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

Hang, Ai; Wang, Yujun; He, Ling; Liu, Jing-Gen

doi:10.1038/aps.2015.32

Cited by 61 publications

(53 citation statements)

References 94 publications

(141 reference statements)

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“…The anti-anxiety responses of norBNI in the NIH and EPM tests are in line with several publications on anxiolytic-like effects of the long-acting KOPR antagonists norBNI, JDTic, GNTI and DIPPA in rat or mouse tests of anxiety, including the EPM, NIH, defensive burying, open field and fear-potentiated startle tests (see [4;5] for reviews).…”

Section: Discussionsupporting

confidence: 85%

“…or s.c.) were carried out in a volume of 0.1 ml per 10 g of body weight. Doses used for zyklophin and norBNI were chosen following previous publications [5;8], and that for LY2444296 selected based on its dose responses in forced swim tests (our unpublished data).…”

Section: Methodsmentioning

confidence: 99%

“…KOPR agonists produce depression and dysphoria in humans [2] and conditioned place aversion in animals [3]. Several groups have demonstrated that KOPR antagonists norbinaltorphimine (norBNI), 5′-guanidinonaltrindole (5′-GNTI) and the JDTic reduced anxiety-/fear-like behaviors in rat and mouse tests, including the novelty-induced hypophagia (NIH), elevated plus maze (EPM), defensive burying, open field, and fear-potentiated startle tests [see [4;5] for reviews].…”

Section: Introductionmentioning

confidence: 99%

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Two short-acting kappa opioid receptor antagonists (zyklophin and LY2444296) exhibited different behavioral effects from the long-acting antagonist norbinaltorphimine in mouse anxiety tests

Huang

Yakovleva

Aldrich

et al. 2016

Neuroscience Letters

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Prototypical long-acting kappa opioid receptor (KOPR) antagonists [e.g., norbinaltorphimine (norBNI)] have been reported to exert anxiolytic-like effects in several commonly used anxiety tests in rodents including the novelty-induced hypophagia (NIH) and elevated plus maze (EPM) tests. It remains unknown if the short-acting KOPR antagonists (e.g., zyklophin and LY2444296) have similar effects. In this study effects of zyklophin and LY2444296 (s.c.) were investigated in the NIH and EPM tests in mice 1 h post-injection and compared with norBNI (i.p.) 48 h post-administration. In the NIH test, zyklophin at 3 and 1 mg/kg, but not 0.3 mg/kg, or LY2444296 at 30 mg/kg decreased the latency of palatable food consumption in novel cages, but had no effect in training cages, similar to norBNI (10 mg/kg). Zyklophin at 3 or 1 mg/kg increased or had a trend of increasing the amount of palatable food consumption in novel cages, with no effects in training cages, further indicating its anxiolytic-like effect, but norBNI (10mg/kg) and LY2444296 (30 mg/kg) did not. In the EPM test, norBNI (10 mg/kg) increased open arm time and % open arm entries or time, but zyklophin at all three doses and LY2444296 (30 mg/kg) had no effects. In addition, zyklophin at 3 mg/kg increased numbers of close and total arm entries on EPM, suggesting increased activity; however, norBNI and LY2444296 had no effects on close and total arm entries. Thus, all three KOPR antagonists had anxiolytic-like effects in the NIH test. However, only the long-acting one (norBNI), but not the short-acting ones (zyklophin and LY2444296), demonstrated anti-anxiety like effects in the EPM test. It remains to be investigated if the differences are due to the differences in their durations of action and/or pharmacodynamic properties.

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Section: Discussionsupporting

confidence: 85%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Two short-acting kappa opioid receptor antagonists (zyklophin and LY2444296) exhibited different behavioral effects from the long-acting antagonist norbinaltorphimine in mouse anxiety tests

Huang

Yakovleva

Aldrich

et al. 2016

Neuroscience Letters

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“…κOR activation leads to antinociception without the side effects associated with μOR activation such as physical dependence, respiratory depression, or inhibition of gastrointestinal transit (4,5). In addition, κOR agonists have antipruritic effects and can block the effects of psychostimulants (6)(7)(8). Thus, κOR agonists could be potential therapeutics to treat addiction, visceral pain, pruritus, or pain killers with low abuse potential (9)(10)(11)(12).…”

mentioning

confidence: 99%

“…Thus, κOR agonists could be potential therapeutics to treat addiction, visceral pain, pruritus, or pain killers with low abuse potential (9)(10)(11)(12). However, in vivo κOR activation is associated with side effects like anxiety, stress, diuresis, dysphoria/aversion, and psychomimetic effects (6)(7)(8). Also, activation of the κOR system has been implicated in relapse to drugs of abuse; this limits the use of κOR agonists in the treatment of drug addiction (13,14).…”

mentioning

confidence: 99%

Collybolide is a novel biased agonist of κ-opioid receptors with potent antipruritic activity

Gupta

Gomes

Bobeck

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Among the opioid receptors, the κ-opioid receptor (κOR) has been gaining considerable attention as a potential therapeutic target for the treatment of complex CNS disorders including depression, visceral pain, and cocaine addiction. With an interest in discovering novel ligands targeting κOR, we searched natural products for unusual scaffolds and identified collybolide (Colly), a nonnitrogenous sesquiterpene from the mushroom Collybia maculata. This compound has a furyl-δ-lactone core similar to that of Salvinorin A (Sal A), another natural product from the plant Salvia divinorum. Characterization of the molecular pharmacological properties reveals that Colly, like Sal A, is a highly potent and selective κOR agonist. However, the two compounds differ in certain signaling and behavioral properties. Colly exhibits 10-to 50-fold higher potency in activating the mitogen-activated protein kinase pathway compared with Sal A. Taken with the fact that the two compounds are equipotent for inhibiting adenylyl cyclase activity, these results suggest that Colly behaves as a biased agonist of κOR. Behavioral studies also support the biased agonistic activity of Colly in that it exhibits ∼10-fold higher potency in blocking non-histamine-mediated itch compared with Sal A, and this difference is not seen in pain attenuation by these two compounds. These results represent a rare example of functional selectivity by two natural products that act on the same receptor. The biased agonistic activity, along with an easily modifiable structure compared with Sal A, makes Colly an ideal candidate for the development of novel therapeutics targeting κOR with reduced side effects.G-protein-coupled receptors | natural compounds | salvinorin A | dynorphin | antinociception

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Prescription Opioid Use and Risk for Major Depressive Disorder and Anxiety and Stress-Related Disorders

2021

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IMPORTANCEGrowing evidence suggests that prescription opioid use affects depression and anxiety disorders; however, observational studies are subject to confounding, making causal inference and determining the direction of these associations difficult.OBJECTIVE To investigate the potential bidirectional associations between the genetic liability for prescription opioid and other nonopioid pain medications and both major depressive disorder (MDD) and anxiety and stress-related disorders (ASRD) using genetically based methods. DESIGN, SETTING, AND PARTICIPANTSWe performed 2-sample mendelian randomization (MR) using summary statistics from genome-wide association studies (GWAS) to assess potential associations of self-reported prescription opioid and nonopioid analgesics, including nonsteroidal anti-inflammatories (NSAIDs) and acetaminophen-like derivatives use with MDD and ASRD. The GWAS data were derived from participants of predominantly European ancestry included in observational cohorts. Data were analyzed February 20, 2020, to May 4, 2020.MAIN OUTCOMES AND MEASURES Major depressive disorder, ASRD, and self-reported pain medications (opioids, NSAIDs, anilides, and salicylic acid). RESULTSThe GWAS data were derived from participants of predominantly European ancestry included in the population-based UK Biobank and Lundbeck Foundation Initiative for Integrative Psychiatric Research studies: approximately 54% of the initial UK Biobank sample and 55.6% of the Lundbeck Foundation Initiative for Integrative Psychiatric Research sample selected for the ASRD GWAS were women. In a combined sample size of 737 473 study participants, single-variable MR showed that genetic liability for increased prescription opioid use was associated with increased risk of both MDD (odds ratio [OR] per unit increase in log odds opioid use, 1.14; 95% CI, 1.06-1.22; P < .001) and ASRD (OR, 1.24; 95% CI, 1.07-1.44; P = .004). Using multivariable MR, these opioid use estimates remained after accounting for other nonopioid pain medications (MDD OR, 1.14; 95% CI, 1.04-1.25; P = .005; ASRD OR, 1.30; 95% CI, 1.08-1.46; P = .006), and in separate models, accounting for comorbid pain conditions. Bidirectional analyses showed that genetic liability for MDD but not ASRD was associated with increased prescription opioid use risk (OR, 1.18; 95% CI, 1.08-1.30; P < .001). These estimates were generally consistent across single-variable and multivariable inverse variance-weighted (MV-IVW) and MR-Egger sensitivity analyses. Pleiotropy-robust methods did not indicate bias in any MV-IVW estimates. CONCLUSIONS AND RELEVANCEThe findings of this mendelian randomization analysis suggest evidence for potential causal associations between the genetic liability for increased prescription opioid use and the risk for MDD and ASRD. While replication studies are necessary, these findings may inform prevention and intervention strategies directed toward the opioid epidemic and depression.

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

Cited by 61 publications

References 94 publications

Two short-acting kappa opioid receptor antagonists (zyklophin and LY2444296) exhibited different behavioral effects from the long-acting antagonist norbinaltorphimine in mouse anxiety tests

Two short-acting kappa opioid receptor antagonists (zyklophin and LY2444296) exhibited different behavioral effects from the long-acting antagonist norbinaltorphimine in mouse anxiety tests

Collybolide is a novel biased agonist of κ-opioid receptors with potent antipruritic activity

Prescription Opioid Use and Risk for Major Depressive Disorder and Anxiety and Stress-Related Disorders

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