gerrits MA, Alekseenko OV, Van Ree JM . Chronic cocaine injections attenuate behavioral response of κ-opioid receptors to U-50,488H agonist. B Exp Biol Med 2005; 140: 305–7.
Privette TH, Tertian DM . Kappa opioid agonists produce anxiolytic-like behavior on the elevated plus-maze. Psychopharmacology 1995; 118: 444–50.
Braida D, Capurro V, Zani A, Rubino T, Viganò D, Parolaro D, et al. Potential anxiolytic- and antidepressant-like effects of salvinorin A, the main active ingredient of Salvia divinorum, in rodents. Br J Pharmacol 2009; 157: 844–53.
Wall PM, Messier C . U-69,593 microinjection in the infralimbic cortex reduces anxiety and enhances spontaneous alternation memory in mice. Brain Res 2000; 856: 259–80.
Kuzmin A, Madjid N, Terenius L, Ogren SO, Bakalkin G . Big dynorphin, a prodynorphin-derived peptide produces NMDA receptor-mediated effects on memory, anxiolytic-like and locomotor behavior in mice. Neuropsychopharmacology 2006; 31: 1928–37.
Femenía T, Pérez-Rial S, Urigüen L, Manzanares J . Prodynorphin gene deletion increased anxiety-like behaviours, impaired the anxiolytic effect of bromazepam and altered GABAA receptor subunits gene expression in the amygdala. J Psychopharmacol 2011; 25: 87–96.
Bilkei-Gorzo A, Racz I, Michel K, Mauer D, Zimmer A, Klingmuller D . Control of hormonal stress reactivity by the endogenous opioid system. Psychoneuroendocrinology 2008; 33: 425–36.
Filliol D, Ghozland S, Chluba J, Martin M, Matthes HW, Simonin F, et al. Mice deficient for delta- and mu-opioid receptors exhibit opposing alterations of emotional responses. Nat Genet 2000; 25: 195–200.
Simonin F, Valverde O, Smadja C, Slowe S, Kitchen I, Dierich A, et al. Disruption of the kappa-opioid receptor gene in mice enhances sensitivity to chemical visceral pain, impairs pharmacological actions of the selective kappa-agonist U-50,488H and attenuates morphine withdrawal. EMBO J 1998; 17: 886–97.
Rubino T, Guidali C, Vigano D, Realini N, Valenti M, Massi P, et al. CB1 receptor activation in specific brain areas differently modulates anxiety-related behavior. Neuropharmacology 2008; 54: 151–60.
Rogala B, Li Y, Li S, Chen XY, Kirouac GJ . Effects of a post-shock injection of the kappa opioid receptor antagonist norbinaltorphimine (norBNI) on fear and anxiety in rats. PLoS One 2012; 7: e49669.
Schank JR, Goldstein AL, Rowe KE, King CE, Marusich JA, Wiley JL, et al. The kappa opioid receptor antagonist JDTic attenuates alcohol seeking and withdrawal anxiety. Addict Biol 2012; 17: 634–47.
Knoll AT, Muschamp JW, Sillivan SE, Ferguson D, Dietz DM, Meloni EG, et al. Kappa opioid receptor signaling in the basolateral amygdala regulates conditioned fear and anxiety in rats. Biol Psychiatry 2011; 70: 425–33.
Peters MF, Zacco A, Gordon J, Maciag CM, Litwin LC, Thompson C, et al. Identification of short-acting κ-opioid receptor antagonists with anxiolytic-like activity. Eur J Pharmacol 2011; 661: 27–34.
Carr GV, Lucki I . Comparison of the kappa-opioid receptor antagonist DIPPA in tests of anxiety-like behavior between Wistar Kyoto and Sprague Dawley rats. Psychopharmacology 2010; 210: 295–302.
Jackson KJ, Carroll FI, Negus SS, Damaj MI . Effect of the selective kappa-opioid receptor antagonist JDTic on nicotine antinociception, reward, and withdrawal in the mouse. Psychopharmacology 2010; 210: 285–94.
Bruchas MR, Land BB, Lemos JC, Chavkin C . CRF1-R activation of the dynorphin/kappa opioid system in the mouse basolateral amygdala mediates anxiety-like behavior. PLoS One 2009; 4: e8528.
Knoll AT, Meloni EG, Thomas JB, Carroll FI, Carlezon WA Jr . Anxiolytic-like effects of kappa-opioid receptor antagonists in models of unlearned and learned fear in rats. J Pharmacol Exp Ther 2007; 323: 838–45.
Knoll AT, Carlezon WA Jr . Dynorphin, stress, and depression. Brain Res 2010; 1314: 56–73.
Bruchas MR, Land BB, Chavkin C . The dynorphin/kappa opioid system as a modulator of stress-induced and pro-addictive behaviors. Brain Res 2010; 1314: 44–5.
Koob GF . Corticotropin-releasing factor, norepinephrine, and stress. Biol Psychiatry 1999; 46: 1167–80.
Roth KA, Weber E, Barchas JD, Chang D, Chang JK . Immunoreactive dynorphin-(1–8) and corticotropin-releasing factor in subpopulation of hypothalamic neurons. Science 1983; 219: 189–91.
Meister B, Villar MJ, Ceccatelli S, Hokfelt T . Localization of chemical messengers in magnocellular neurons of the hypothalamic supraoptic and paraventricular nuclei: an immunohistochemical study using experimental manipulations. Neurosciences 1990; 37: 603–33.
Marchant NJ, Densmore VS, Osborne PB . Coexpression of prodynorphin and corticotrophin-releasing hormone in the rat central amygdala: evidence of two distinct endogenous opioid systems in the lateral division. J Comp Neurol 2007; 504: 702–15.
Reyes BA, Drolet G, Van Bockstaele EJ . Dynorphin and stress-related peptides in rat locus coeruleus: contribution of amygdalar efferents. J Comp Neurol 2008; 508: 663–75.
Nikolarakis KE, Almeida OF, Herz A . Stimulation of hypothalamic beta-endorphin and dynorphin release by corticotropin-releasing factor (in vitro). Brain Res 1986; 399: 152–5.
Song ZH, Takemori AE . Stimulation by corticotropin-releasing factor of the release of immunoreactive dynorphin A from mouse spinal cords in vitro. Eur J Pharmacol 1992; 222: 27–32.
Van't Veer A, Yano JM, Carroll FI, Cohen BM, Carlezon WA Jr . Corticotropin-releasing factor (CRF)-induced disruption of attention in rats is blocked by the kappa-opioid receptor antagonist JDTic. Neuropsychopharmacol 2012; 37: 2809–16.
Swanson LW . The projections of the ventral tegmental area and adjacent regions: a combined fluorescent retrograde tracer and immunofluorescence study in the rat. Brain Res Bull 1982; 9: 321–53.
Svingos AL, Chavkin C, Colago EE, Pickel VM . Major coexpression of kappa-opioid receptors and the dopamine transporter in nucleus accumbens axonal profiles. Synapse 2001; 42: 185–92.
Svingos AL, Colago EE, Pickel VM . Cellular sites for dynorphin activation of kappa-opioid receptors in the rat nucleus accumbens shell. J Neurosci 1999; 19: 1804–13.
Ford CP, Beckstead MJ, Williams JT . Kappa opioid inhibition of somatodendritic dopamine inhibitory postsynaptic currents. J Neurophysiol 2007; 97: 883–91.
Di Chiara G, Imperato A . Opposite effects of mu and kappa opiate agonists on dopamine release in the nucleus accumbens and in the dorsal caudate of freely moving rats. J Pharmacol Exp Ther 1988; 244: 1067–80.
Carlezon WA Jr, Beguin C, DiNieri JA, Baumann MH, Richards MR, Todtenkopf MS, et al. Depressive-like effects of the kappa-opioid receptor agonist salvinorin A on behavior and neurochemistry in rats. J Pharmacol Exp Ther 2006; 316: 440–7.
Carlezon WA Jr, Thomas MJ . Biological substrates of reward and aversion: a nucleus accumbens activity hypothesis. Neuropharmacol 2009; 56: 122–32.
Maier SF, Watkins LR . Stressor controllability and learned helplessness: the roles of the dorsal raphe nucleus, serotonin, and corticotropinreleasing factor. Neurosci Biobehav Rev 2005; 29: 829–41.
Land BB, Bruchas MR, Schattauer S, Giardino WJ, Aita M, Messinger D, et al. Activation of the kappa opioid receptor in the dorsal raphe nucleus mediates the aversive effects of stress and reinstates drug seeking. Proc Natl Acad Sci U S A 2009; 106: 19168–73.
Bruchas MR, Schindler AG, Shankar H, Messinger DI, Miyatake M, Land BB, et al. Selective p38α MAPK deletion in serotonergic neurons produces stress resilience in models of depression and addiction. Neuron 2011; 71: 498–511.
Van Bockstaele EJ, Reyes BA, Valentino RJ . The locus coeruleus: a key nucleus where stress and opioids intersect to mediate vulnerability to opiate abuse. Brain Res 2010; 1314: 162–74.
Kreibich A, Reyes BA, Curtis AL, Ecke L, Chavkin C, Van Bockstaele EJ, et al. Presynaptic inhibition of diverse afferents to the locus ceruleus by kappa-opiate receptors: a novel mechanism for regulating the central norepinephrine system. J Neurosci 2008; 28: 6516–25.
Reyes BA, Glaser JD, Magtoto R, Van Bockstaele EJ . Proopiomelanocortin colocalizes with corticotropin-releasing factor in axon terminals of the noradrenergic nucleus locus coeruleus. Eur J Neurosci 2006; 23: 2067–77.
Reyes BA, Johnson AD, Glaser JD, Commons KG, Van Bockstaele EJ . Dynorphin-containing axons directly innervate noradrenergic neurons in the rat nucleus locus coeruleus. Neurosciences 2007; 145: 1077–86.
Reyes BA, Chavkin C, Van Bockstaele EJ . Subcellular targeting of kappa-opioid receptors in the rat nucleus locus coeruleus. J Comp Neurol 2009; 512: 419–31.
Aston-Jones G, Rajkowski J, Cohen J . Role of locus coeruleus in attention and behavioral flexibility. Biol Psychiatry 1999; 46: 1309–20.
Devilbiss DM, Waterhouse BD, Berridge CW, Valentino R . Corticotropin-releasing factor acting at the locus coeruleus disrupts thalamic and cortical sensory-evoked responses. Neuropsychopharmacology 2012; 37: 2020–30.
AI-Hasani R, McCal JG, Foshage AM, Bruchas MR . Locus coeruleus kappa-opioid receptors modulate reinstatement of cocaine place preference through a noradrenergic mechanism. Neuropsychopharmacology 2013; 38: 2484–97.
Li C, Pleil KE, Stamatakis AM, Busan S, Vong L, Lowell BB, et al. Presynaptic inhibition of gamma-aminobutyric acid release in the bed nucleus of the stria terminalis by kappa opioid receptor signaling. Biol Psychiatry 2012; 71: 725–32.
Walker DL, Toufexis DJ, Davis M . Role of the bed nucleus of the stria terminalis versus the amygdala in fear, stress, and anxiety. Eur J Pharmacol 2003; 463: 199–216.
Schindler AG, Li S, Chavkin C . Behavioral stress may increase the rewarding valence of cocaineassociated cues through a dynorphin/kappa-opioid receptor-mediated mechanism without affecting associative learning or memory retrieval mechanisms. Neuropsychopharmacology 2010; 35: 1932–42.
Lemos JC, Roth CA, Messinger DI, Gill HK, Phillips PE, Chavkin C . Repeated stress dysregulates κ-opioid receptor signaling in the dorsal raphe through a p38αMAPK-dependent mechanism. J Neurosci 2012; 32: 12325–36.
Flaisher-Grinberg S, Persaud SD, Loh HH, Wei LN . Stress-induced epigenetic regulation of κ-opioid receptor gene involves transcription factor c-Myc. Proc Natl AcadSci U S A 2012; 109: 9167–72.
Schindler AG, Messinger DI, Smith JS, Shankar H, Gustin RM, Schattauer SS, et al. Stress produces aversion and potentiates cocaine reward by releasing endogenous dynorphins in the ventral striatum to locally stimulate serotonin reuptake. J Neurosci 2012; 32: 17582–96.
Al-Hasani R, McCall JG, Bruchas MR . Exposure to chronic mild stress prevents kappa opioid-mediated reinstatement of cocaine and nicotine place preference. Front Pharmacol 2013; 4: 96.
Kenakin T . Functional selectivity and biased receptor signaling. J Pharmacol Exp Ther 2011; 336: 296–302.
Pradhan AA, Smith ML, Kieffer BL, Evans CJ . Ligand-directed signaling within the opioid receptor family. Br J Pharmacol 2012; 167: 960–9.
Bruchas MR, Macey TA, Lowe JD, Chavkin C . Kappa opioid receptor activation of p38 MAPKis GRK3- and arrestin-dependent in neurons and astrocytes. J Biol Chem 2006; 281: 18081–9.
Bruchas MR, Land BB, Aita M, Xu M, Barot SK, Li S, et al. Stress-induced p38 mitogen-activated protein kinase activation mediates kappa-opioid-dependent dysphoria. J Neurosci 2007; 27: 11614–23.
This research was supported by grant 2013CB835100 (to Jing-gen LIU) from the Ministry of Science and Technology of China and by grants 81130087, 91232716 (to Jing-gen LIU) and 81401107 (Yu-jun WANG) from the National Natural Science Foundation of China.
About this article
Cite this article
Hang, A., Wang, Yj., He, L. et al. The role of the dynorphin/κ opioid receptor system in anxiety. Acta Pharmacol Sin 36, 783–790 (2015). https://doi.org/10.1038/aps.2015.32
- κ opioid receptor
Amygdala dynorphin/κ opioid receptor system modulates depressive-like behavior in mice following chronic social defeat stress
Acta Pharmacologica Sinica (2022)
The anxiolytic- and antidepressant-like effects of ATPM-ET, a novel κ agonist and μ partial agonist, in mice