The dynorphin/κ-opioid receptor system and its role in psychiatric disorders

Tejeda, Hugo A.; Shippenberg, Toni S.; Henriksson, Richard

doi:10.1007/s00018-011-0844-x

Cited by 144 publications

(148 citation statements)

References 448 publications

(595 reference statements)

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“…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 neurons [18,19] . Dynorphin peptides, potent endogenous κ opioid recep- [20] , 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 disorders [22] .…”

Section: Introductionmentioning

confidence: 99%

The role of the dynorphin/κ opioid receptor system in anxiety

Hang

Wang

et al. 2015

Acta Pharmacol Sin

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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.

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Section: Introductionmentioning

confidence: 99%

The role of the dynorphin/κ opioid receptor system in anxiety

Hang

Wang

et al. 2015

Acta Pharmacol Sin

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“…Dynorphin acting on kappa opioid receptors (KORs) is a powerful mediator of behavioral stress reactivity and negative effect (Bruchas et al, 2010;Tejeda et al, 2012;Van't Veer and Carlezon, 2013b). KORs are present in limbic and cortical regions involved in these functions, such as the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA), and mPFC KORs may have a crucial role in anxiety and stress.…”

Section: Introductionmentioning

confidence: 99%

Prefrontal Cortical Kappa Opioid Receptors Attenuate Responses to Amygdala Inputs

Tejeda

Hanks

Scott

et al. 2015

Neuropsychopharmacol

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Kappa opioid receptors (KORs) have been implicated in anxiety and stress, conditions that involve activation of projections from the basolateral amygdala (BLA) to the medial prefrontal cortex (mPFC). Although KORs have been studied in several brain regions, their role on mPFC physiology and on BLA projections to the mPFC remains unclear. Here, we explored whether KORs modify synaptic inputs from the BLA to the mPFC using in vivo electrophysiological recordings with electrical and optogenetic stimulation. Systemic administration of the KOR agonist U69,593 inhibited BLA-evoked synaptic responses in the mPFC without altering hippocampus-evoked responses. IntramPFC U69,593 inhibited electrical and optogenetic BLA-evoked synaptic responses, an effect blocked by the KOR antagonist nor-BNI. Bilateral intra-mPFC injection of the KOR antagonist nor-BNI increased center time in the open field test, suggesting an anxiolytic effect. The data demonstrate that mPFC KORs negatively regulate glutamatergic synaptic transmission in the BLA-mPFC pathway and anxiety-like behavior. These findings provide a framework whereby KOR signaling during stress and anxiety can regulate the flow of emotional state information from the BLA to the mPFC.

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“…It has been suggested that KOR antagonists might have a wide range of indications, including the treatment of depressive-, anxiety-, and addictive disorders (for review, see Carlezon et al, 2009;Wee and Koob, 2010;Tejeda et al, 2012;Carlezon and Carroll, 2013). A general ability to reduce the impact of stress may explain how KOR antagonists can have efficacy in such a wide variety of animal models that would appear to represent different disease states Knoll and Carlezon, 2010;Van't Veer et al, 2012;Carlezon and Carroll, 2013).…”

Section: Introductionmentioning

confidence: 99%

Ablation of Kappa-Opioid Receptors from Brain Dopamine Neurons has Anxiolytic-Like Effects and Enhances Cocaine-Induced Plasticity

Veer

Bechtholt

Onvani

et al. 2013

Neuropsychopharmacol

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Brain kappa-opioid receptors (KORs) are implicated in states of motivation and emotion. Activation of KORs negatively regulates mesolimbic dopamine (DA) neurons, and KOR agonists produce depressive-like behavioral effects. To further evaluate how KOR function affects behavior, we developed mutant mice in which exon 3 of the KOR gene (Oprk1) was flanked with Cre-lox recombination (loxP) sites. By breeding these mice with lines that express Cre-recombinase (Cre) in early embryogenesis (EIIa-Cre) or only in DA neurons (dopamine transporter (DAT)-Cre), we developed constitutive KOR knockouts (KOR À / À ) and conditional knockouts that lack KORs in DA-containing neurons (DAT-KOR lox/lox ). Autoradiography demonstrated complete ablation of KOR binding in the KOR À / À mutants, and reduced binding in the DAT-KOR lox/lox mutants. Quantitative reverse transcription PCR (qPCR) studies confirmed that KOR mRNA is undetectable in the constitutive mutants and reduced in the midbrain DA systems of the conditional mutants. Behavioral characterization demonstrated that these mutant lines do not differ from controls in metrics, including hearing, vision, weight, and locomotor activity. Whereas KOR À / À mice appeared normal in the open field and light/dark box tests, DAT-KOR lox/lox mice showed reduced anxiety-like behavior, an effect that is broadly consistent with previously reported effects of KOR antagonists. Sensitization to the locomotor-stimulating effects of cocaine appeared normal in KOR À / À mutants, but was exaggerated in DAT-KOR lox/lox mutants. Increased sensitivity to cocaine in the DAT-KOR lox/lox mutants is consistent with a role for KORs in negative regulation of DA function, whereas the lack of differences in the KOR À / À mutants suggests compensatory adaptations after constitutive receptor ablation. These mouse lines may be useful in future studies of KOR function.

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The dynorphin/κ-opioid receptor system and its role in psychiatric disorders

Cited by 144 publications

References 448 publications

The role of the dynorphin/κ opioid receptor system in anxiety

The role of the dynorphin/κ opioid receptor system in anxiety

Prefrontal Cortical Kappa Opioid Receptors Attenuate Responses to Amygdala Inputs

Ablation of Kappa-Opioid Receptors from Brain Dopamine Neurons has Anxiolytic-Like Effects and Enhances Cocaine-Induced Plasticity

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