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Background: Kappa-opioid receptors (KOR) are hypothesized to be involved in mediating ongoing methamphetamine self-administration. Previous rat studies have demonstrated that treatment with the KOR antagonist nor-binaltorphimine (nor-BNI) decreases methamphetamine self-administration. However, KOR antagonist effects on methamphetamine self-administration in nonhuman primates are unknown., Methods: Operant behavior was maintained under a concurrent schedule of banana-flavored pellets (fixed-ratio 100 schedule) and intravenous methamphetamine injections (0-0.32mg/kg/injection, fixed-ratio 10 schedule) in male rhesus monkeys (n=3). Methamphetamine choice dose-effect functions were determined 7 days before and for up to 28 days following 10mg/kg, intramuscular nor-BNI treatment., Results: Under continuous saline treatment conditions, methamphetamine-maintained a dose-dependent increase in choice over the alternative food reinforcer. 10mg/kg nor-BNI failed to attenuate methamphetamine choice and trended towards increased methamphetamine choice. Methamphetamine choice returned to pre-nor-BNI treatment levels by 21 or 28 days in all 3 monkeys., Conclusions: The present results do not support the hypothesis that the KOR/dynorphin system robustly modulates methamphetamine self-administration and that KOR antagonists should be considered as methamphetamine use disorder pharmacotherapies. In contrast, these results suggest KOR antagonism may increase methamphetamine reinforcement through blockade of methamphetamine-induced dynorphin release and consequent feedback inhibition., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

It is widely recognized that developing bi- or multifunctional opioid compounds could offer a valuable approach to pain management with fewer side effects compared to single-target compounds. In this study, we designed and characterized two novel chimeric peptides, EM-1-DLS and EM-2-DLS, incorporating endomorphins (EMs) and the ghrelin receptor antagonist [D-Lys3]-GHRP-6 (DLS). Functional assays demonstrated that EM-1-DLS and EM-2-DLS acted as κ-opioid receptor (κ-OR)-preferring agonists, weak μ-opioid receptors (μ-OR) and ghrelin receptor (GHSR) agonists. Upon intracerebroventricular (i.c.v.) administration in mice, both EM-1-DLS and EM-2-DLS exhibited dose- and time-dependent antinociceptive effects in the tail withdrawal test. EM-1-DLS demonstrated the highest antinociceptive potency among the peptides, with an ED 50 approximately 8-fold greater than EM-1, while EM-2-DLS showed comparable effects to EM-2. The antinociceptive actions of EM-1-DLS involved activation of GHS-R1α, μ-OR, and κ-OR, whereas EM-2-DLS acted via GHS-R1α, δ-OR, and κ-OR pathways. Additionally, acute antinociceptive tolerance was investigated, revealing that EM-1-DLS induced a tolerance ratio of 2.33-fold, significantly lower than the 5.19-fold ratio induced by EM-1. Cross-tolerance ratios between the chimeric peptides and EMs ranged from 0.92 to 1.76, indicating reduced tolerance compared to EMs alone. These findings highlight the potential of these chimeric peptides to mitigate pain with diminished tolerance development, suggesting a promising strategy for the development of new analgesic therapies with improved safety profiles., Competing Interests: Declaration of competing interest The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2024 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Naltrexone (NTX), a homolog of the opiate antidote naloxone, is an orally active long-acting general opioid receptor antagonist used in the treatment of opiate dependence. NTX is also found to relieve craving for alcohol and is one of few FDA-approved medications for treatment of alcohol use disorder (AUD). While it was early on established that NTX acts by blocking the binding of endogenous opioid peptide ligands released by alcohol, experimental evidence emerged that could not be fully accounted for by this explanation alone, suggesting that NTX may have additional modes of action. Mu- and kappa-opioid receptors (MOP and KOP, respectively) are structurally related G-protein-coupled receptors (GPCRs), but they are anatomically differently distributed and functionally distinct, often mediating opposite responses, with MOP typically promoting euphoria and reward, while KOP is associated with dysphoria and aversive states. While the actions of NTX on MOP are extensively characterized, the interactions with KOP are not. Here, we used sensitive fluorescence-based methods with single-molecule sensitivity to study in live cells the influence of alcohol (ethanol, EtOH) on KOP and the interaction between KOP and NTX. Our data show that alcohol, at relevant concentrations (10-40 mM), alters KOP interactions with the lipid environment in the plasma membrane. The counteracting effects of NTX are exerted by both its canonical action on KOP and its hitherto unrevealed effects on the lateral dynamics and organization of lipids in the plasma membrane. The KOP-specific antagonist LY2444296, in clinical trial for major depressive disorder (MDD), blocks KOP but does not show the full action profile of NTX. The therapeutic effect of NTX treatment in AUD may in part be due to direct actions on KOP and in part due to its effect on the surrounding lipid environment., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: All experiments were done in the laboratory and did not involve humans or animals. The experiments did not involve tissues from humans or other vertebrates. All experiments were done in accordance with scientific standards., (© 2024. The Author(s).)

Anhedonia and avolition are emotions frequently endorsed by individuals with stress related disorders. Kappa opioid receptor (KOR) activation can induce negative emotions and recent clinical evidence suggests that KOR antagonism can alleviate anhedonia in a transdiagnostic cohort of patients. However, the behavioral consequences of KOR activation and antagonism in modulating motivation, as assessed by schedule-controlled behavioral performance without preexisting conditions (stress or substance use), have not been formally assessed. To address this gap in the literature, this report utilized male and female Sprague Dawley rats to (1) evaluate the impact of the selective KOR agonist U50,488, on the performance of animals responding for sucrose pellets under a progressive ratio (PR) schedule and (2) determine the effects of the short-acting KOR antagonist LY2444296 alone and on U50,488 mediated reductions in PR performance. Overall, U50,488 5 mg/kg significantly reduced the breakpoint and number of rewards obtained by animals. This occurred in the absence of motor impairment and independent of evidence for satiation. LY2444296 did not alter PR performance when administered alone but effectively blocked the deficits induced by U50,488. To further delineate the behavioral alterations that underlie these reductions in responding, a more detailed analysis was conducted on PR performance in the first 15 min of the session, the period of time when animals obtained the most reinforcers. During this period, U50,488 increased the length of the post-reinforcement pause and reduced the running rate on PR schedules. These changes in behavior produced by acute activation of KORs are consistent with a reduction of effort-related motivation in rodents. These data contribute to the understanding of how KORs modulate motivation, which is critical to future efforts to evaluate performance in the context of stress and assess how KOR antagonists alleviate anhedonic behaviors associated with stress., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The effective management of moderate to severe pain often relies on the use of analgesic agents. However, the widespread utility of these medications is hindered by the occurrence of several undesirable side effects. In light of this challenge, there is growing interest in the development of κ opioid receptor (KOR) agonists, which have shown promise in mitigating these adverse effects. In this study, leveraging the structural scaffold of compound D (our previous study), we embarked on the design, synthesis, and evaluation of a series of N'-benzyl-3-chloro-N- ((1S,3R,4R)-3-((dimethylamino)methyl)-4-hydroxy-4-(3-methoxyphenyl)cyclohexyl)benzenesulfonamide derivatives. These compounds were subjected to comprehensive in vitro and in vivo test. Through systematic structure-activity relationship (SAR) exploration, we successfully identified compound 23p (K i(KOR) :1.9 nM) as a highly selective KOR ligand of new chemotype. 23p showed high clearance in vitro PK test, and abdominal contraction test showed potent antinociceptive effect. 23p and its O-demethyl metabolite 25 were both found in the plasma of mouse, 25 also showed potent affinity toward KOR (K i (KOR): 3.1 nM), both they contribute to the analgesic effect. Moreover, 23p exhibited potent antinociceptive activity in abdominal constriction test, which was effectively abolished by pre-treatment of nor-BNI, a selective KOR antagonist., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Background: Approximately 30 % of persons with Major Depressive Disorder (MDD) inadequately respond to conventional antidepressants. Kappa opioid receptor (KOR) antagonists, aticaprant and navacaprant, are in development as treatments for MDD. Herein, we aim to comprehensively evaluate the safety, efficacy and pharmacology of aticaprant and navacaprant for MDD., Methods: We performed a systematic review of primary research investigating aticaprant and navacaprant on PubMed, OVID, and Scopus databases from inception to April 2024. Studies that reported on the pharmacological profile and/or safety and efficacy of aticaprant and navacaprant were included., Results: Navacaprant monotherapy and aticaprant adjunctive therapy are in development for MDD. Navacaprant exhibits 300-fold selectivity for the KOR compared to the mu-opioid receptor, while aticaprant exhibits 30-fold selectivity. At clinically-relevant doses, navacaprant and aticaprant occupy 87-95 % and 73-94 % of KORs, respectively. Clinical trials of the foregoing agents (navacaprant as monotherapy and actiprant as adjunctive therapy) reported significant improvement in depressive symptoms and may clinically benefit measures of anhedonia. Both agents appear well-tolerated, with most adverse events mild and no known safety concerns., Limitations: Aticaprant and navacaprant treatment for MDD are in early stages of clinical trials and results from Phase 3 pivotal trials are not yet available., Conclusions: Kappa opioid receptor antagonists may serve as mechanistically-novel treatments for MDD and persons who inadequately respond to index conventional antidepressants. Anhedonia is debilitating and insufficiently treated with conventional antidepressants. Future research vistas should establish the efficacy and safety of KORAs in phase 3 studies in both acute and maintenance paradigms., Competing Interests: Declaration of competing interest Dr. Roger S. McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China (NSFC) and the Milken Institute; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Neurawell, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, Abbvie and Atai Life Sciences. Dr. S. Roger McIntyre is a CEO of Braxia Scientific Corp. Dr. Joshua D. Rosenblat has received research grant support from the Canadian Institute of Health Research (CIHR), Physician Services, Inc. (PSI) Foundation, Labatt Brain Health Network, Brain and Cognition Discovery Foundation (BCDF), Canadian Cancer Society, Canadian Psychiatric Association, Academic Scholars Award, American Psychiatric Association, American Society of Psychopharmacology, University of Toronto, University Health Network Center for Mental Health, Joseph M. West Family Memorial Fund, and Timeposters Fellowship and industry funding for speaker/consultation/research fees from iGan, Boehringer Ingelheim, Janssen, Allergan, Lundbeck, Sunovion, Braxia Health, Braxia Scientific Corp., and COMPASS. Dr. Taeho Greg Rhee was supported in part by the National Institute on Aging (#R21AG070666; R21AG078972; R01AG088647), National Institute of Mental Health (#R01MH131528), and National Institute on Drug Abuse (#R21DA057540). Dr. Rhee serves as a review committee member for Patient-Centered Outcomes Research Institute (PCORI) and Substance Abuse and Mental Health Services Administration (SAMHSA) and has received honoraria payments from PCORI and SAMHSA. Dr. Rhee has also served as a stakeholder/consultant for PCORI and received consulting fees from PCORI. Dr. Rhee serves as an advisory committee member for International Alliance of Mental Health Research Funders (IAMHRF). Dr Roger Ho has received National University of Singapore iHeathtech Other Operating Expenses (A-0001415-09-00). Kayla M. Teopiz has received fees from Braxia Scientific Corp. Sabrina Wong, Gia Han Le, Shreya Vasudeva, Lee Phan, Shakila Meshkat, Angela T.H. Kwan, Hayun Choi, Bing Cao have no conflicts of interest to report., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Kappa opioid receptors (KORs) are implicated in the pathophysiology of various psychiatric and neurological disorders creating interest in targeting the KOR system for therapeutic purposes. Accordingly, navacaprant (NMRA-140) is a potent, selective KOR antagonist being evaluated as a treatment for major depressive disorder. In the present report, we have extended the pharmacological characterization of navacaprant by further demonstrating its selective KOR antagonist properties and confirming its lack of agonist activity at KORs and related targets involved in opioid-related abuse. Using CHO-K1 cells expressing human KOR, mu (MOR), or delta (DOR) opioid receptors, navacaprant demonstrated selective antagonist properties at KOR (IC 50  = 0.029 μM) versus MOR (IC 50  = 3.3 μM) and DOR (IC 50  > 10 μM) in vitro. In vivo, navacaprant (10-30 mg/kg, i.p.) dose-dependently abolished KOR-agonist induced analgesia in the mouse tail-flick assay. Additionally, navacaprant (10, 30 mg/kg, p.o.) significantly reduced KOR agonist-stimulated prolactin release in mice and rats, confirming KOR antagonism in vivo. Navacaprant showed no agonist activity at any opioid receptor subtype (EC 50  > 10 μM) in vitro and exhibited no analgesic effect in the tail-flick assays at doses ≤100 mg/kg, p.o. thereby confirming a lack of opioid receptor agonist activity in vivo. Importantly, navacaprant did not alter extracellular dopamine concentrations in the nucleus accumbens shell of freely-moving rats following doses ≤100 mg/kg, p.o., whereas morphine (10, 20 mg/kg, i.p.) significantly increased dopamine levels. These results demonstrate that navacaprant is a KOR-selective antagonist with no pharmacological properties implicated in opioid-related abuse., Competing Interests: Declaration of competing interest Filomene G. Morrison, Lori Jean Van Orden, Karla Zeitz, and Tanya L. Wallace are employees of Neumora Therapeutics, Inc. (which acquired BlackThorn Therapeutics, Inc.) and have ownership interest (stock, stock options, royalty, receipt of intellectual property rights/patent holder, excluding diversified mutual funds) in Neumora Therapeutics, Inc. Sharon L. Smith and David J. Heal are shareholders and employees of DevelRx Ltd which is a consultancy company that advises the pharmaceutical industry on the discovery and development of central nervous system drugs. Eloise J. Kuijer has no declaration of competing interests. The opinions expressed in this manuscript are exclusively those of the authors and have not been influenced by any public, commercial, or not-for-profit organization., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Alcohol use disorder (AUD) is a chronic relapsing disease that is deleterious at individual, familial, and societal levels. Although AUD is one of the highest preventable causes of death in the USA, therapies for the treatment of AUD are not sufficient given the heterogeneity of the disorder and the limited number of approved medications. To provide better pharmacological strategies, it is important to understand the neurological underpinnings of AUD. Evidence implicates the endogenous dynorphin (DYN)/κ-opioid receptor (KOR) system recruitment in dysphoric and negative emotional states in AUD to promote maladaptive behavioral regulation. The nucleus accumbens shell (AcbSh), mediating motivational and emotional processes that is a component of the mesolimbic dopamine system and the extended amygdala, is an important site related to alcohol's reinforcing actions (both positive and negative) and neuroadaptations in the AcbSh DYN/KOR system have been documented to induce maladaptive symptoms in AUD. We have previously shown that in other nodes of the extended amygdala, site-specific KOR antagonism can distinguish different symptoms of alcohol dependence and withdrawal. In the current study, we examined the role of the KOR signaling in the AcbSh of male Wistar rats in operant alcohol self-administration, measures of negative affective-like behavior, and physiological symptoms during acute alcohol withdrawal in alcohol-dependence. To induce alcohol dependence, rats were exposed to chronic intermittent ethanol vapor for 14 h/day for three months, during which stable escalation of alcohol self-administration was achieved and pharmacological AcbSh KOR antagonism ensued. The results showed that AcbSh KOR antagonism significantly reduced escalated alcohol intake and negative affective-like states but did not alter somatic symptoms of withdrawal. Understanding the relative contribution of these different drivers is important to understand and inform therapeutic efficacy approaches in alcohol dependence and further emphasis the importance of the KOR/DYN system as a target for AUD therapeutics., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Major depression is a common, disabling mental health condition associated with the highest disease burden for any neuropsychiatric disorder worldwide, according to the WHO. Due to the imperfect efficacy and tolerability profiles of existing treatments, investigational compounds in novel treatment classes are needed. Opioid-receptor antagonists are a potential new class of treatments currently under investigation., Areas Covered: Major depressive disorder is first overviewed. Existing treatments, both their mechanisms of action and their place within the antidepressant space, are discussed herein. Then, the profile of Aticaprant and the wider context of kappa-opioid antagonism for depression are discussed in focus., Expert Opinion: Early evidence indicates that Aticaprant may possess desirable pharmacodynamic and pharmacokinetic properties. A lack of convincing efficacy data at the time of writing precludes any definitive statement on its potential as an antidepressant.

This was a double-blind, randomized, phase 2 study of adults (18-64 years) with DSM-5 diagnosis of major depressive disorder (MDD), with moderate-to-severe episode severity (Montgomery-Åsberg Depression Rating Scale [MADRS] ≥25) despite an adequate course with ongoing antidepressant for ≥6 weeks to ≤12 months. Following a double-blind placebo lead-in period (up to 3 weeks), participants were randomized to receive once daily aticaprant 10 mg or continue placebo, added to their ongoing treatment, for 6 weeks. Of 184 participants enrolled, 169 were included in safety analyses (aticaprant n = 85, placebo n = 84) and 166 in full intent-to-treat (fITT) efficacy analyses; 121 placebo lead-in non-responders (<30% reduction in MADRS total score) in fITT were included in enriched ITT (eITT) analyses. Improvement (least squares mean difference [upper limit 1-sided 80% CI] versus placebo) in MADRS total score at week 6 for aticaprant was significant versus placebo (eITT: -2.1 [-1.09], 1-sided p = 0.044; effect size (ES) 0.23; fITT -3.1 [2.21], 1-sided p = 0.002; ES 0.36). The between-group difference was larger among participants with Snaith-Hamilton Pleasure Scale (SHAPS) score greater/equal to versus less than baseline median SHAPS. The most common treatment-emergent adverse events reported for aticaprant (versus placebo) were headache (11.8% versus 7.1%), diarrhea (8.2% versus 2.4%), nasopharyngitis (5.9% versus 2.4%), and pruritus (5.9% versus 0%). One participant (1.2%) in each arm discontinued treatment due to an adverse event. In this study of participants with MDD and inadequate response to SSRI/SNRI, adjunctive treatment with aticaprant significantly reduced depressive symptoms versus placebo, without resulting in significant safety signals, supporting further investigation in larger trials., (© 2024. The Author(s).)

Kappa opioid receptor (KOR) antagonists have potential therapeutic applications in the treatment of stress-induced relapse to substance abuse and mood disorders. The dynorphin A analog arodyn (Ac[Phe 1,2,3 ,Arg 4 ,D-Ala 8 ]dynorphin A-(1-11)-NH 2 ) exhibits potent and selective kappa opioid receptor antagonism. Multiple cyclizations in longer peptides, such as dynorphin and its analogs, can extend the conformational constraint to additional regions of the peptide beyond what is typically constrained by a single cyclization. Here, we report the design, synthesis, and pharmacological evaluation of a bicyclic arodyn analog with two constraints in the opioid peptide sequence. The peptide, designed based on structure-activity relationships of monocyclic arodyn analogs, was synthesized by solid-phase peptide synthesis and cyclized by sequential ring-closing metathesis (RCM) in the C- and N-terminal sequences. Molecular modeling studies suggest similar interactions of key aromatic and basic residues in the bicyclic peptide with KOR as found in the cryoEM structure of KOR-bound dynorphin, despite substantial differences in the backbone conformations of the two peptides. The bicyclic peptide's affinities at KOR and mu opioid receptors (MOR) were determined in radioligand binding assays, and its KOR antagonism was determined in the [ 35 S]GTPγS assay in KOR-expressing cells. The bicyclic analog retains KOR affinity and selectivity (K i = 26 nM, 97-fold selectivity over MOR) similar to arodyn and exhibits potent KOR antagonism in the dynorphin-stimulated [ 35 S]GTPγS assay. This bicyclic peptide represents a promising advance in preparing cyclic opioid peptide ligands and opens avenues for the rational design of additional bicyclic opioid peptide analogs.

Immediately following spinal cord injury (SCI) patients experience pain associated with injury to the spinal cord and nerves as well as with accompanying peripheral injuries. This pain is usually treated with opioids, and most commonly with morphine. However, in a rodent model we have shown that, irrespective of the route of administration, morphine administered in the acute phase of SCI undermines long-term locomotor recovery. Our previous data suggest that activation of kappa opioid receptors (KORs) mediates these negative effects. Blocking KORs with norbinaltorphimine (norBNI), prior to a single dose of epidural morphine, prevented the morphine-induced attenuation of locomotor recovery. Because numerous cellular changes occur with chronic opioid administration compared with a single dose, the current study tested whether norBNI was also effective in a more clinically relevant paradigm of repeated, intravenous morphine administration after SCI. We hypothesized that blocking KOR activation during repeated, intravenous morphine administration would also protect recovery. Supporting this hypothesis, we found that blocking KOR activation in young, male rats prevented the negative effects of morphine on locomotor recovery, although neither norBNI nor morphine had an effect on long-term pain at the doses used. We also found that norBNI treatment blocked the adverse effects of morphine on lesion size. These data suggest that a KOR antagonist given in conjunction with morphine may provide a clinical strategy for effective analgesia without compromising locomotor recovery after SCI.

Ingestion of alkaloid metabolites from the bark of Galbulimima (GB) sp. leads to psychotropic and excitatory effects in humans 1-4 . Limited, variable supply of GB alkaloids 5 , however, has impeded their biological exploration and clinical development 6 . Here we report a solution to the supply of GB18, a structural outlier and putative psychotropic principle of Galbulimima bark. Efficient access to its challenging tetrahedral attached-ring motif required the development of a ligand-controlled endo-selective cross-electrophile coupling and a diastereoselective hydrogenation of a rotationally dynamic pyridine. Reliable, gram-scale access to GB18 enabled its assignment as a potent antagonist of κ- and μ-opioid receptors-the first new targets in 35 years-and lays the foundation to navigate and understand the biological activity of Galbulimima metabolites., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Major depression disorder is a severe and recurrent neuropsychological disorder characterized by lowered mood and social activity and cognitive impairment. Owing to unclear molecular mechanisms of depression, limited interventions are available in clinic. In this study we investigated the role of dynorphin/κ opioid receptor system in the development of depression. Mice were subjected to chronic social defeat stress for 14 days. Chronic social defeat stress induced significant social avoidance in mice characterized by decreased time duration in the interaction zone and increased time duration in the corner zone. Pre-administration of a κ opioid receptor antagonist norBNI (10 mg/kg, i.p.) could prevent the development of social avoidance induced by chronic social defeat stress. Social avoidance was not observed in κ opioid receptor knockout mice subjected to chronic social defeat stress. We further revealed that social defeat stress activated c-fos and ERK signaling in the amygdala without affecting the NAc, hippocampus and hypothalamus, and ERK activation was blocked by systemic injection of norBNI. Finally, the expression of dynorphin A, the endogenous ligand of κ opioid receptor, was significantly increased in the amygdala following social defeat stress; microinjection of norBNI into the amygdala prevented the development of depressive-like behaviors caused by social defeat stress. The present study demonstrates that upregulated dynorphin/κ opioid receptor system in the amygdala leads to the emergence of depression following chronic social defeat stress, and sheds light on κ opioid receptor antagonists as potential therapeutic agents for the prevention and treatment of depression following chronic stress., (© 2021. The Author(s), under exclusive licence to CPS and SIMM.)

It has been shown that kappa opioid receptor (KOR) antagonists, such as nor-binaltorphimine (nor-BNI), have antinociceptive effects in some pain models that affect the trigeminal system. Also, its anxiolytic-like effect has been extensively demonstrated in the literature. The present study aimed to investigate the systemic, local, and central effect of nor-BNI on trigeminal neuropathic pain using the infraorbital nerve constriction model (CCI-ION), as well as to evaluate its effect on anxiety-like behavior associated with this model. Animals received nor-BNI systemically; in the trigeminal ganglion (TG); in the subarachnoid space to target the spinal trigeminal nucleus caudalis (Sp5C) or in the central amygdala (CeA) 14 days after CCI-ION surgery. Systemic administration of nor-BNI caused a significant reduction of facial mechanical hyperalgesia and promoted an anxiolytic-like effect, which was detected in the elevated plus-maze and the light-dark transition tests. When administered in the TG or CeA, the KOR antagonist was able to reduce facial mechanical hyperalgesia induced by CCI-ION, but without changing the anxiety-like behavior. Moreover, no change was observed on nociception and anxiety-like behavior after nor-BNI injection into the Sp5C. The present study demonstrated antinociceptive and anxiolytic-like effects of nor-BNI in a model of trigeminal neuropathic pain. The antinociceptive effect seems to be dissociated from the anxiolytic-like effect, at both the sites involved and at the dose need to achieve the effect. In conclusion, the kappa opioid system may represent a promising target to be explored for the control of trigeminal pain and associated anxiety. However, further studies are necessary to better elucidate its functioning and modulatory role in chronic trigeminal pain states., (Copyright © 2021. Published by Elsevier B.V.)

Brain kappa-opioid receptors (KORs) are implicated in the pathophysiology of depressive and anxiety disorders, stimulating interest in the therapeutic potential of KOR antagonists. Research on KOR function has tended to focus on KOR-expressing neurons and pathways such as the mesocorticolimbic dopamine system. However, KORs are also expressed on non-neuronal cells including microglia, the resident immune cells in the brain. The effects of KOR antagonists on microglia are not understood despite the potential contributions of these cells to overall responsiveness to this class of drugs. Previous work in vitro suggests that KOR activation suppresses proinflammatory signaling mediated by immune cells including microglia. Here, we examined how KOR antagonism affects microglia function in vivo, together with its effects on physiological and behavioral responses to an immune challenge. Pretreatment with the prototypical KOR antagonist JDTic potentiates levels of proinflammatory cytokines (IL-1β, IL-6) in blood following administration of lipopolysaccharide (LPS), an immune-activating agent, without triggering effects on its own. Using magnetic-activated cell sorting (MACs), we found that KOR antagonism potentiates LPS-induced cytokine expression within microglia. This effect is accompanied by potentiation of LPS-induced hyperthermia, although reductions in body weight and locomotion were not affected. Histological analyses confirm that LPS produces visible changes in microglia morphology consistent with activation, but this effect is not altered by KOR antagonism. Considering that inflammation is increasingly implicated in depressive and anxiety disorders, these findings raise the possibility that KOR antagonist actions on microglia may detract from actions on neurons that contribute to their therapeutic potential., (Copyright © 2021 Elsevier Inc. All rights reserved.)

A new series of enkephalin-like tetrapeptide analogs modified at the C-terminus by an N-(3,4-dichlorophenyl)-N-(piperidin-4-yl)propionamide (DPP) moiety were designed, synthesized, and tested for their binding affinities at opioid receptors and monoamine transporters to evaluate their potential multifunctional activity for the treatment of chronic pain. Most ligands exhibited high binding affinities in the nanomolar range at the opioid receptors with a slight delta-opioid receptor (DOR) selectivity over mu-opioid receptor (MOR) and kappa-opioid receptor (KOR) and low binding affinities in the micromolar range at the monoamine transporters, SERT and NET. Ligands of which the positions 1 and 4 were substituted by Dmt and Phe(4-X) residues, respectively, showed the excellent binding affinities at three opioid receptors. Among them, Dmt-d-Tic-Gly-Phe(4-F)-DPP was the most promising considering its excellent opioid affinities, particularly unexpected high binding affinity (Ki = 0.13 nM) at the KOR, and moderate interactions with serotonin/norepinephrine reuptake inhibitors (SNRIs). Docking studies revealed that the ligand was a good fit for the KOR binding pocket (binding score = 8,750)., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Aims: Dezocine and pentazocine, widely prescribed in China for postoperative pain, were initially considered as mixed agonist/antagonist targeting μ-opioid receptors (MORs) and κ-opioid receptors (KORs). However, dezocine has been revealed to alleviate chronic neuropathic pain through MOR activation and norepinephrine reuptake inhibition (NRI). This study investigated dezocine- and pentazocine-induced antinociception and physical dependence development, compared to the typical MOR-NRI opioid tapentadol., Main Methods: Calcium mobilization assay was conducted to assess the potency of the drugs while hot-plate test was performed to compare the antinociception. Physical dependence development was compared with morphine., Key Findings: Treatment with dezocine, pentazocine and tapentadol stimulated calcium mobilization in HEK293 cells stably expressed MORs but not KORs, whereas dezocine and pentazocine inhibited KOR activities. Subcutaneously injected dezocine-, tapentadol- and pentazocine-induced antinociception dose-dependently, in hot-plate test. Intrathecally injected MOR antagonist CTAP, norepinephrine depletor 6-OHDA and α 2 -adrenoceptor (α 2 -AR) antagonist yohimbine partially antagonized dezocine, pentazocine and tapentadol antinociception. Whereas specific KOR antagonist GNTI did not alter their antinociception, the putative inverse KOR agonist nor-BNI reduced dezocine and pentazocine antinociception. Moreover, combined CTAP and 6-OHDA or yohimbine blocked dezocine and tapentadol antinociception but displayed the same partial inhibition on pentazocine antinociception as CTAP alone. Furthermore, compared to morphine and pentazocine, long-term treatment with dezocine and tapentadol produced much less physical dependence-related withdrawal signs, which were restored by spinal 6-OHDA or yohimbine treatment., Significance: Our findings illustrated that dezocine and tapentadol, but not pentazocine, exert remarkable antinociception in nociceptive pain with less abuse liability via dual mechanisms of MOR activation and NRI., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Antipruritic effects of kappa opioid receptor (KOR) agonists have been shown in rodent models of acute and chronic scratching (itchlike behavior). Three KOR agonists, nalfurafine, difelikefalin, and nalbuphine, are in clinical studies for antipruritic effects in chronic itch of systemic and skin diseases. Nalfurafine (in Japan) and difelikefalin (in the USA) were approved to be used in the treatment of chronic itch in hemodialysis patients. The FDA-approved nalbuphine has been used in clinic for over 40 years, and it is the only narcotic agonist that is not scheduled. We aimed to study (a) antiscratch activity of nalbuphine against TAT-HIV-1 protein (controls HIV transcription)-, deoxycholic acid (DCA, bile acid)-, and chloroquine (CQ)-induced scratching in a mouse model of acute itch; and (b) whether the effect of nalbuphine is produced via KORs. First, dose-responses were developed for pruritogens. Mice were pretreated with nalbuphine (0.3-10 mg/kg) and then a submaximal dose of pruritogens were administered and the number of scratching bouts was counted. To study if the antiscratch effect of nalbuphine is produced via KOR, we used KOR knock out mice and pharmacologic inhibition of KORs using nor-binaltorphimine, a KOR antagonist. For this aim, we used CQ as a pruritogen. We found that: (a) TAT-HIV-1 protein elicits scratching in a dose-dependent manner; (b) nalbuphine inhibits scratching induced by TAT-HIV-1, DCA, and CQ dose-dependently; and (c) nalbuphine inhibits scratching induced by CQ through KORs. In conclusion, nalbuphine inhibits scratching elicited by multiple pruritogens.

Objectives: We aimed to observe the protective effect of κ opioid receptor ( κ -OR) agonist on myocardial injury in heart failure (HF) rats and its effect on Ca 2+ -SERCA2a and to explore the regulatory mechanism with the Nrf2/HO-1 signaling pathway., Methods: 50 Sprague-Dawley rats were randomly divided into the following groups: the sham operation group (sham group), HF model group (HF group), HF+ κ -OR agonist U50488 group (HU group), HF+U50488H+novel calmodulin-dependent protein kinase II (CaMKII) agonist (oleic acid) (HUO group), and HF+U50488H+Nrf2 inhibitor (HUM group). The HF rat's model was established through surgical ligation of the left anterior descending coronary artery and the exhausting swimming exercise. After that, rat's cardiac function was monitored by echocardiography. HE and MASSON staining was used to detect the myocardial injury, and TUNEL staining was used to detect the myocardial apoptosis. ELISA was performed to detect the biomarkers of oxidative stress. Moreover, the distribution of reactive oxygen species (ROS) and Nrf2 was detected under immunofluorescence. The expression of sarco/endoplasmic reticulum calcium (Ca 2+ ) ATPase (SERCA) 2a, calmodulin, endoplasmic reticulum stress- (ERS-) related proteins, and Nrf2/HO-1 signaling pathway-related proteins were detected by Western Blotting., Results: κ -OR agonist U50488H can significantly enhance rat's cardiac function, reduce the injury and apoptosis of myocardial cells, and alleviate endoplasmic reticulum stress injury in HF rats via upregulating the SERCA2a expression and inhibiting the Ca 2+ influx. Furthermore, U50488H could also inhibit the phosphorylation of CaMKII and cAMP-response element binding protein (CREB). Additionally, administration of CaMKII-specific agonist could partially block the therapeutic effect of κ -OR agonist on the myocardium of HF rats. Interestingly, the antagonist of Nrf2 could also significantly reverse the therapeutic effect of κ -OR agonist. Therefore, these results suggested that the effect of U50488H on HF rats is dependent on regulating CaMKII phosphorylation and activating the Nrf2/HO-1 pathway., Conclusion: κ -OR agonists U50488H can improve ERS in cardiomyocytes and relieve myocardial injury in HF rats through activating the Nrf2/HO-1 pathway and regulating Ca 2+ -SERCA2a to inhibit Ca 2+ influx., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2021 Tengfei Wu et al.)

Peptide therapeutics offer numerous advantages in the treatment of diseases and disorders of the central nervous system (CNS). However, they are not without limitations, especially in terms of their pharmacokinetics where their metabolic lability and low blood-brain barrier penetration hinder their application. Targeted nanoparticle delivery systems are being tapped for their ability to improve the delivery of therapeutics into the brain non-invasively. We have developed a family of mannosylated glycoliposome delivery systems for targeted drug delivery applications. Herein, we demonstrate via in vivo distribution studies the potential of these glycoliposomes to improve the utility of CNS active therapeutics using dynantin, a potent and selective dynorphin peptide analogue antagonist of the kappa opioid receptor (KOR). Glycoliposomal entrapment protected dynantin against known rapid metabolic degradation and ultimately improved brain levels of the peptide by approximately 3-3.5-fold. Moreover, we linked this improved brain delivery with improved KOR antagonist activity by way of an approximately 30-40% positive modulation of striatal dopamine levels 20 min after intranasal administration. Overall, the results clearly highlight the potential of our glycoliposomes as a targeted delivery system for therapeutic agents of the CNS.

The rising opioid crisis has become a worldwide societal and public health burden, resulting from the abuse of prescription opioids. Targeting the κ-opioid receptor (KOR) in the periphery has emerged as a powerful approach to develop novel pain medications without central side effects. Inspired by the traditional use of sunflower ( Helianthus annuus ) preparations for analgesic purposes, we developed novel stabilized KOR ligands (termed as helianorphins) by incorporating different dynorphin A sequence fragments into a cyclic sunflower peptide scaffold. As a result, helianorphin-19 selectively bound to and fully activated the KOR with nanomolar potency. Importantly, helianorphin-19 exhibited strong KOR-specific peripheral analgesic activity in a mouse model of chronic visceral pain, without inducing unwanted central effects on motor coordination/sedation. Our study provides a proof of principle that cyclic peptides from plants may be used as templates to develop potent and stable peptide analgesics applicable via enteric administration by targeting the peripheral KOR for the treatment of chronic abdominal pain.

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is characterized by diffuse inflammation of the lung parenchyma and refractory hypoxemia. Butorphanol is commonly used clinically for perioperative pain relief, but whether butorphanol can regulate LPS-induced alveolar macrophage polarization is unclear. In this study, we observed that butorphanol markedly attenuated sepsis-induced lung tissue injury and mortality in mice. Moreover, butorphanol also decreased the expression of M1 phenotype markers (TNF-α, IL-6, IL-1β and iNOS) and enhanced the expression of M2 marker (CD206) in alveolar macrophages in the bronchoalveolar lavage fluid (BALF) of LPS-stimulated mice. Butorphanol administration reduced LPS-induced numbers of proinflammatory (M1) macrophages and increased numbers of anti-inflammatory (M2) macrophages in the lungs of mice. Furthermore, we found that butorphanol-mediated suppression of the LPS-induced increases in M1 phenotype marker expression (TNF-α, IL-6, IL-1β and iNOS) in bone marrow-derived macrophages (BMDMs), and this effect was reversed by κ-opioid receptor (KOR) antagonists. Moreover, butorphanol inhibited the interaction of TLR4 with MyD88 and further suppressed NF-κB and MAPKs activation. In addition, butorphanol prevented the Toll/IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF)-mediated IFN signaling pathway. These effects were ameliorated by KOR antagonists. Thus, butorphanol may promote macrophage polarization from a proinflammatory to an anti-inflammatory phenotype secondary to the inhibition of NF-κB, MAPKs, and the TRIF-mediated IFN signaling pathway through κ receptors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Luan, Pan, Bu, Wu, Wang and Xu.)

Opioids, which are widely used for the treatment of chronic pain, have an analgesic effect by mainly activating mu-opioid receptor (MOR). Paradoxically, a high dose of naloxone, non-selective opioid receptor antagonist, is also known to induce analgesia, but the underlying mechanism remains unclear. Since kappa-opioid receptor (KOR) and dynorphin (KOR ligand) have been implicated in the naloxone-induced analgesia, we aimed to elucidate its mechanism by focusing on the kappa-opioid system in the brain under inflammatory pain condition. Systemic administration of naloxone (10 mg/kg, i.p.) decreased spontaneous pain behaviors only in complete Freund's adjuvant (CFA)-induced chronic inflammatory pain model but not in the formalin-induced acute pain model. Immunohistochemistry analysis in the CFA model revealed both a significant decrease in MOR expression and an increase in prodynorphin density in the central nucleus of theamygdala (CeA) and nucleus accumbens (NAc) but not in other brain areas. Systemic administration of KOR antagonist (norbinaltorphimine, nor-BNI 10 mg/kg) also decreased spontaneous pain behaviors in the CFA model. Furthermore, microinjection of both naloxone and nor-BNI into NAc and CeA significantly reduced spontaneous chronic pain behavior. Taken together, our results suggest that naloxone-induced analgesia may be mediated by blocking facilitated kappa-opioid systems in the NAc and CeA., (Copyright © 2021. Published by Elsevier B.V.)

The mu opioid receptor antagonist/kappa opioid receptor (KOR) partial agonist nalmefene (NMF), a close structural analog of naltrexone (NTX), has been shown to reduce cocaine reward in preclinical models. Given the greater KOR potency and improved bioavailability compared to NTX, NMF may be a promising pharmacotherapeutic for cocaine use disorder (CUD). Here we examine the effects of NMF pretreatment on chronic daily extended access (4h) cocaine intravenous self-administration (IVSA) in adult male C57Bl/6J mice., Methods: separate groups of mice had daily 4h cocaine IVSA sessions (0.25 or 0.5 mg/kg/inf, FR1) for 14 days. Starting on day 8, mice were pretreated with NMF (0, 1, or 10 mg/kg) 30m before each session. A separate group of mice acquired cocaine IVSA [seven days FR1 then four FR3 of 4h daily sessions (0.5 mg/kg/inf)] prior to a single progressive ratio 3 session to examine the effect of 1 mg/kg NMF on cocaine motivation., Results: No significant effect of NMF pretreatment on cocaine intake was observed. Acute pretreatment of 1 mg/kg NMF significantly potentiated cocaine motivation as measured by progressive ratio breakpoint., Conclusions: NMF did not significantly attenuate cocaine intake and increased motivation for cocaine suggesting that NMF may not be suitable for non-abstinent CUD patients. Further research is needed with KOR selective partial or full agonists to determine their effect on cocaine reinforcement., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Novel short-acting κ(kappa)-opioid receptor selective antagonists are translational tools to examine the impact of the κ-receptor/dynorphin system in assays related to central nervous system dysfunction (e.g., substance use disorders, anhedonia and depression). The effects of such compounds have been compared in males and females under very limited conditions., Aims: The goal of this study was to examine potential sex differences in the effects of a κ-agonist and a short-acting κ-antagonist in an ethologically relevant test of anhedonia, the "splash test" of self-grooming, and also in the forced swim test and in locomotor activity., Methods: We examined the dose-dependence of grooming deficits caused by the κ-agonist U50,488 (0.1-3.2 mg/kg intraperitoneal (i.p.)) in gonadally intact adult male and female C57BL/6J mice. We then compared the effects of the short-acting κ-antagonist LY2795050 ((3-chloro-4-(4-(((2S)-2-pyridin-3-ylpyrrolidin-1-yl)methyl) phenoxy)benzamide)); 0.032-0.1 mg/kg i.p.) in blocking grooming deficits caused by U50,488 (3.2 mg/kg). The effects of LY2795050 were also studied in the forced swim test (FST). The effects of LY2795050 in blocking the locomotor depressant effects of U50,488 (10 mg/kg) were also studied., Results: U50,488 produced dose-dependent grooming deficits in male and female mice, and LY2795050 prevented these effects. In contrast, LY2795050 decreased immobility in the FST in males at a dose of 0.1 mg/kg, but not in females, up to a dose of 0.32 mg/kg. Also, LY2795050 (0.32 mg/kg) prevented and also reversed the locomotor-depressant effects of U50,488 (10 mg/kg), in males and females., Conclusions: This study further implicates the κ-receptor system in ethologically relevant aspects of anhedonia, and confirms sexual dimorphism in some behavioral effects of novel κ-antagonists.

Kappa opioid receptor (KOR) antagonists have recently shown potential for treating drug addiction and mood disorders. The linear acetylated dynorphin A analog arodyn (Ac[Phe 1,2,3 ,Arg 4 ,d-Ala 8 ]dynorphin A-(1-11)NH 2 ), synthesized in our laboratory, demonstrated potent and selective KOR antagonism. Cyclization of arodyn could potentially stabilize the bioactive conformation and enhance its metabolic stability. The cyclization strategy employed involved ring closing metathesis between adjacent meta - or para -substituted Tyr(allyl) residues in the "message" sequence that were predicted in a docking study to yield analogs that would bind to the KOR with binding poses similar to arodyn. Consistent with the modeling, the resulting analogs retained KOR affinity similar to arodyn; the peptides involving cyclization between para O -allyl groups also retained high KOR selectivity, with one analog exhibiting KOR antagonist potency ( K B = 15 nM) similar to arodyn. These promising cyclized analogs with constrained aromatic residues represent novel leads for further exploration of KOR pharmacology.

Perinatal nicotine exposure (PNE) produces frontal cortical hypo-dopaminergic state and attention and working memory deficits consistent with neurodevelopmental disorders such as attention deficit hyperactivity disorder (ADHD). Methylphenidate alleviates ADHD symptoms by increasing extracellular dopamine and noradrenaline. Kappa opioid receptor (KOR) antagonism may be another mechanism to achieve the same results because KOR activation inhibits frontal cortical dopamine release. We administered the selective KOR antagonist norbinaltorphimine (norBNI) (20 mg/kg; intraperitoneal) or methylphenidate (0.75 mg/kg; intraperitoneal) to PNE mouse model and examined frontal cortical monoamine release, attention, and working memory. Both compounds increased dopamine and noradrenaline release but neither influenced serotonin release. Both compounds improved object-based attention and working memory in the PNE group, with norBNI's effects evident at 2.5 h and 5.5 h but absent at 24 h. Methylphenidate's effects were evident at 0.5 h but not at 2.5 h. norBNI's effects temporally coincided with frontal cortical c-Jun N-terminal kinase phosphorylation. norBNI did not alter tissue dopamine content in the nucleus accumbens, offering preliminary support for lack of reinforcement., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Activation of the kappa opioid receptor (KOR) contributes to the aversive properties of stress, and modulates key neuronal circuits underlying many neurobehavioral disorders. KOR agonists directly inhibit ventral tegmental area (VTA) dopaminergic neurons, contributing to aversive responses (Margolis et al. 2003, 2006); therefore, selective KOR antagonists represent a novel therapeutic approach to restore circuit function. We used whole cell electrophysiology in acute rat midbrain slices to evaluate pharmacological properties of four novel KOR antagonists: BTRX-335140, BTRX-395750, PF-04455242, and JNJ-67953964. Each compound concentration-dependently reduced the outward current induced by the KOR selective agonist U-69,593. BTRX-335140 and BTRX-395750 fully blocked U-69,593 currents (IC50 = 1.2 ± 0.9 and 1.2 ± 1.3 nM, respectively). JNJ-67953964 showed an IC50 of 3.0 ± 4.6 nM. PF-04455242 exhibited partial antagonist activity asymptoting at 55% blockade (IC50 = 6.7 ± 15.1 nM). In 3/8 of neurons, 1 μM PF-04455242 generated an outward current independent of KOR activation. BTRX-335140 (10 nM) did not affect responses to saturating concentrations of the mu opioid receptor (MOR) agonist DAMGO or the delta opioid receptor (DOR) agonist DPDPE, while JNJ-67953964 (10 nM) partially blocked DAMGO and DPDPE responses. Importantly, BTRX-335140 (10 nM) rapidly washed out with complete recovery of U-69,593 responses within 10 min. Collectively, we show electrophysiological evidence of key differences amongst KOR antagonists that could impact their therapeutic potential and have not been observed using recombinant systems. The results of this study demonstrate the value of characterizing compounds in native neuronal tissue and within circuits implicated in the neurobehavioral disorders of interest., Competing Interests: Competing interest: TLW, LJVO and WJM are employees of BlackThorn Therapeutics and have ownership interest (stock, stock options, royalty, receipt of intellectual property rights/patent holder, excluding diversified mutual funds) in BlackThorn Therapeutics TLW, LJVO, WJM have no other competing interests to declare. TLW, LJVO, WJM affiliation with BlackThorn Therapeutics and patent (WO2018170492; Kappa Opioid Receptor Antagonists and Products and Methods Related Thereto) does not alter our adherence to PLOS ONE policies on sharing data and materials.

Rationale: Major depressive disorder is a leading cause of disability worldwide and is likely precipitated by chronic stress. Although many antidepressants are currently available, these drugs require weeks to months of daily administration before reduction of symptoms occurs and many patients remain treatment-resistant despite several courses of treatment. There is a pressing need for new treatments for stress-related disorders. Kappa opioid receptors (KORs) are a promising new therapeutic target for major depressive disorder and anhedonia because acute KOR blockade prevents many effects of stress in rodents., Objectives: The following study assessed whether repeated treatment with the selective KOR antagonist aticaprant (also known as JNJ-67953964, and previously LY-2456302 and CERC-501) was effective in reversing behaviors in rodents following exposure to unpredictable chronic mild stress (UCMS)., Methods: Adult male C57BL/6J mice were exposed to 4 weeks of UCMS. After 3 weeks of stress, aticaprant (10 mg/kg) was administered daily for 11 treatments. Behavioral assessments included the sucrose preference test, nesting, forced swim test, hot plate test, light-dark test, and social interaction test., Results: Aticaprant significantly reversed stress-induced deficits produced by UCMS on the SPT, nesting, FST, and hot plate test. The effects of aticaprant persisted through a stress and treatment recovery period. Aticaprant was not effective at reversing behavioral effects caused by stress in the light-dark and social interaction tests., Conclusions: The results support further study of the role of KORs in regulating circuits related to reward, self-care, and cognition when they are disrupted by chronic stress. They are also consistent with the clinical development of aticaprant as a therapeutic for stress-related disorders targeted at anhedonia, such as depression and post-traumatic stress disorder.

Emerging evidence suggests that females are less sensitive than males to the effects of kappa opioid receptor (KOR) ligands across multiple behavioral measures. The effects of the KOR agonist U50,488 and the KOR antagonist aticaprant were assessed on nest building behavior, an ethologically relevant indicator of overall well-being and affect, in adult male and female C57BL/6J mice. Females required a higher dose of U50,488 to suppress nesting, and a higher dose of aticaprant to restore U50,488-induced impairment of nesting. Females also required a higher dose of aticaprant to decrease immobility scores in the forced swim test. Pretreatment with the estrogen receptor modulator tamoxifen, at a dose which blocked estrogen receptors, augmented the effect of U50,488 on nesting in female mice, suggesting that estrogen receptors play a key role in attenuating the effects of KOR ligands in female mice. Together, these results suggest that females are less sensitive to KOR mediation, requiring a higher dose to achieve comparable results to males. This behavioral sensitivity, as measured by nesting, may be mediated by estrogen receptors. Together these studies highlight the importance of comparing sex differences in response to KOR regulation on behaviors related to affective states., (Published by Elsevier Ltd.)

Nalfurafine, a moderately selective kappa opioid receptor (KOR) agonist, is used in Japan for treatment of itch without causing dysphoria or psychotomimesis. Here we characterized the pharmacology of compound 42B, a 3-dehydroxy analogue of nalfurafine and compared with that of nalfurafine. Nalfurafine and 42B acted as full KOR agonists and partial μ opioid receptor (MOR) agonists, but 42B showed much lower potency for both receptors and lower KOR/MOR selectivity, different from previous reports. Molecular modeling revealed that water-mediated hydrogen-bond formation between 3-OH of nalfurafine and KOR accounted for its higher KOR potency than 42B. The higher potency of both at KOR over MOR may be due to hydrogen-bond formation between nonconserved Y 7.35 of KOR and their carbonyl groups. Both showed modest G protein signaling biases. In mice, like nalfurafine, 42B produced antinociceptive and antiscratch effects and did not cause conditioned place aversion (CPA) in the effective dose ranges. Unlike nalfurafine, 42B caused motor incoordination and hypolocomotion. As both agonists showed G protein biases, yet produced different effects on locomotor activity and motor incoordination, the findings and those in the literature suggest caution in correlating in vitro biochemical data with in vivo behavior effects. The factors contributing to the disconnect, including pharmacodynamic and pharmacokinetic issues, are discussed. In addition, our results suggest that among the KOR-induced adverse behaviors, CPA can be separated from motor incoordination and hypolocomotion.

Dynantin is a potent and selective synthetic polypeptide kappa opioid receptor antagonist which has potential antidepressant and anxiolytic-like therapeutic applications, however its clinical development has been hampered by plasma stability issues and poor penetration of the blood brain barrier. Targeted liposome delivery systems represent a promising and non-invasive approach to improving the delivery of therapeutic agents across the blood brain barrier. As part of our work focused on targeted drug delivery, we have developed a novel mannosylated liposome system. Herein, we investigate these glycoliposomes for the targeted delivery of dynantin to the central nervous system. Cholesterol was tested and optimized as a formulation excipient, where it improved particle stability as measured via particle size, entrapment and ex vivo plasma stability of dynantin. The in vitro PRESTO-TANGO assay system was used to confirm that glycoliposomal entrapment did not impact the affinity or activity of the peptide at its receptor. Finally, in vivo distribution studies in mice showed that the mannosylated glycoliposomes significantly improved delivery of dynantin to the brain. Overall, the results clearly demonstrate the potential of our glycoliposomes as a targeted delivery system for therapeutic agents of the central nervous system., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Preclinical data indicate that selective kappa opioid receptor antagonists reduce nicotine self-administration and withdrawal symptoms. The aim of the current study was to determine whether treatment with CERC-501, an orally available, potent, and selective kappa opioid receptor antagonist, could alleviate nicotine withdrawal and craving and mitigate mood alterations associated with nicotine withdrawal in humans. Healthy, adult cigarette smokers were enrolled into this randomized, multisite, double-blind, placebo-controlled, crossover study. Participants completed two 8-day treatment phases during which they received either CERC-501 (15 mg, p.o., once daily) or placebo. On the seventh day of each dosing phase, participants were admitted as inpatients for an 18-hour cigarette abstinence period followed by experimental testing. The primary outcome measures were (a) performance on the McKee Smoking Lapse test (ie, latency to smoke in exchange for money) and (b) number of cigarettes self-administered during a 60-minute ad lib smoking period. Other outcomes included measures of craving, mood, anxiety, nicotine withdrawal, and subjective effects of cigarette smoking. A total of 71 participants who smoked an average of approximately 23 cigarettes per day were enrolled, and 56 subjects completed the study. CERC-501 was well tolerated, but it did not significantly alter the latency to start smoking (CERC-501: 16.5 min vs placebo: 17.7 min) or the number of cigarettes smoked (CERC-501: 3.3 cigarettes vs placebo: 3.1 cigarettes). Compared with placebo, CERC-501 also did not affect cigarette craving, mood, anxiety, nicotine withdrawal, or subjective effects of smoking. These findings do not support a role for CERC-501 in the treatment of nicotine use disorder., (© 2019 Society for the Study of Addiction.)

Pain is the most important clinical feature of acute pancreatitis (AP); however, its specific mechanism is currently unclear. In this study, we showed that AP caused an increase in nitric oxide (NO) secretion, activated the NF- κ B pathway in the dorsal root ganglia (DRGs), and caused pain. We established an AP model in vivo and tested the expression of NO, the kappa opioid receptor (KOR), and pain factors. We showed that NO in AP was significantly elevated and increased the expression of pain factors. Next, by treating DRGs in vitro, it was found that NO activated the NF- κ B pathway; conversely, NF- κ B had no effect on NO. Moreover, inhibition of NF- κ B promoted the KOR, whereas NF- κ B did not change after KOR activation. Finally, behavioral experiments showed that a NO donor increased the pain behavior of mice, while a NO scavenger, NF- κ B inhibitor, or KOR agonist attenuated the pain response in mice. These results suggest that iNOS/NO/NF- κ B/KOR may be a key mechanism of pain in AP, providing a theoretical basis for the use of peripheral-restricted KOR agonists for pain treatment in AP., Competing Interests: The authors declare that there is no conflict of interests., (Copyright © 2020 Mengwen Xue et al.)

Dipyrone is an analgesic pro-drug used clinically to control moderate pain with a high analgesic efficacy and low toxicity. Dipyrone is hydrolyzed to 4-methylaminoantipyrine (4-MAA), which is metabolized to 4-aminoantipyrine (4-AA). Here, were investigate the involvement of peripheral cannabinoid CB 2 and opioid receptor activation in the local antihyperalgesic effect of dipyrone and 4-MAA. The inflammatory agent, carrageenan was administered to the hindpaw of male Wistar rats, and the mechanical nociceptive threshold was quantified by electronic von Frey test. Dipyrone or 4-MAA were locally administered 2.5 h after carrageenan. Following dipyrone injection, hindpaw tissue was harvested and its hydrolysis to 4-MAA was analyzed by mass spectrometry (MS). The selective CB 2 receptor antagonist (AM630), naloxone (a non-selective opioid receptor antagonist), nor-BNI (a selective kappa-opioid receptor), CTOP (a selective mu-opioid receptor), or naltrindole (a selective delta-opioid receptor) was administered 30 min prior to 4-MAA. The results demonstrate that carrageenan-induced mechanical hyperalgesia was inhibited by dipyrone or 4-MAA in a dose-dependent manner. Dipyrone administered to the hindpaw was completely hydrolyzed to 4-MAA. The antihyperalgesic effect of 4-MAA was completely reversed by AM630, naloxone and nor-BNI, but not by CTOP or naltrindole. These data suggest that the local analgesic effect of dipyrone is mediated by its hydrolyzed bioactive form, 4-MAA and, at least in part, depends on CB 2 receptor and kappa-opioid receptor activation. In conclusion, the analgesic effect of dipyrone may involve a possible interaction between the cannabinoid and opioid system in peripheral tissue., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Mitochondrial dynamics, determining mitochondrial morphology, quality and abundance, have recently been implicated in myocardial ischemia and reperfusion (MI/R) injury. The roles of κ-opioid receptor activation in cardioprotection have been confirmed in our previous studies, while the underlying mechanism associated with mitochondrial dynamics remains unclear. This study aims to investigate the effect of κ-opioid receptor activation on the pathogenesis of MI/R and its underlying mechanisms. MI/R mouse model and hypoxia-reoxygenation cardiomyocyte model were established in this study. Mitochondrial dynamics were analyzed with transmission electron microscopy in vivo and confocal microscopy in vitro. STAT3 phosphorylation and OPA1 expression were detected by Western blotting. We show here that κ-opioid receptor activation with its selective receptor agonist U50,488H promoted mitochondrial fusion and enhanced myocardial resistance to MI/R injury, while these protective effects were blockaded by nor-BNI, a selective κ-opioid receptor antagonist. In addition, κ-opioid receptor activation increased STAT3 phosphorylation and OPA1 expression, which were blockaded by nor-BNI. Furthermore, inhibition of STAT3 phosphorylation by stattic, a specific STAT3 inhibitor, repressed the effects of κ-opioid receptor activation on promoting OPA1 expression and mitochondrial fusion, as well as inhibiting cell apoptosis and oxidative stress both in vivo and in vitro during MI/R injury. Overall, our data for the first time provide evidence that κ-opioid receptor activation promotes mitochondrial fusion and enhances myocardial resistance to MI/R injury via STAT3-OPA1 pathway. Targeting the pathway regulated by κ-opioid receptor activation may be a potential therapeutic strategy for MI/R injury., Competing Interests: Declaration of competing interest None., (Copyright © 2020. Published by Elsevier B.V.)

Proper learning from an aversive experience is essential for survival, yet it is an aberrant process in a wide range of mental disorders, as well as dopaminergic neurodegenerative disease. While the mesolimbic dopamine system is known to be essential for reward learning, the characterization of a potential pattern of dopamine signaling that guides avoidance remains unknown. Aversive stimuli may directly modulate dopamine signaling through the dynorphin/kappa opioid receptor (KOR) system, as kappa opioid receptors are expressed in this neural circuit and their activation is aversive in both rodents and humans. Ventral tegmental area (VTA) KORs are ideally positioned to directly shape aversion-induced reductions in dopamine signaling, but their role in this process has received little consideration. To determine the necessity of VTA KOR activity in the regulation of dopamine signaling and avoidance, we tested the effects of VTA KOR blockade on real time dopaminergic responses to aversive stimuli and learned avoidance in male Sprague-Dawley rats. We found that blockade of VTA KORs attenuated aversion-induced reductions in dopamine, and this treatment also prevented avoidance following the aversive experience. To determine whether aversion-induced reductions in striatal dopamine are necessary for avoidance, we tested avoidance following treatment with an intra nucleus accumbens D2 receptor agonist. This treatment also prevented avoidance and is consistent with the view that aversion-induced reductions in dopamine reduce dopamine signaling at high affinity D2 receptors and disinhibit an aversion-sensitive striatal output circuit to promote avoidance., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The National Institute of Mental Health (NIMH) 'fast-fail' approach seeks to improve too-often-misleading early-phase drug development methods by incorporating biomarker-based proof-of-mechanism (POM) testing in phase 2a. This first comprehensive application of the fast-fail approach evaluated the potential of κ-opioid receptor (KOR) antagonism for treating anhedonia with a POM study determining whether robust target engagement favorably impacts the brain circuitry hypothesized to mediate clinical effects. Here we report the results from a multicenter, 8-week, double-blind, placebo-controlled, randomized trial in patients with anhedonia and a mood or anxiety disorder (selective KOR antagonist (JNJ-67953964, 10 mg; n = 45) and placebo (n = 44)). JNJ-67953964 significantly increased functional magnetic resonance imaging (fMRI) ventral striatum activation during reward anticipation (primary outcome) as compared to placebo (baseline-adjusted mean: JNJ-67953964, 0.72 (s.d. = 0.67); placebo, 0.33 (s.d. = 0.68); F(1,86) = 5.58, P < 0.01; effect size = 0.58 (95% confidence interval, 0.13-0.99)). JNJ-67953964, generally well tolerated, was not associated with any serious adverse events. This study supports proceeding with assessment of the clinical impact of target engagement and serves as a model for implementing the 'fast-fail' approach.

Binge drinking is the most common pattern of excessive alcohol consumption and is a significant contributor to the development of Alcohol Use Disorder and dependence. Previous studies demonstrated involvement of kappa opioid receptors (KOR) in binge-like drinking in mice using the Drinking-in-the-Dark model. The current studies examined the role of KOR specifically in the bed nucleus of the stria terminals (BNST) in binge-like alcohol consumption in male and female mice. Direct administration of the long lasting KOR antagonist, nor-BNI, into the BNST decreased binge-like alcohol consumption and blood alcohol concentrations in male and female C57BL/6J mice. Similarly, direct nor-BNI administration into the BNST modestly reduced sucrose consumption and the suppression of fluid intake was not related to reduced locomotor activity. To further determine the role of KOR within the BNST on binge-like alcohol consumption, the KOR agonist U50,488 was administered systemically which resulted in a robust increase in alcohol intake. Microinjection of nor-BNI into the BNST blocked the high level of alcohol intake after systemic U50,488 challenge reducing intake and resultant blood alcohol concentrations. Together, these data suggest that KOR activity in the BNST contributes to binge-like alcohol consumption in both male and female mice. This article is part of the special issue on 'Neuropeptides'., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Opioid receptors (ORs) are among the best-studied G protein-coupled receptors due to their involvement in neurological disorders and important role in pain treatment. Contrary to the classical monomeric model, indirect evidence suggests that ORs might form dimers, which could be endowed with a distinct pharmacological profile, and, thus, be targeted to develop innovative pharmacological therapies. However, direct evidence for the spontaneous formation of OR dimers in living cells under physiological conditions is missing. Despite a growing interest in the κ opioid receptor (KOR), KOR-selective fluorescent probes are particularly scarce in the literature. Herein, we present the first set of fluorescent KOR-selective probes with antagonistic properties. Two of these were employed in single-molecule microscopy (SMM) experiments to investigate KOR homodimerization, localization, and trafficking. Our findings indicate that most KORs labeled with the new fluorescent probes are present as apparently freely diffusing monomers on the surface of a simple cell model.

Rationale: Cocaine addiction is a chronic brain disease characterized by compulsive drug intake and dysregulation of brain reward systems. Few preclinical studies have modeled the natural longitudinal course of cocaine addiction. Extended access self-administration protocols are powerful tools for modeling the advanced stages of addiction; however, few studies have duration of drug access longer than 12 h/session, potentially limiting their construct validity. Identification of changes in cocaine intake patterns during the development of addictive-like states may allow better treatments for vulnerable subjects. The kappa opioid receptor (KOPr) system has been implicated in the neurobiological regulation of addictive states as well as mood and stress disorders, with selective KOPr antagonists proposed as possible pharmacotherapeutic agents. Chronic cocaine exposure increases the expression of KOPr and its endogenous agonists, the dynorphins, in several brain areas in rodents., Objectives: To examine the behavioral pattern of intake during chronic (14 days) 18 h intravenous cocaine self-administration (0.5 mg/kg/infusion) and the effect of a novel short-acting KOPr antagonist LY2444296 HCl (3 mg/kg) administered during sessions 8 to 14 of chronic 18 h/day cocaine self-administration and prior to a single re-exposure session after 2 cocaine-free withdrawal days., Results: Both daily and hourly cocaine intake patterns changed over 14 days of 18 h self-administration. LY pretreatment affected the pattern of self-administration across the second week of extended access cocaine self-administration and prevented the increase in cocaine intake during re-exposure., Conclusions: Overall, the KOPr antagonist attenuated escalated cocaine consumption in a rat model of extended access cocaine self-administration.

Mu opioid receptor (MOPr) agonists are thought to produce analgesia via modulation of G-protein-coupled intracellular signalling pathways whereas the β-arrestin2 pathway is proposed to mediate opioid-related adverse effects. Here, we report the antinociception, constipation and respiratory depressant profile of CYX-6, a potent MOPr agonist that is also a delta and a kappa opioid receptor (DOPr/KOPr) antagonist and that lacks β-arrestin2 recruitment at each of the MOPr, DOPr and the KOPr. In anaesthetised male Sprague Dawley rats, an intracerebroventricular (i.c.v.) guide cannula was stereotaxically implanted. After 5-7 days post-surgical recovery, rats received a single i.c.v. bolus dose of CYX-6 (3-30 nmol), morphine (100 nmol) or vehicle. Antinociception was assessed using the warm water tail flick test (52.5 ± 0.5 °C). Constipation was assessed using the charcoal meal gut motility test and the castor oil-induced diarrhoea test. Respiratory depression was measured by whole-body plethysmography in awake, freely moving animals, upon exposure to a hypercapnic gas mixture (8% CO 2 , 21% O 2 and 71% N 2 ). The intrinsic pharmacology of CYX-6 given by the i.c.v. route in rats showed that it produced dose-dependent antinociception. It also produced respiratory stimulation rather than depression and it had a minimal effect on intestinal motility in contrast to the positive control, morphine. CYX-6 is an endomorphin-2 analogue that dissociates antinociception from constipation and respiratory depression in rats. Our findings provide useful insight to inform the discovery and development of novel opioid analgesics with a superior tolerability profile compared with morphine., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Tissue injury produces a delicate balance between latent pain sensitization (LS) and compensatory endogenous opioid receptor analgesia that continues for months, even after re-establishment of normal pain thresholds. To evaluate the contribution of mu (MOR), delta (DOR), and/or kappa (KOR) opioid receptors to the silencing of chronic postoperative pain, we performed plantar incision at the hindpaw, waited 21 days for the resolution of hyperalgesia, and then intrathecally injected subtype-selective ligands. We found that the MOR-selective inhibitor CTOP (1-1000 ng) dose-dependently reinstated mechanical hyperalgesia. Two DOR-selective inhibitors naltrindole (1-10 μg) and TIPP[Ψ] (1-20 μg) reinstated mechanical hyperalgesia, but only at the highest dose that also produced itching, licking, and tail biting. Both the prototypical KOR-selective inhibitors nor-BNI (0.1-10 μg) and the newer KOR inhibitor with more canonical pharmocodynamic effects, LY2456302 (0.1-10 μg), reinstated mechanical hyperalgesia. Furthermore, LY2456302 (10 μg) increased the expression of phosphorylated signal-regulated kinase (pERK), a marker of central sensitization, in dorsal horn neurons but not glia. Sex studies revealed that LY2456302 (0.3 μg) reinstated hyperalgesia and pERK expression to a greater degree in female as compared to male mice. Our results suggest that spinal MOR and KOR, but not DOR, maintain LS within a state of remission to reduce the intensity and duration of postoperative pain, and that endogenous KOR but not MOR analgesia is greater in female mice., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Exposure to stressful stimuli activates kappa opioid receptor (KOR) signaling, a process known to produce aversion and dysphoria in humans and other species. This endogenous opioid system is dysregulated in stress-related disorders, specifically in major depressive disorder (MDD). These findings serve as the foundation for a growing interest in the therapeutic potential of KOR antagonists as novel antidepressants. In this review, data supporting the hypothesis of dysregulated KOR function in MDD are considered. The clinical data demonstrating the therapeutic efficacy and safety of selective and mixed opioid antagonists are then presented. Finally, the preclinical evidence illustrating the induction of behaviors relevant to the endophenotypes of MDD and KOR antagonist activity in stress-naïve and stress-exposed animals is evaluated. Overall, this review highlights the emergent literature supporting the pursuit of KOR antagonists as novel therapeutics for MDD and other stress-related disorders.

Substance use disorders represent a global public health issue. This mental health disorder is hypothesized to result from neurobiological changes as a result of chronic drug exposure and clinically manifests as inappropriate behavioral allocation toward the procurement and use of the abused substance and away from other behaviors maintained by more adaptive nondrug reinforcers (e.g., social relationships, work). The dynorphin/kappa-opioid receptor (KOR) is one receptor system that has been altered following chronic exposure to drugs of abuse (e.g., cocaine, opioids, alcohol) in both laboratory animals and humans, implicating the dynorphin/KOR system in the expression, mechanisms, and treatment of substance use disorders. KOR antagonists have reduced drug self-administration in laboratory animals under certain experimental conditions, but not others. Recently, several human laboratory and clinical trials have evaluated the effectiveness of KOR antagonists as candidate pharmacotherapies for cocaine or tobacco use disorder to test hypotheses generated from preclinical studies. KOR antagonists failed to significantly alter drug use metrics in humans suggesting translational discordance between some preclinical drug self-administration studies and consistent with other preclinical drug self-administration studies that provide concurrent access to an alternative nondrug reinforcer (e.g., food). The implications of this translational discordance and future directions for examining the therapeutic potential of KOR agonists or antagonists as candidate substance use disorder pharmacotherapies are discussed.

For thousands of years opioids have been the first-line treatment option for pain management. However, the tolerance and addiction potential of opioids limit their applications in clinic. NFP, a MOR/KOR dual-selective opioid antagonist, was identified as a ligand that significantly antagonized the antinociceptive effects of morphine with lesser withdrawal effects than naloxone at similar doses. To validate the potential application of NFP in opioid addiction treatment, a series of in vitro and in vivo assays were conducted to further characterize its pharmacological profile. In calcium mobilization assays and MOR internalization studies, NFP showed the apparent capacity to antagonize DAMGO-induced calcium flux and etorphine-induced MOR internalization. In contrast to the opioid agonists DAMGO and morphine, cells pretreated with NFP did not show apparent desensitization and down regulation of the MOR. Though in vitro bidirectional transport studies showed that NFP might be a P-gp substrate, in warm-water tail-withdrawal assays it was able to antagonize the antinociceptive effects of morphine indicating its potential central nervous system activity. Overall these results suggest that NFP is a promising dual selective opioid antagonist that may have the potential to be used therapeutically in opioid use disorder treatment., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The mechanisms behind relapse to ethanol intake in recovering alcoholics are still unclear. The negative reinforcing effects contributing to ethanol addiction, including relapse, are considered to be partly driven by the κ-opioidergic system. As the κ-opioidergic system interacts with the mesolimbic reward pathway, the aim of the study was to clarify the role of nucleus accumbens shell κ-opioidergic mechanisms in relapse to ethanol intake by using the alcohol deprivation effect (ADE) paradigm. The ADE is defined as a transient increase in voluntary ethanol intake after a forced period of abstinence. Male Long-Evans rats were trained to voluntarily consume 10% (v/v) ethanol solution. Ethanol access and deprivation cycles were initiated after stable ethanol intake baselines had been reached and bilateral guide cannulas had been implanted above the nucleus accumbens shell. One cycle consisted of 10 days of 90 min access to ethanol followed by 6 days of ethanol deprivation. The ADE was measured in the beginning of a new cycle. Rats received JDTic, a selective κ-antagonist, either subcutaneously (10 mg/kg) or intra-accumbally (15 µg/site) or, as a reference substance, systemic naltrexone (0.3 mg/kg) before ethanol re-access, and the effects on the ADE were evaluated. Systemic and intra-accumbal JDTic significantly attenuated the ADE on the first day of ethanol re-access, as did systemic naltrexone. Additionally, naltrexone decreased ethanol intake levels. These results suggest that nucleus accumbens shell κ-opioidergic mechanisms may have a role in mediating relapse to ethanol intake. Additionally, κ-antagonism could be a valuable adjunct in ethanol relapse prevention., (Copyright © 2019 Elsevier B.V. and ECNP. All rights reserved.)

Background: New treatments for stress-related disorders including depression, anxiety, and substance use disorder are greatly needed. Kappa opioid receptors are expressed in the central nervous system, including areas implicated in analgesia and affective state. Although kappa opioid receptor agonists share the antinociceptive effects of mu opioid receptor agonists, they also tend to produce negative affective states. In contrast, selective kappa opioid receptor antagonists have antidepressant- and anxiolytic-like effects, stimulating interest in their therapeutic potential. The prototypical kappa opioid receptor antagonists (e.g., norBNI, JDTic) have an exceptionally long duration of action that complicates their use in humans, particularly in tests to establish safety. This study was designed to test dose- and time-course effects of novel kappa opioid receptor antagonists with the goal of identifying short-acting lead compounds for future medication development., Methods: We screened 2 novel, highly selective kappa opioid receptor antagonists (CYM-52220 and CYM-52288) with oral efficacy in the warm water tail flick assay in rats to determine initial dose and time course effects. For comparison, we tested existing kappa opioid receptor antagonists JDTic and LY-2456302 (also known as CERC-501 or JNJ-67953964)., Results: In the tail flick assay, the rank order of duration of action for the antagonists was LY-2456302 < CYM-52288 < CYM-52220 << JDTic. Furthermore, LY-2456302 blocked the depressive (anhedonia-producing) effects of the kappa opioid receptor agonist U50,488 in the intracranial self-stimulation paradigm, albeit at a higher dose than that needed for analgesic blockade in the tail flick assay., Conclusions: These results suggest that structurally diverse kappa opioid receptor antagonists can have short-acting effects and that LY-2456302 reduces anhedonia as measured in the intracranial self-stimulation test., (© The Author(s) 2019. Published by Oxford University Press on behalf of CINP.)

Schizophrenia is a debilitating mental illness that affects approximately 1% of the world's population. Despite much research in its neurobiology to aid in developing new treatments, little progress has been made. One system that has not received adequate attention is the kappa opioid system and its potential role in the emergence of symptoms, as well as its therapeutic potential. Here we present an overview of the kappa system and review various lines of evidence derived from clinical studies for dynorphin and kappa opioid receptor involvement in the pathology of both the positive and negative symptoms of schizophrenia. This overview includes evidence for the psychotomimetic effects of kappa opioid receptor agonists in healthy volunteers and their reversal by the pan-opioid antagonists naloxone and naltrexone and evidence for a therapeutic benefit in schizophrenia for 4 pan-opioid antagonists. We describe the interactions between kappa opioid receptors and the dopaminergic pathways that are disrupted in schizophrenia and the histologic evidence suggesting abnormal kappa opioid receptor signaling in schizophrenia. We conclude by discussing future directions., (Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)