Role Of Kappa Opioid Receptors Research Articles

The ultrasonic vocalization (USV) syllable profile during neonatal opioid withdrawal and a kappa opioid receptor component to increased USV emissions in female mice.

Opioid use during pregnancy can lead to negative infant health outcomes, including neonatal opioid withdrawal syndrome (NOWS). NOWS comprises gastrointestinal, autonomic nervous system, and neurological dysfunction that manifest during spontaneous withdrawal. Variability in NOWS severity necessitates a more individualized treatment approach. Ultrasonic vocalizations (USVs) in neonatal mice are emitted in isolation as a stress response and are increased during opioid withdrawal, thus modeling a negative affective state that can be utilized to test new treatments. We sought to identify the behavioral and USV profile, brainstem transcriptomic adaptations, and role of kappa opioid receptors in USVs during neonatal opioid withdrawal. We employed a third trimester-approximate opioid exposure model, where neonatal inbred FVB/NJ pups were injected twice-daily with morphine (10mg/kg, s.c.) or saline (0.9%, 20 ul/g, s.c.) from postnatal day(P) 1 to P14. This protocol induces reduced weight gain, hypothermia, thermal hyperalgesia, and increased USVs during spontaneous morphine withdrawal. On P14, there were increased USV emissions and altered USV syllables during withdrawal, including an increase in Complex 3 syllables in FVB/NJ females (but not males). Brainstem bulk mRNA sequencing revealed an upregulation of the kappa opioid receptor (Oprk1), which contributes to withdrawal-induced dysphoria. The kappa opioid receptor (KOR) antagonist, nor-BNI (30 mg/kg, s.c.), significantly reduced USVs in FVB/NJ females, but not males during spontaneous morphine withdrawal. Furthermore, the KOR agonist, U50,488h (0.625 mg/kg, s.c.), was sufficient to increase USVs on P10 (both sexes) and P14 (females only) in FVB/NJ mice. We identified an elevated USV syllable, Complex 3, and a female-specific recruitment of the dynorphin/KOR system in increased USVs associated with neonatal opioid withdrawal severity.

The ultrasonic vocalization (USV) syllable profile during neonatal opioid withdrawal and a kappa opioid receptor component to increased USV emissions in female mice.

Opioid use during pregnancy can lead to negative infant health outcomes, including neonatal opioid withdrawal syndrome (NOWS). NOWS comprises gastrointestinal, autonomic nervous system, and neurological dysfunction that manifest during spontaneous withdrawal. Variability in NOWS severity necessitates a more individualized treatment approach. Ultrasonic vocalizations (USVs) in neonatal mice are emitted in isolation as a stress response and are increased during opioid withdrawal, thus modeling a negative affective state that can be utilized to test new treatments. We sought to identify the behavioral and USV profile, brainstem transcriptomic adaptations, and role of kappa opioid receptors in USVs during neonatal opioid withdrawal. We employed a third trimester-approximate opioid exposure model, where neonatal inbred FVB/NJ pups were injected twice-daily with morphine (10mg/kg, s.c.) or saline (0.9%, 20 ul/g, s.c.) from postnatal day(P) 1 to P14. This protocol induces reduced weight gain, hypothermia, thermal hyperalgesia, and increased USVs during spontaneous morphine withdrawal. On P14, there were increased USV emissions and altered USV syllables during withdrawal, including an increase in Complex 3 syllables in FVB/NJ females (but not males). Brainstem bulk mRNA sequencing revealed an upregulation of the kappa opioid receptor (Oprk1), which contributes to withdrawal-induced dysphoria. The kappa opioid receptor (KOR) antagonist, nor-BNI (30 mg/kg, s.c.), significantly reduced USVs in FVB/NJ females, but not males during spontaneous morphine withdrawal. Furthermore, the KOR agonist, U50,488h (0.625 mg/kg, s.c.), was sufficient to increase USVs on P10 (both sexes) and P14 (females only) in FVB/NJ mice. We identified an elevated USV syllable, Complex 3, and a female-specific recruitment of the dynorphin/KOR system in increased USVs associated with neonatal opioid withdrawal severity.

Peripheral Kappa Opioid Receptor Activation Drives Noxious Cold Hypersensitivity in Mice

Noxious cold sensation is associated with peripheral neuropathies, yet little is known about the mechanisms underlying cold hypersensitivity and pain. Here we identify a role for the kappa opioid receptor (KOR) system in driving cold hypersensitivity. The cold plate assay was used to determine the cold hypersensitivity in wildtype (WT) (C57BL/6J) and Transient receptor potential (TRP) Ankyrin –1(A1) KO mice. Fluorescent in-situ hybridization (FISH) assay was used to determine the expression of KOR in the dorsal root ganglion (DRG) and its co-expression with TRPA1 transcripts in mouse and human DRG's. Ex-vivo calcium imaging was used to investigate calcium dynamics between KOR and TRPA1 in the modulation of cold hypersensitivity in mouse DRG's. Activation of KOR by the agonist U50,488 (U50) increased the number of jumps on a cold plate at the noxious temperature of 3°C in WT mice. We show that this cold hypersensitivity is mediated by peripherally expressed KOR. To begin to explore how peripherally expressed KOR modulates cold hypersensitivity, using FISH, we found that KOR colocalized with TRPA1 transcripts in both mice (WT) and human DRG. Interestingly, KOR activation potentiated TRPA1-dependent calcium signaling in DRG neurons of WT mice. Furthermore, we show that KOR mediated cold hypersensitivity is attenuated in TRPA1-/- mice on cold plate at 3°C, suggesting that KOR mediated cold hypersensitivity might be through TRPA1. Together, we have identified a novel role for peripheral KOR activation in driving cold hypersensitivity, and this behavior is likely mediated through potentiated TRPA1 activity. We have identified a novel role for kappa opioid receptors (KOR) in driving cold hypersensitivity via TRPA1. These findings will have major implications not only in our understanding of cold sensitivity, but also the potential to open up alternative therapeutic targets to allow us to treat cold hypersensitivity and pain.

Mediation of the behavioral effects of ketamine and (2R,6R)-hydroxynorketamine in mice by kappa opioid receptors.

Emerging evidence has implicated the endogenous opioid system in mediating ketamine's antidepressant activity in subjects with major depressive disorder. To date, mu opioid receptors have been suggested as the primary opioid receptor of interest. However, this hypothesis relies primarily on observations that the opioid antagonist naltrexone blocked the effects of ketamine in humans and rodents. This report confirms previous findings that pretreatment with naltrexone (1mg/kg) just prior to ketamine (10mg/kg) administration effectively blocks the behavioral effect of ketamine in the mouse forced swim test 24h post-treatment. Furthermore, pharmacological blockade of kappa opioid receptors prior to ketamine administration with the selective, short-acting antagonist LY2444296 successfully blocked ketamine's effects in the forced swim test. Likewise, the ability of the ketamine metabolite (2R,6R)-hydroxynorketamine to reduce immobility scores in the forced swim test was also blocked following pretreatment with either naltrexone or LY2444296. These data support a potential role of kappa opioid receptors in mediating the behavioral activity of ketamine and its non-dissociate metabolite (2R,6R)-hydroxynorketamine.

Kappa opioid receptor blockade in the nucleus accumbens shell prevents sex-dependent alcohol deprivation effect induced by inflammatory pain.

Pain-induced negative affect reduces life quality of patients by increasing psychiatric comorbidities, including alcohol use disorders (AUDs). Indeed, clinical data suggest pain as a risk factor to suffer AUDs, predicting relapse drinking in abstinent patients. Here, we analyse the impact of pain on alcohol relapse and the role of kappa opioid receptor (KOR) activation in mediating these pain-induced effects because KORs play an important role in pain-driven negative affect and AUD. Female and male Sprague-Dawley rats underwent 2 alcohol intermittent access periods separated by a forced abstinence period. The complete Freund adjuvant model of inflammatory pain was introduced during abstinence, and alcohol intake before and after alcohol reintroduction was assessed. In addition, we used behavioural approaches to measure stress and memory impairment and biochemical assays to measure KOR expression in abstinence and reintroduction periods. Only female CFA-treated rats increased alcohol intake during the reintroduction period. Concomitantly, this group showed enhanced anxiety-like behaviour and increased KOR expression in the nucleus accumbens shell that was developed during abstinence and remained during the reintroduction period. Finally, KOR antagonist norbinaltorphimine was administered in the nucleus accumbens shell during abstinence to prevent a pain-induced alcohol deprivation effect, a phenomenon observed in CFA-female rats. The administration of norbinaltorphimine effectively blocked a pain-induced alcohol deprivation effect in female rats. Our data evidenced that inflammatory pain constitutes a risk factor to increase alcohol consumption during a reintroduction phase only in female rats by the rise and maintenance of stress probably mediated by KOR signalling in the nucleus accumbens.

Peripheral kappa opioid receptor activation drives cold hypersensitivity in mice

Noxious cold sensation is commonly associated with peripheral neuropathies, however, there has been limited progress in understanding the mechanism of cold pain. Here we identify a role for kappa opioid receptors (KOR) in driving cold hypersensitivity. First, we show that systemic activation of KOR by U50,488 (U50), increases the latency to jump and the number of jumps on a cold plate at 3°C. KOR antagonist, NorBNI, attenuates U50-induced cold hypersensitivity. However, the central administration of NorBNI does not block U50-induced cold hypersensitivity suggesting that peripheral KORs may modulate this effect. To directly test this, we use the peripherally-restricted KOR agonist, ff(nle)r-NH2 and also show cold hypersensitivity. To begin to understand how peripheral KORs drive cold hypersensitivity we investigated whether KORs interact with transient receptor potential ankyrin 1(TRPA1) channels, known to facilitate the perception of noxious cold, in dorsal root ganglion (DRG). Using fluorescent in situ hybridization, we show that KOR mRNA colocalizes with the transcripts for the cold-activated TRPA1 channels in DRG. We also show a potentiation in intracellular calcium release in DRG during the simultaneous application of the TRPA1 agonist, mustard oil (MO), and a KOR agonist, U50, when compared to MO alone. Together our data suggest that peripheral KORs may induce cold hypersensitivity through modulation of TRPA1 channels.

Activation of Kappa Opioid Receptor Regulates the Hypothermic Response to Calorie Restriction and Limits Body Weight Loss.

Mammals maintain a nearly constant core body temperature (Tb) by balancing heat production and heat dissipation. This comes at a high metabolic cost that is sustainable if adequate calorie intake is maintained. When nutrients are scarce or experimentally reduced such as during calorie restriction (CR), endotherms can reduce energy expenditure by lowering Tb [1-6]. This adaptive response conserves energy, limiting the loss of body weight due to low calorie intake [7-10]. Here we show that this response is regulated by the kappa opioid receptor (KOR). CR is associated with increased hypothalamic levels of the endogenous opioid Leu-enkephalin, which is derived from the KOR agonist precursor dynorphin [11]. Pharmacological inhibition of KOR, but not of the delta or the mu opioid receptor subtypes, fully blocked CR-induced hypothermia and increased weight loss during CR independent of calorie intake. Similar results were seen with DIO mice subjected to CR. In contrast, inhibiting KOR did not change Tb in animals fed ad libitum (AL). Chemogenetic inhibition of KOR neurons in the hypothalamic preoptic area reduced the CR-induced hypothermia, whereas chemogenetic activation of prodynorphin-expressing neurons in the arcuate or the parabrachial nucleus lowered Tb. These data indicate that KOR signaling is a pivotal regulator of energy homeostasis and can affect body weight during dieting by modulating Tb and energy expenditure.

Effects of the Alpha-1 Antagonist Prazosin on KOR Agonist-Induced Reinstatement of Alcohol Seeking.

BackgroundStress is associated with relapse to alcohol seeking during abstinence, but the processes underlying this relationship are poorly understood. Noradrenaline is a key transmitter in stress responses and in stress-induced drug seeking. The alpha-1 adrenoceptor antagonist prazosin has been investigated as a treatment for alcoholism and for chronic stress disorders that are frequently comorbid with alcoholism. In rats, we previously showed that prazosin blocks reinstatement of alcohol seeking induced by footshock and yohimbine stressors and reduces yohimbine-induced brain activation. The role of alpha-1 adrenoceptors in reinstatement induced by other stressors is not known. Our most recent work is on the role of kappa opioid receptors in stress-induced reinstatement of alcohol seeking and have reported that the selective kappa opioid receptor agonist U50,488 induces reinstatement and neuronal activation in stress- and relapse-related brain regions. Here we determine the involvement of alpha-1 receptors in reinstatement and brain activation induced by U50,488.MethodsWe trained male Long-Evans rats to self-administer alcohol (12% w/v), extinguished alcohol-reinforced responding, and then determined the effects of prazosin (1 mg/kg) on U50,488 (2.5 mg/kg)-induced reinstatement and regional Fos expression.ResultsPrazosin blocked U50,488-induced reinstatement and decreased U50,488-induced Fos expression in the orbitofrontal cortex, nucleus accumbens core, ventral bed nucleus of the stria terminalis, central and basolateral amygdalar nuclei and ventral tegmental area.ConclusionsThese findings suggest that prazosin may reduce U50,488-induced relapse by inhibiting activity in 1 or more of these brain areas.

Role of Kappa Opioid Receptors in Symptoms of Schizophrenia: What Is the Neurobiology?

The opioid peptide–containing neurons comprise a neuromodulatory system that is widespread across the central nervous system with three classical cognate receptors (mu, delta, and kappa subtypes), all with their preferred endogenous peptide ligands. The kappa opioid receptors (KORs) have the strongest affinity for the endogenous ligand dynorphin (1) and demonstrate specific distribution patterns, concentrated along the spinal nociceptive pathways, brainstem, striatum, subcortical limbic regions, and cortex.

Molecular and behavioral mechanisms mediating paclitaxel‐induced changes in affect‐like behavior in mice

The antineoplastic paclitaxel is associated with negative affective outcomes, such as depression, anxiety, and decreased quality of life during treatment and convalescence. With the Baby Boomer population approaching peak cancer age, it is dire that the mechanisms behind paclitaxel‐induced changes in mood are uncovered. Cancer‐free male and female C57BL/6J mice were treated with one set of four injections of vehicle or paclitaxel (32mg/kg cumulative), or two sets of four injections of vehicle or paclitaxel (64mg/kg cumulative), and periodically assessed for depression‐like behaviors. Paclitaxel caused significant, time‐dependent deficits in sucrose preference and operant responding for palatable food. Because there is growing evidence to support the role of kappa opioid receptors (KORs) in stress‐mediated depression and reward dysfunction, we investigated KOR signaling as a putative mechanism of paclitaxel‐induced depression‐like behaviors. The selective KOR antagonist norbinaltorphimine (norBNI) reversed paclitaxel‐induced attenuation of sucrose preference. At the molecular level, paclitaxel time‐dependently induced an increase in the expression of Prodynorphin mRNA, the precursor for endogenous KOR agonists, in the nucleus accumbens (NAc). Using the [35S]GTPγS assay, we discovered that a history of paclitaxel time‐dependently attenuated activation of dopamine D2 receptors (D2R) and KORs in the NAc but not caudate putamen. These data suggest that paclitaxel‐induced changes in affect‐like behavior may be due to time‐ and region‐dependent dysregulation of KOR and D2R signaling. These observations help to establish the roles of KOR and D2R systems in paclitaxel‐induced disruption of behavioral reward, thus revealing potential neurochemical targets for therapeutic intervention in cancer survivors with treatment‐resistant depression.Support or Funding InformationSupported by: Ruth L. Kirschstein National Research Service Award Individual Predoctoral Fellowship to Promote Diversity in Health‐Related Research 1F31CA224930‐01A1; NIH grant 1R01‐CA206028‐01; NIHNCI Cancer Center Support Grant P30‐CA016059.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The blocking of kappa-opioid receptor reverses the changes in dorsolateral striatum dopamine dynamics during the amphetamine sensitization.

Kappa-opioid receptors (KOR) control dopamine (DA) levels in the striatum and contribute significantly to the progression of drug addiction. Repeated exposure to psychostimulants has been associated with up-regulated KOR activity and increased DA levels in dorsal striatum. However, it has not been tested if both processes are linked. In this work, we studied if a mechanism mediated by KOR is contributing to the increase in DA levels in the dorsolateral striatum (DLS) after amphetamine (AMPH) sensitization. The AMPH sensitization was assessed after single or repeated once-a-day AMPH injections (1mg/kg). Only repeated AMPH exposure produced a significant locomotor sensitization. No-net flux microdialysis was used to assess basal DA dialysate, DA extracellular concentration (Cext ), and DA uptake in DLS of anesthetized rats. The role of KOR on DA dynamics in DLS was evaluated by local perfusion (250μM) and systemic administration (10mg/kg) of the KOR antagonist nor-binaltorphimine. A significant decrease in DA Cext is observed in the DLS after an AMPH challenge in rats exposed to a single dose of AMPH. The decrease in DA Cext was associated with both a decreased basal DA dialysate and an increased DA uptake. Conversely, the expression of AMPH sensitization was accompanied by a significant increase in DA Cext associated with an increased basal DA dialysate and an attenuation in DA uptake. Both local and systemic administration of nor-binaltorphimine reversed changes in DLS after AMPH pre-treatment. These findings indicate that endogenous KOR system tunes DLS DA dynamics during the progression to AMPH sensitization.

Maladaptive behavioral regulation in alcohol dependence: Role of kappa-opioid receptors in the bed nucleus of the stria terminalis

There is an important emerging role for the endogenous opioid dynorphin (DYN) and the kappa-opioid receptor (KOR) in the treatment of alcohol dependence. Evidence suggests that the DYN/KOR system in the bed nucleus of the stria terminalis (BNST) contributes to maladaptive behavioral regulation during withdrawal in alcohol dependence. The current experiments were designed to assess dysregulation of the BNST DYN/KOR system by evaluating alcohol dependence-induced changes in DYN/KOR gene expression (Pdyn and Oprk1, respectively), and the sensitivity of alcohol self-administration, negative affective-like behavior and physiological withdrawal to intra-BNST KOR antagonism during acute withdrawal. Wistar rats trained to self-administer alcohol, or not trained, were subjected to an alcohol dependence induction procedure (14 h alcohol vapor/10 h air) or air-exposure. BNST micropunches from air- and vapor-exposed animals were analyzed using RT-qPCR to quantify dependence-induced changes in Pdyn and Oprk1 mRNA expression. In addition, vapor- and air-exposed groups received an intra-BNST infusion of a KOR antagonist or vehicle prior to measurement of alcohol self-administration. A separate cohort of vapor-exposed rats was assessed for physiological withdrawal and negative affective-like behavior signs following intra-BNST KOR antagonism. During acute withdrawal, following alcohol dependence induction, there was an upregulation in Oprk1 mRNA expression in alcohol self-administering animals, but not non-alcohol self-administering animals, that confirmed dysregulation of the KOR/DYN system within the BNST. Furthermore, intra-BNST KOR antagonism attenuated escalated alcohol self-administration and negative affective-like behavior during acute withdrawal without reliably impacting physiological symptoms of withdrawal. The results confirm KOR system dysregulation in the BNST in alcohol dependence, illustrating the therapeutic potential of targeting the KOR to treat alcohol dependence.

The distinct role of kappa opioid receptor in attenuating relapse to morphine/methamphetamine (polydrug) dependence in mice

A Combination of 0.3mg/kg buprenorphine and 1.0 mg/kg naltrexone treatment shows a promising result due to its ability to attenuate reinstatement (relapse) in morphine/methamphetamine (polydrug)-dependent mice in a conditioned place preference (CPP) model. This prompted us to identify which opioid receptor that contributes to its anti-relapse activity. Using the same CPP model, 10 mg/kg nor- BNI (a selective kappa opioid receptor [KOR] antagonist) was used to evaluate the involvement of KOR in mediating relapse to polydrug dependence. By applying the immunohistochemistry (IHC) technique, the investigation was extended to the mice brain using KOR antibody (EPR18881), focusing on the brain regions that are abundant in KOR density. The results showed that nor-BNI alone failed to attenuate relapse to polydrug dependence. However, the IHC results proved that the number of KOR significantly increased in the striatum during reinstatement compared to post-conditioning (p <0.05). The KOR was significantly suppressed in the treatment group which strengthens the findings from previous studies proving that the KOR plays an important role in mediating relapse to polydrug dependence.

The Role of Kappa Opioid Receptors in Glutamate Input Selection in the Ventral Striatum.

The ventral striatum is an important controller of motivated behavior. This nucleus receives dopamine afferents from the ventral tegmental area and glutamate afferents from the basolateral amygdala, thalamus, medial prefrontal cortex (mPFC), and ventral hippocampus, which encode emotional, sensory,

Effects of pharmacological manipulation of the kappa opioid receptors on the aversive effects of nicotine

Nicotine, an addictive component of tobacco smoke, produces both rewarding and aversive effects. Increasing the aversive effects of nicotine may help in promoting smoking cessation. However, neural targets mediating the aversive effects of nicotine have not been fully identified. In this study, we evaluated the role of kappa opioid receptors (KORs) in the aversive effects of nicotine (0.4 mg/kg, base; s.c.) using the nicotine-induced conditioned taste aversion (CTA) model in Wistar rats. The KORs were activated using the selective KOR agonist (±)U-50,488H (0, 0.03, 0.15 & 0.3mg/kg; s.c.) and inhibited using the KOR antagonist nor-binaltorphimine (nor-BNI; 0, 15 & 30mg/kg; s.c.) in separate groups of rats using a between-subjects design. Pretreatment with the KOR agonist (±)U-50,488H (0.3mg/kg) significantly increased aversion for the nicotine-associated solution. Additionally, (±)U-50,488H (0.3mg/kg) on its own induced aversion to the flavored solution associated with it even in the absence of nicotine, suggesting that the KOR agonist induced increase in nicotine-induced aversion was an additive effect. Interestingly, administration of the KOR antagonist nor-BNI (30mg/kg) prior to conditioning with nicotine/saline, but not after conditioning with nicotine/saline, attenuated nicotine-induced aversive effects compared to saline controls. Taken together, these data suggest a role for KORs in the aversive effects of nicotine.

Switch from excitatory to inhibitory actions of ethanol on dopamine levels after chronic exposure: Role of kappa opioid receptors

Acute ethanol exposure is known to stimulate the dopamine system; however, chronic exposure has been shown to downregulate the dopamine system. In rodents, chronic intermittent exposure (CIE) to ethanol also increases negative affect during withdrawal, such as, increases in anxiety- and depressive-like behavior. Moreover, CIE exposure results in increased ethanol drinking and preference during withdrawal. Previous literature documents reductions in CIE-induced anxiety-, depressive-like behaviors and ethanol intake in response to kappa opioid receptor (KOR) blockade. KORs are located on presynaptic dopamine terminals in the nucleus accumbens (NAc) and inhibit release, an effect which has been linked to negative affective behaviors. Previous reports show an upregulation in KOR function following extended CIE exposure; however it is not clear whether there is a direct link between KOR upregulation and dopamine downregulation during withdrawal from CIE. This study aimed to examine the effects of KOR modulation on dopamine responses to ethanol of behaving mice exposed to air or ethanol vapor in a repeated intermittent pattern. First, we showed that KORs have a greater response to an agonist after moderate CIE compared to air exposed mice using ex vivo fast scan cyclic voltammetry. Second, using in vivo microdialysis, we showed that, in contrast to the expected increase in extracellular levels of dopamine following an acute ethanol challenge in air exposed mice, CIE exposed mice exhibited a robust decrease in dopamine levels. Third, we showed that blockade of KORs reversed the aberrant inhibitory dopamine response to ethanol in CIE exposed mice while not affecting the air exposed mice demonstrating that inhibition of KORs “rescued” dopamine responses in CIE exposed mice. Taken together, these findings indicate that augmentation of dynorphin/KOR system activity drives the reduction in stimulated (electrical and ethanol) dopamine release in the NAc. Thus, blockade of KORs is a promising avenue for developing pharmacotherapies for alcoholism.

Supersensitive Kappa Opioid Receptors Promotes Ethanol Withdrawal-Related Behaviors and Reduce Dopamine Signaling in the Nucleus Accumbens.

Background:Chronic ethanol exposure reduces dopamine transmission in the nucleus accumbens, which may contribute to the negative affective symptoms associated with ethanol withdrawal. Kappa opioid receptors have been implicated in withdrawal-induced excessive drinking and anxiety-like behaviors and are known to inhibit dopamine release in the nucleus accumbens. The effects of chronic ethanol exposure on kappa opioid receptor-mediated changes in dopamine transmission at the level of the dopamine terminal and withdrawal-related behaviors were examined.Methods:Five weeks of chronic intermittent ethanol exposure in male C57BL/6 mice were used to examine the role of kappa opioid receptors in chronic ethanol-induced increases in ethanol intake and marble burying, a measure of anxiety/compulsive-like behavior. Drinking and marble burying were evaluated before and after chronic intermittent ethanol exposure, with and without kappa opioid receptor blockade by nor-binaltorphimine (10mg/kg i.p.). Functional alterations in kappa opioid receptors were assessed using fast scan cyclic voltammetry in brain slices containing the nucleus accumbens.Results:Chronic intermittent ethanol-exposed mice showed increased ethanol drinking and marble burying compared with controls, which was attenuated with kappa opioid receptor blockade. Chronic intermittent ethanol-induced increases in behavior were replicated with kappa opioid receptor activation in naïve mice. Fast scan cyclic voltammetry revealed that chronic intermittent ethanol reduced accumbal dopamine release and increased uptake rates, promoting a hypodopaminergic state of this region. Kappa opioid receptor activation with U50,488H concentration-dependently decreased dopamine release in both groups; however, this effect was greater in chronic intermittent ethanol-treated mice, indicating kappa opioid receptor supersensitivity in this group.Conclusions:These data suggest that the chronic intermittent ethanol-induced increase in ethanol intake and anxiety/compulsive-like behaviors may be driven by greater kappa opioid receptor sensitivity and a hypodopaminergic state of the nucleus accumbens.

Dynorphin activation of kappa opioid receptor reduces neuronal excitability in the paraventricular nucleus of mouse thalamus

It has been reported that kappa opioid receptor (KOR) is expressed in the paraventricular nucleus of thalamus (PVT), a brain region associated with arousal, drug reward and stress. Although intra-PVT infusion of KOR agonist was found to inhibit drug-seeking behavior, it is still unclear whether endogenous KOR agonists directly regulate PVT neuron activity. Here, we investigated the effect of the endogenous KOR agonist dynorphin-A (Dyn-A) on the excitability of mouse PVT neurons at different developmental ages. We found Dyn-A strongly inhibited PVT neurons through a direct postsynaptic hyperpolarization. Under voltage-clamp configuration, Dyn-A evoked an obvious outward current in majority of neurons tested in anterior PVT (aPVT) but only in minority of neurons in posterior PVT (pPVT). The Dyn-A current was abolished by KOR antagonist nor-BNI, Ba2+ and non-hydrolyzable GDP analogue GDP-β-s, indicating that Dyn-A activates KOR and opens G-protein-coupled inwardly rectifying potassium channels in PVT neurons. More interestingly, by comparing Dyn-A currents in aPVT neurons of mice at various ages, we found Dyn-A evoked significant larger current in aPVT neurons from mice around prepuberty and early puberty stage. In addition, KOR activation by Dyn-A didn't produce obvious desensitization, while mu opioid receptor (MOR) activation induced obvious desensitization of mu receptor itself and also heterologous desensitization of KOR in PVT neurons. Together, our findings indicate that Dyn-A activates KOR and inhibits aPVT neurons in mice at various ages especially around puberty, suggesting a possible role of KOR in regulating aPVT-related brain function including stress response and drug-seeking behavior during adolescence.

Does the kappa opioid receptor system contribute to pain aversion?

The kappa opioid receptor (KOR) and the endogenous peptide-ligand dynorphin have received significant attention due the involvement in mediating a variety of behavioral and neurophysiological responses, including opposing the rewarding properties of drugs of abuse including opioids. Accumulating evidence indicates this system is involved in regulating states of motivation and emotion. Acute activation of the KOR produces an increase in motivational behavior to escape a threat, however, KOR activation associated with chronic stress leads to the expression of symptoms indicative of mood disorders. It is well accepted that KOR can produce analgesia and is engaged in chronic pain states including neuropathic pain. Spinal studies have revealed KOR-induced analgesia in reversing pain hypersensitivities associated with peripheral nerve injury. While systemic administration of KOR agonists attenuates nociceptive sensory transmission, this effect appears to be a stress-induced effect as anxiolytic agents, including delta opioid receptor agonists, mitigate KOR agonist-induced analgesia. Additionally, while the role of KOR and dynorphin in driving the dysphoric and aversive components of stress and drug withdrawal has been well characterized, how this system mediates the negative emotional states associated with chronic pain is relatively unexplored. This review provides evidence that dynorphin and the KOR system contribute to the negative affective component of pain and that this receptor system likely contributes to the high comorbidity of mood disorders associated with chronic neuropathic pain.

Endogenous kappa opioid receptors play a role in angiotensin II high salt diet hypertensive rats (860.24)

Central kappa opioid receptor (KOR) activation produces a marked increase in renal sympathetic nerve activity with a concurrent free water diuresis in conscious rats. However, the role of KOR in the angiotensin II high salt diet (AngII) mediated hypertension model is yet to be determined. This study examines cFOS expression in several brain regions of AngII rats as compared to normal rats. In addition, cFos expression in these brain regions was examined following intracerebroventricular (ICV) microinjection of norbinaltorphimine (Nor‐BNI; 1 μg/5μl), a selective KOR antagonist. Alternate sets of forebrain sections were processed for c‐Fos using a commercially available antibody. Sections were also double labeled with vasopressin to anatomically define specific brain regions. Fos expression was significantly increased in several lamina terminalis and hypothalamic sites. ICV nor‐BNI produced significant decreases in cFos staining in the PVN (AngII, 106 ± 12; nor‐BNI 62 ± 7; P &lt; .01) and OVLT (AngII, 132 ± 7; nor‐BNI 73 ± 5; P &lt; .05). There was no significant change in urine and sodium excretion in all groups. Altogether, this data provides new information concerning the role of KOR in the regulation of blood pressureGrant Funding Source: 5SC2HL104639‐03