kappa opioid receptor

κ 阿片受体
  • 文章类型: Journal Article
    背景:丹参(Epling和Játiva)是拉丁美洲人传统上用于各种药用目的的精神活性植物。SalvinorinA(SalA),S.divinorum的主要生物活性成分,是一种天然的高选择性κ阿片受体(KOR)激动剂。考虑到地诺兰和内源性海马强啡肽/κ阿片受体(KOR)系统发挥抗惊厥功能的抗炎作用,我们假设SalA可能是治疗癫痫的潜在候选药物.这里,我们在动物模型和体外模型中确定了SalA是否改善了癫痫发作和神经元损伤,并研究了其潜在机制。
    方法:在通过Racine分类评估癫痫发作后,通过毛果芸香碱诱导小鼠癫痫模型。海马组织获得遗传,蛋白质,和组织学调查。此外,脂多糖(LPS)激活的BV2小胶质细胞用于验证SalA的抗炎和小胶质细胞极化调节作用。
    结果:SalA治疗显着延长了癫痫状态的潜伏期(SE)并缩短了毛果芸香碱诱导模型中SE的持续时间。它还通过激活AMPK/JNK/p-38MAPK通路和抑制海马组织中的凋亡相关蛋白来减轻神经元损伤。此外,SalA通过调节小胶质细胞极化,剂量依赖性地降低了SE小鼠和LPS激活的BV2小胶质细胞中促炎细胞因子的表达,并增加了抗炎因子的水平。此外,SalA在体外的作用被KOR拮抗剂nor-BNI完全阻断。
    结论:SalA治疗通过调节小胶质M1/M2极化抑制炎症反应,从而在毛果芸香碱诱导的模型中保护癫痫发作和神经元损伤。本研究可为SalA及其类似物的临床应用提供理论依据,并为抗癫痫药物的开发提供新的见解。
    BACKGROUND: Salvia divinorum (Epling and Játiva) is a psychoactive plant traditionally used by the Latinos for various medicinal purposes. Salvinorin A (Sal A), the main bioactive constituent of S. divinorum, is a natural highly selective kappa opioid receptor (KOR) agonist. Considering the anti-inflammatory effect of S. divinorum and endogenous hippocampal dynorphin/ kappa opioid receptor (KOR) system playing an anticonvulsant function, we hypothesis that Sal A can be a potential candidate to treat epilepsy. Here, we identified whether Sal A ameliorated epileptic seizures and neuronal damages in animal model and in vitro model and investigated its underlying mechanisms.
    METHODS: Mice epilepsy model was induced by pilocarpine following seizures assessed by Racine classification. Hippocampus tissues were obtained for genetic, protein, and histological investigation. Furthermore, lipopolysaccharide (LPS)-activated BV2 microglial cells were utilized to validate the anti-inflammatory and microglia polarization regulation effects of Sal A.
    RESULTS: Sal A treatment significantly prolonged the latency to status epileptics (SE) and shortened the duration of SE in the pilocarpine-induced model. It also alleviated neuronal damages via activation of the AMPK/JNK/p-38 MAPK pathway and inhibition of apoptosis-related protein in hippocampus tissues. Furthermore, Sal A dose-dependently reduced microglia-mediated expression of pro-inflammatory cytokines and increased anti-inflammatory factors levels in SE mice and LPS-activated BV2 microglial cells by regulating microglia polarization. In addition, the effect of Sal A in vitro was totally blocked by KOR antagonist nor-BNI.
    CONCLUSIONS: Sal A treatment protects against epileptic seizures and neuronal damages in pilocarpine-induced models by suppressing the inflammation response through regulating microglial M1/M2 polarization. This study might serve as a theoretical basis for clinical applications of Sal A and its analogs and provide a new insight into the development of anti-seizure drugs.
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  • 文章类型: Journal Article
    快感缺失和剥夺是经常由患有压力相关疾病的个体认可的情绪。Kappa阿片受体(KOR)激活可引起负面情绪,最近的临床证据表明,KOR拮抗作用可缓解跨诊断队列患者的快感缺失。然而,KOR激活和拮抗在调节动机中的行为后果,通过时间表控制的行为表现评估,没有预先存在的条件(压力或物质使用),尚未正式评估。为了解决文献中的这一差距,本报告利用雄性和雌性SpragueDawley大鼠(1)评估选择性KOR激动剂U50,488对在渐进比例(PR)方案下对蔗糖颗粒反应的动物表现的影响,以及(2)确定单独使用短效KOR拮抗剂LY2444296和对U50,488介导的PR表现降低的影响.总的来说,U50,4885mg/kg显着降低了动物获得的断点和奖励数量。这发生在没有运动障碍的情况下,并且独立于满足的证据。LY2444296单独给药时没有改变PR性能,但有效阻断了U50,488诱导的缺陷。为了进一步描绘这些反应减少背后的行为改变,对会议前15分钟的公关表现进行了更详细的分析,动物获得增强剂最多的时期。在此期间,U50,488增加了加固后暂停的长度,并降低了PR时间表上的运行率。由KOR的急性激活产生的这些行为变化与啮齿动物的努力相关动机的减少是一致的。这些数据有助于理解KOR如何调节动机,这对于未来评估压力环境下的表现以及评估KOR拮抗剂如何缓解与压力相关的不良行为至关重要。
    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.
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  • 文章类型: Journal Article
    酒精使用障碍(AUD)是一种慢性复发性疾病,对个体有害,家族性,和社会水平。尽管AUD是美国最高可预防的死亡原因之一,考虑到疾病的异质性和批准的药物数量有限,用于治疗AUD的疗法还不够.为了提供更好的药理策略,重要的是要了解AUD的神经基础。证据表明,内源性强啡肽(DYN)/κ阿片受体(KOR)系统在焦虑和负性情绪状态下募集,以促进适应不良的行为调节。伏隔核壳(AcbSh),调解动机和情绪过程,是中脑边缘多巴胺系统和扩展杏仁核的组成部分,在AcbShDYN/KOR系统中,是与酒精的强化作用(阳性和阴性)和神经适应相关的重要部位,已被证明在AUD中诱发适应不良症状。我们之前已经证明,在扩展杏仁核的其他节点中,位点特异性KOR拮抗作用可以区分酒精依赖和戒断的不同症状。在目前的研究中,我们研究了KOR信号在雄性Wistar大鼠AcbSh中的作用,消极情感样行为的衡量标准,酒精依赖急性酒精戒断期间的生理症状。诱导酒精依赖,大鼠暴露于慢性间歇性乙醇蒸气14小时/天,持续三个月,在此期间实现了酒精自我给药的稳定升级,随后出现了药物AcbShKOR拮抗作用.结果表明,AcbShKOR拮抗作用显着降低了酒精摄入量的增加和负面的情感样状态,但并未改变戒断的躯体症状。了解这些不同驱动因素的相对贡献对于理解和告知酒精依赖的治疗功效方法很重要,并进一步强调KOR/DYN系统作为AUD治疗目标的重要性。
    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.
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  • 文章类型: Journal Article
    轻度创伤性脑损伤(mTBI)会增加情感障碍的风险,焦虑和物质使用障碍。侧突(LHb)在精神疾病的病理生理中起着重要作用。最近,我们使用重复的闭合性颅脑损伤mTBI模型证明了mTBI诱导的LHb过度活跃与雄性小鼠的动机缺陷之间的因果关系。对创伤性脑损伤有反应的主要神经调节系统,强啡肽/κ阿片受体(Dyn/KOR)系统影响情感状态并调节LHb活性。然而,mTBI对LHb功能的KOR神经调节的影响尚不清楚。这里,我们首先在雄性和雌性Cre小鼠品系中使用逆行追踪,并确定了几种主要的KOR表达和两个突出的Dyn表达输入投射到小鼠LHb,突出显示内侧前额叶皮质(mPFC)和下丘脑腹内侧核(VMH)作为主要的LHb投射Dyn输入,调节KOR信号传导到LHb。然后,我们在功能上评估了损伤后4周雄性和雌性假手术和mTBI小鼠的LHb中自发突触活性的体外KOR调节的作用。我们观察到谷氨酸和GABA从突触前末端自发释放到LHb神经元的性别特异性差异,与雄性小鼠相比,雌性的突触前谷氨酸和GABA释放水平更高。然而,在雄性和雌性假手术和mTBI小鼠之间,KOR对LHb内自发E/I比率和突触驱动比率的影响没有差异。KOR激活通常抑制自发的谷氨酸能传递,而不改变GABA能传递,导致假小鼠LHb神经元的净自发E/I和突触驱动比的显着但性别相似的降低。在mTBI之后,而LHb谷氨酸能突触对KOR激活的反应保持完整,LHbGABA能突触获得了对KOR介导的抑制的额外敏感性,在mTBI小鼠的LHb神经元中,我们观察到响应KOR刺激的GABA释放概率降低。对KOR激活诱导的自发突触比率的百分比变化的进一步分析显示,与性别无关,mTBI将mTBI小鼠子集中KOR驱动的LHb神经元突触抑制(通常在假小鼠中观察到)向突触兴奋转换,从而导致mTBI诱导的LHb内KOR作用的分歧。总的来说,我们发现了投射到小鼠LHb的主要Dyn/KOR表达突触输入的来源。我们证明了LHb内Dyn/KOR信号的参与在小鼠LHb内提供了全局的KOR驱动的突触抑制,而与性别无关。通过mTBI对LHbGABA能传递的KOR介导的作用的额外参与可能导致mTBI后的E/I失衡,Dyn/KOR信号传导作为mTBI小鼠亚群的LHb神经元的去抑制机制。
    Mild traumatic brain injury (mTBI) increases the risk of affective disorders, anxiety and substance use disorder. The lateral habenula (LHb) plays an important role in pathophysiology of psychiatric disorders. Recently, we demonstrated a causal link between mTBI-induced LHb hyperactivity due to excitation/inhibition (E/I) imbalance and motivational deficits in male mice using a repetitive closed head injury mTBI model. A major neuromodulatory system that is responsive to traumatic brain injuries, influences affective states and also modulates LHb activity is the dynorphin/kappa opioid receptor (Dyn/KOR) system. However, the effects of mTBI on KOR neuromodulation of LHb function are unknown. Here, we first used retrograde tracing in male and female Cre mouse lines and identified several major KOR-expressing and two prominent Dyn-expressing inputs projecting to the mouse LHb, highlighting the medial prefrontal cortex (mPFC) and the ventromedial nucleus of the hypothalamus (VMH) as the main LHb-projecting Dyn inputs that regulate KOR signaling to the LHb. We then functionally evaluated the effects of in vitro KOR modulation of spontaneous synaptic activity within the LHb of male and female sham and mTBI mice at 4 week post-injury. We observed sex-specific differences in spontaneous release of glutamate and GABA from presynaptic terminals onto LHb neurons with higher levels of presynaptic glutamate and GABA release in females compared to male mice. However, KOR effects on the spontaneous E/I ratios and synaptic drive ratio within the LHb did not differ between male and female sham and mTBI mice. KOR activation generally suppressed spontaneous glutamatergic transmission without altering GABAergic transmission, resulting in a significant but sex-similar reduction in net spontaneous E/I and synaptic drive ratios in LHb neurons of sham mice. Following mTBI, while responses to KOR activation at LHb glutamatergic synapses remained intact, LHb GABAergic synapses acquired an additional sensitivity to KOR-mediated inhibition where we observed a reduction in GABA release probability in response to KOR stimulation in LHb neurons of mTBI mice. Further analysis of percent change in spontaneous synaptic ratios induced by KOR activation revealed that independent of sex mTBI switches KOR-driven synaptic inhibition of LHb neurons (normally observed in sham mice) in a subset of mTBI mice toward synaptic excitation resulting in mTBI-induced divergence of KOR actions within the LHb. Overall, we uncovered the sources of major Dyn/KOR-expressing synaptic inputs projecting to the mouse LHb. We demonstrate that an engagement of intra-LHb Dyn/KOR signaling provides a global KOR-driven synaptic inhibition within the mouse LHb independent of sex. The additional engagement of KOR-mediated action on LHb GABAergic transmission by mTBI could contribute to the E/I imbalance after mTBI, with Dyn/KOR signaling serving as a disinhibitory mechanism for LHb neurons of a subset of mTBI mice.
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  • 文章类型: Journal Article
    我们最近开发了一系列nalfurafine类似物(TK10,TK33和TK35),可用作非成瘾候选镇痛药。这些化合物是κ和δ阿片受体(KOR和DOR,分别)并在小鼠温水尾浸泡试验中产生抗伤害感受,而未能产生典型的μ阿片受体(MOR)介导的副作用。温水尾部浸泡试验是一种对疼痛刺激行为的测定,该行为易受产生运动障碍的药物的假阳性镇痛样作用的影响。因此,这项研究评估了TK10,TK33和TK35,在一项最近验证的试验中,对较不容易受到假阳性效应影响的小鼠的疼痛相关行为抑郁进行了评估.为了比较,我们还评估了MOR激动剂/镇痛氢可酮(阳性对照)的作用,神经激肽1受体(NK1R)拮抗剂阿瑞吡坦(阴性对照),作为一种选择性的KOR激动剂,SNC80作为选择性DOR激动剂,和nalfurafine/SNC80混合物。腹膜内注射稀乳酸(IP乳酸)可作为有害刺激,以抑制雄性和雌性ICR小鼠的垂直和水平运动活动。IP乳酸诱导的运动抑制被氢可酮缓解,但阿瑞匹坦不能缓解,nalfurafine,SNC80,nalfurafine/SNC80混合物,或KOR/DOR激动剂。这些结果表明,在推进混合作用KOR/DOR激动剂作为候选镇痛药时需要谨慎。
    We recently developed a series of nalfurafine analogs (TK10, TK33, and TK35) that may serve as non-addictive candidate analgesics. These compounds are mixed-action agonists at the kappa and delta opioid receptors (KOR and DOR, respectively) and produce antinociception in a mouse warm-water tail-immersion test while failing to produce typical mu opioid receptor (MOR)-mediated side effects. The warm-water tail-immersion test is an assay of pain-stimulated behavior vulnerable to false-positive analgesic-like effects by drugs that produce motor impairment. Accordingly, this study evaluated TK10, TK33, and TK35 in a recently validated assay of pain-related behavioral depression in mice that are less vulnerable to false-positive effects. For comparison, we also evaluated the effects of the MOR agonist/analgesic hydrocodone (positive control), the neurokinin 1 receptor (NK1R) antagonist aprepitant (negative control), nalfurafine as a selective KOR agonist, SNC80 as a selective DOR agonist, and a nalfurafine/SNC80 mixture. Intraperitoneal injection of dilute lactic acid (IP lactic acid) served as a noxious stimulus to depress vertical and horizontal locomotor activity in male and female ICR mice. IP lactic acid-induced locomotor depression was alleviated by hydrocodone but not by aprepitant, nalfurafine, SNC80, the nalfurafine/SNC80 mixture, or the KOR/DOR agonists. These results suggest that caution is warranted in advancing mixed-action KOR/DOR agonists as candidate analgesics.
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  • 文章类型: Journal Article
    κ阿片受体(KOR)激动剂由于其镇痛特性以及比作用于μ阿片受体的阿片样物质更低的滥用潜力,代表了有希望的缓解疼痛的治疗剂。然而,典型的KOR激动剂产生镇静和烦躁不安。先前的研究表明,G蛋白信号传导偏向的KOR激动剂可能提供了一种消除所需镇痛特性与不希望的副作用的方法。在本文中,我们报道了一系列新的G蛋白信号偏向的KOR激动剂,在先前报道的KOR激动剂中涉及-S-→-CH2-替代,三唑1.1.有了优化的碳接头,进一步开发支架以研究三唑核心的附件.描述了该系列的结构-活性关系研究,包括几种类似物,与三唑1.1相比,它们显示出增强的效力,同时保持G蛋白信号传导偏差。
    Kappa opioid receptor (KOR) agonists represent promising therapeutics for pain relief due to their analgesic properties along with lower abuse potential than opioids that act at the mu opioid receptor. However, typical KOR agonists produce sedation and dysphoria. Previous studies have shown that G protein signaling-biased KOR agonists may present a means to untangle the desired analgesic properties from undesired side effects. In this paper, we report a new series of G protein signaling-biased KOR agonists entailing -S- → -CH2- replacement in a previously reported KOR agonist, triazole 1.1. With an optimized carbon linker in hand, further development of the scaffold was undertaken to investigate the appendages of the triazole core. The structure-activity relationship study of this series is described, including several analogues that display enhanced potency while maintaining G protein-signaling bias compared to triazole 1.1.
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  • 文章类型: Journal Article
    本文是关于内源性阿片系统研究的年度选集综述的连续第46期,总结2023年发表的研究分子行为效应的文章,阿片多肽和受体的药理学和遗传操作以及阿片/阿片激动剂和拮抗剂的作用。该综述细分为以下特定主题:内源性阿片类药物及其受体的分子生化作用和神经化学定位研究(1),这些阿片类肽和受体在动物(2)和人类(3)的疼痛和镇痛中的作用,非阿片类镇痛药的阿片类敏感和阿片类不敏感作用(4),阿片类肽和受体参与耐受性和依赖性(5),压力和社会地位(6),学习和记忆(7),吃和喝(8)吸毒和酗酒(9),性活动和荷尔蒙,怀孕,发育和内分泌学(10),精神疾病和情绪(11),癫痫发作和神经系统疾病(12),电相关活动和神经生理学(13),一般活动和运动(14),胃肠,肾和肝功能(15),心血管反应(16),呼吸和体温调节(17),和免疫反应(18)。
    This paper is the forty-sixth consecutive installment of the annual anthological review of research concerning the endogenous opioid system, summarizing articles published during 2023 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides and receptors as well as effects of opioid/opiate agonists and antagonists. The review is subdivided into the following specific topics: molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors (1), the roles of these opioid peptides and receptors in pain and analgesia in animals (2) and humans (3), opioid-sensitive and opioid-insensitive effects of nonopioid analgesics (4), opioid peptide and receptor involvement in tolerance and dependence (5), stress and social status (6), learning and memory (7), eating and drinking (8), drug and alcohol abuse (9), sexual activity and hormones, pregnancy, development and endocrinology (10), mental illness and mood (11), seizures and neurologic disorders (12), electrical-related activity and neurophysiology (13), general activity and locomotion (14), gastrointestinal, renal and hepatic functions (15), cardiovascular responses (16), respiration and thermoregulation (17), and immunological responses (18).
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  • 文章类型: Journal Article
    压力已被证明可以促进暴饮暴食行为的发展和持续。然而,应激诱导暴饮暴食行为的神经回路机制在很大程度上没有报道。内源性强啡肽(dyn)/κ阿片样受体(KOR)阿片样神经肽系统已被公认为是压力无张力成分的关键介质。这里,我们旨在剖析应激诱导的暴饮暴食行为的强迫性能控制的基础。我们首先建立了应激诱导的暴饮暴食行为的小鼠行为模型。我们发现,暴露在压力下的小鼠增加了他们熟悉的可口食物的摄取量(高脂肪,高糖,HPD)与非应激小鼠相比。经过全脑分析,我们在Claustrum(CLA)中分离出强大的cfos阳性细胞,具有高度丰富的KOR表达的皮质下结构,跟随压力引起的暴饮暴食行为。我们报告说,使用局部药理学和局部删除KOR,CLA中的KOR信号传导对于这种升高的应激引起的暴饮暴食行为是必需的。使用纤维光度法进行的体内钙记录显示,在HPD进食发作开始时,CLA中存在抑制回路结构。我们使用基因编码的强啡肽生物传感器进一步建立了这种行为的内源性强啡肽能控制的动力学,Klight.结合1光子单细胞钙成像,我们报告了在应激诱导的暴饮暴食过程中与CLA人群的显着异质性,这种行为会减弱局部强啡肽的张力。此外,我们分离出岛前皮层(aIC)作为CLA中内源性强啡肽传入的潜在来源。通过表征CLA内的神经回路和肽能机制,我们发现了一条涉及内源性阿片类药物调节应激诱导暴饮暴食的途径。
    Stress has been shown to promote the development and persistence of binge eating behaviors. However, the neural circuit mechanisms for stress-induced binge-eating behaviors are largely unreported. The endogenous dynorphin (dyn)/kappa opioid receptor (KOR) opioid neuropeptide system has been well established to be a crucial mediator of the anhedonic component of stress. Here, we aimed to dissect the basis of dynorphinergic control of stress-induced binge-like eating behavior. We first established a mouse behavioral model for stress-induced binge-like eating behaviors. We found that mice exposed to stress increased their food intake of familiar palatable food (high fat, high sugar, HPD) compared to non-stressed mice. Following a brain-wide analysis, we isolated robust cFos-positive cells in the Claustrum (CLA), a subcortical structure with highly abundant KOR expression, following stress-induced binge-eating behavior. We report that KOR signaling in CLA is necessary for this elevated stress-induced binge eating behavior using local pharmacology and local deletion of KOR. In vivo calcium recordings using fiber photometry revealed a disinhibition circuit structure in the CLA during the initiation of HPD feeding bouts. We further established the dynamics of endogenous dynorphinergic control of this behavior using a genetically encoded dynorphin biosensor, Klight. Combined with 1-photon single-cell calcium imaging, we report significant heterogeneity with the CLA population during stress-induced binge eating and such behavior attenuates local dynorphin tone. Furthermore, we isolate the anterior Insular cortex (aIC) as the potential source of endogenous dynorphin afferents in the CLA. By characterizing neural circuits and peptidergic mechanisms within the CLA, we uncover a pathway that implicates endogenous opioid regulation stress-induced binge eating.
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  • 文章类型: Journal Article
    目的:κ阿片受体(KOR)信号参与骨关节炎(OA)的关节发育和炎症,而生化机制仍未阐明。本研究旨在探讨KOR激活的下游分子事件,为OA病理学提供新的观点。
    方法:U50,488H,选择性KOR激动剂,作为OA模型,在内侧半月板(DMM)失稳后关节内注射小鼠,以PBS注射作为对照。通过热板试验和红色固体绿色染色评估行为和组织学评估,分别。通过RNA-seq评估mRNA和蛋白质表达的变化,RT-qPCR,用TNF-α或TNF-αU50,488H处理的软骨细胞的免疫组织化学和蛋白质印迹(WB)。与KOR相互作用的蛋白质使用邻近标记然后通过质谱进行探索,然后通过共免疫沉淀(Co-IP)测定和免疫荧光(IF)进行验证。
    结果:在DMM小鼠中,当KOR激活时,OA诱导的疼痛减轻并且软骨退化减轻。在软骨细胞中,KOR的激活逆转了MMP的上调,IL-6,IL-1β和磷酸化(p-)STAT3,由TNF-α刺激,而NF-κB的表达,MAPK和AKT信号没有逆转。RNA-seq和IF结果表明,在TNF-α刺激下,KOR激活明显减少了软骨细胞中STAT3的核易位。减少可能是由于质膜中KOR和STAT3的结合,通过邻近标签和Co-IP结果显示。
    结论:KOR激活保护软骨免受OA,这种保护作用主要是通过螯合STAT3在质膜上发挥的,导致STAT3依赖性免疫反应失活,否则会导致OA。
    OBJECTIVE: Kappa opioid receptor (KOR) signaling is involved in joint development and inflammation in Osteoarthritis (OA), while the biochemical mechanism remains unclarified. This study aims to investigate downstream molecular events of KOR activation, to provide novel perspectives in OA pathology.
    METHODS: U50,488H, a selective KOR agonist, was intra-articularly injected in mice upon destabilization of the medial meniscus (DMM) as OA models, with PBS injection as control. The behavioral and histological evaluation was assessed by hot plate test and red solid green staining, respectively. Alterations in mRNA and protein expression were assessed by RNA-seq, RT-qPCR, immunohistochemistry and western blotting (WB) in chondrocytes treated with TNF-α or TNF-α + U50,488H. Proteins interacted with KOR were explored using proximity labeling followed by mass spectrometry and then testified by co-immunoprecipitation (Co-IP) assay and immunofluorescence (IF).
    RESULTS: OA-induced pain was reduced and cartilage degeneration was alleviated upon KOR activation in DMM mice. In chondrocytes, activation of KOR reversed the upregulation of MMPs, IL-6, IL-1β and phosphorylated(p-) STAT3, stimulated by TNF-α, while the expression of NF-κB, MAPKs and AKT signaling weren\'t reversed. RNA-seq and IF results presented that KOR activation evidently reduced STAT3 nuclear translocation in chondrocytes upon TNF-α stimuli. The reduction may be resulted from the binding of KOR and STAT3 in the plasma membrane, revealed by proximity labeling and Co-IP results.
    CONCLUSIONS: KOR activation protects cartilage from OA, and this protective effect is mainly exerted via sequestering STAT3 on the plasma membrane, resulting in inactivation of STAT3-dependent immune responses which otherwise contributes to OA.
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  • 文章类型: Journal Article
    许多滥用药物,包括酒精,破坏背侧纹状体谷氨酸突触的长期突触抑制(LTD)。这种破坏对于由G蛋白偶联受体(GPCR)介导的许多形式的LTD是常见的,所述G蛋白偶联受体通过G蛋白的抑制性Gi/o类发出信号。LTD的损失被认为是介导与物质使用障碍发展相关的行为变化。我们先前在多项研究中表明,由Gi/o偶联μ阿片受体介导的LTD被青春期和成年小鼠体内阿片样物质和酒精暴露所破坏。我们以前的一项研究表明,由δ和κ阿片受体介导的LTD对体内阿片暴露的LTD干扰特性具有抗性。我们假设δ和κ阿片受体介导的LTD将是可推广的观察结果的例外,即背侧纹状体Gi/o偶联受体LTD的形式被滥用药物破坏。具体来说,我们预测这些形式的LTD将抵抗饮酒的有害影响,就像他们对阿片类药物暴露有抵抗力一样。的确,在成年雄性小鼠中饮酒3周,δ和κ阿片受体介导的LTD在谷氨酸能输入到背外侧纹状体中的直接途径和间接途径中的多刺神经元时不受酒精的影响。这些数据表明,酒精对GPCR介导的LTD的影响在所有类型的Gi/o偶联的GPCR中都不是可推广的。
    Many drugs of abuse, including alcohol, disrupt long-term synaptic depression (LTD) at dorsal striatal glutamate synapses. This disruption is common to many forms of LTD that are mediated by G protein coupled receptors (GPCRs) that signal through the inhibitory Gi/o class of G proteins. A loss of LTD is thought to mediate behavioral changes associated with the development of substance use disorders. We have previously shown in multiple studies that LTD mediated by the Gi/o-coupled mu opioid receptor is disrupted by in vivo opioid and alcohol exposure in adolescent and adult mice. One of our previous studies suggested that LTD mediated by delta and kappa opioid receptors was resistant to the LTD-disrupting properties of in vivo opioid exposure. We hypothesized that delta and kappa opioid receptor-mediated LTD would be exceptions to the generalizable observation that forms of dorsal striatal Gi/o-coupled receptor LTD are disrupted by drugs of abuse. Specifically, we predicted that these forms of LTD would be resistant to the deleterious effects of alcohol consumption, just as they were resistant to opioid exposure. Indeed, in adult male mice that drank alcohol for 3 weeks, delta and kappa opioid receptor-mediated LTD at glutamatergic inputs to direct pathway and indirect pathway medium spiny neurons in the dorsolateral striatum was unaffected by alcohol. These data demonstrate that alcohol effects on GPCR-mediated LTD are not generalizable across all types of Gi/o-coupled GPCRs.
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