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Frontiers in Endocrinology 2022Feedback from oestradiol (E2) plays a critical role in the regulation of major events in the physiological menstrual cycle including the release of gonadotrophins to... (Review)
Review
Feedback from oestradiol (E2) plays a critical role in the regulation of major events in the physiological menstrual cycle including the release of gonadotrophins to stimulate follicular growth, and the mid-cycle luteinising hormone (LH) surge that leads to ovulation. E2 predominantly exerts its action oestrogen receptor-alpha (ERα), however, as gonadotrophin releasing hormone (GnRH) neurons lack ERα, E2-feedback is posited to be indirectly mediated upstream neurons. Kisspeptin (KP) is a neuropeptide expressed in hypothalamic KP-neurons that control GnRH secretion and plays a key role in the central mechanism regulating the hypothalamic-pituitary-gonadal (HPG) axis. In the rodent arcuate (ARC) nucleus, KP is co-expressed with Neurokinin B and Dynorphin; and thus, these neurons are termed 'Kisspeptin-Neurokinin B-Dynorphin' (KNDy) neurons. ARC KP-neurons function as the 'GnRH pulse generator' to regulate GnRH pulsatility, as well as mediating negative feedback from E2. A second KP neuronal population is present in the rostral periventricular area of the third ventricle (RP3V), which includes anteroventral periventricular (AVPV) nucleus and preoptic area neurons. These RP3V KP-neurons mediate positive feedback to induce the mid-cycle luteinising hormone (LH) surge and subsequent ovulation. Here, we describe the role of KP-neurons in these two regions in mediating this differential feedback from oestrogens. We conclude by considering reproductive diseases for which exploitation of these mechanisms could yield future therapies.
Topics: Kisspeptins; Neurokinin B; Dynorphins; Luteinizing Hormone; Gonadotropin-Releasing Hormone; Neurons
PubMed: 36479214
DOI: 10.3389/fendo.2022.951938 -
Brain : a Journal of Neurology Mar 2023Increased vigilance in settings of potential threats or in states of vulnerability related to pain is important for survival. Pain disrupts sleep and conversely, sleep...
Increased vigilance in settings of potential threats or in states of vulnerability related to pain is important for survival. Pain disrupts sleep and conversely, sleep disruption enhances pain, but the underlying mechanisms remain unknown. Chronic pain engages brain stress circuits and increases secretion of dynorphin, an endogenous ligand of the kappa opioid receptor (KOR). We therefore hypothesized that hypothalamic dynorphin/KOR signalling may be a previously unknown mechanism that is recruited in pathological conditions requiring increased vigilance. We investigated the role of KOR in wakefulness, non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep in freely moving naïve mice and in mice with neuropathic pain induced by partial sciatic nerve ligation using EEG/EMG recordings. Systemic continuous administration of U69,593, a KOR agonist, over 5 days through an osmotic minipump decreased the amount of NREM and REM sleep and increased sleep fragmentation in naïve mice throughout the light-dark sleep cycle. We used KORcre mice to selectively express a Gi-coupled designer receptor activated by designer drugs (Gi-DREADD) in KORcre neurons of the hypothalamic paraventricular nucleus, a key node of the hypothalamic-pituitary-adrenal stress response. Sustained activation of Gi-DREADD with clozapine-N-oxide delivered in drinking water over 4 days, disrupted sleep in these mice in a similar way as systemic U69,593. Mice with chronic neuropathic pain also showed disrupted NREM and total sleep that was normalized by systemic administration of two structurally different KOR antagonists, norbinaltorphimine and NMRA-140, currently in phase II clinical development, or by CRISPR/Cas9 editing of paraventricular nucleus KOR, consistent with endogenous KOR activation disrupting sleep in chronic pain. Unexpectedly, REM sleep was diminished by either systemic KOR antagonist or by CRISPR/Cas9 editing of paraventricular nucleus KOR in sham-operated mice. Our findings reveal previously unknown physiological and pathophysiological roles of dynorphin/KOR in eliciting arousal. Physiologically, dynorphin/KOR signalling affects transitions between sleep stages that promote REM sleep. Furthermore, while KOR antagonists do not promote somnolence in the absence of pain, they normalized disrupted sleep in chronic pain, revealing a pathophysiological role of KOR signalling that is selectively recruited to promote vigilance, increasing chances of survival. Notably, while this mechanism is likely beneficial in the short-term, disruption of the homeostatic need for sleep over longer periods may become maladaptive resulting in sustained pain chronicity. A novel approach for treatment of chronic pain may thus result from normalization of chronic pain-related sleep disruption by KOR antagonism.
Topics: Mice; Animals; Receptors, Opioid, kappa; Dynorphins; Chronic Pain; Wakefulness; Narcotic Antagonists; Neuralgia
PubMed: 35485490
DOI: 10.1093/brain/awac153 -
Brain Research Feb 2010Stress is a complex experience that carries both aversive and motivating properties. Chronic stress causes an increase in the risk of depression, is well known to... (Review)
Review
Stress is a complex experience that carries both aversive and motivating properties. Chronic stress causes an increase in the risk of depression, is well known to increase relapse of drug seeking behavior, and can adversely impact health. Several brain systems have been demonstrated to be critical in mediating the negative affect associated with stress, and recent evidence directly links the actions of the endogenous opioid neuropeptide dynorphin in modulating mood and increasing the rewarding effects of abused drugs. These results suggest that activation of the dynorphin/kappa opioid receptor (KOR) system is likely to play a major role in the pro-addictive effects of stress. This review explores the relationship between dynorphin and corticotropin-releasing factor (CRF) in the induction of dysphoria, the potentiation of drug seeking, and stress-induced reinstatement. We also provide an overview of the signal transduction events responsible for CRF and dynorphin/KOR-dependent behaviors. Understanding the recent work linking activation of CRF and dynorphin/KOR systems and their specific roles in brain stress systems and behavioral models of addiction provides novel insight to neuropeptide systems that regulate affective state.
Topics: Animals; Brain; Comorbidity; Corticotropin-Releasing Hormone; Dynorphins; Humans; Mood Disorders; Receptors, Corticotropin-Releasing Hormone; Receptors, Opioid, kappa; Recurrence; Stress, Psychological; Substance-Related Disorders
PubMed: 19716811
DOI: 10.1016/j.brainres.2009.08.062 -
Cell Reports Jan 2023The mechanism by which arcuate nucleus kisspeptin (ARN) neurons co-expressing glutamate, neurokinin B, and dynorphin intermittently synchronize their activity to...
The mechanism by which arcuate nucleus kisspeptin (ARN) neurons co-expressing glutamate, neurokinin B, and dynorphin intermittently synchronize their activity to generate pulsatile hormone secretion remains unknown. An acute brain slice preparation maintaining synchronized ARN neuron burst firing was used alongside in vivo GCaMP GRIN lens microendoscope and fiber photometry imaging coupled with intra-ARN microinfusion. Studies in intact and gonadectomized male mice revealed that ARN neuron synchronizations result from near-random emergent network activity within the population and that this was critically dependent on local glutamate-AMPA signaling. Whereas neurokinin B operated to potentiate glutamate-generated synchronizations, dynorphin-kappa opioid tone within the network served as a gate for synchronization initiation. These observations force a departure from the existing "KNDy hypothesis" for ARN neuron synchronization. A "glutamate two-transition" mechanism is proposed to underlie synchronizations in this key hypothalamic central pattern generator driving mammalian fertility.
Topics: Mice; Male; Animals; Neurokinin B; Dynorphins; Kisspeptins; Arcuate Nucleus of Hypothalamus; Neurons; Glutamates; Hormones; Mammals
PubMed: 36640343
DOI: 10.1016/j.celrep.2022.111914 -
International Journal of Molecular... May 2023The downstream regulatory element antagonist modulator (DREAM) is a multifunctional Ca-sensitive protein exerting a dual mechanism of action to regulate several... (Review)
Review
The downstream regulatory element antagonist modulator (DREAM) is a multifunctional Ca-sensitive protein exerting a dual mechanism of action to regulate several Ca-dependent processes. Upon sumoylation, DREAM enters in nucleus where it downregulates the expression of several genes provided with a consensus sequence named dream regulatory element (DRE). On the other hand, DREAM could also directly modulate the activity or the localization of several cytosolic and plasma membrane proteins. In this review, we summarize recent advances in the knowledge of DREAM dysregulation and DREAM-dependent epigenetic remodeling as a central mechanism in the progression of several diseases affecting central nervous system, including stroke, Alzheimer's and Huntington's diseases, amyotrophic lateral sclerosis, and neuropathic pain. Interestingly, DREAM seems to exert a common detrimental role in these diseases by inhibiting the transcription of several neuroprotective genes, including the sodium/calcium exchanger isoform 3 (NCX3), brain-derived neurotrophic factor (BDNF), pro-dynorphin, and c-fos. These findings lead to the concept that DREAM might represent a pharmacological target to ameliorate symptoms and reduce neurodegenerative processes in several pathological conditions affecting central nervous system.
Topics: Kv Channel-Interacting Proteins; Repressor Proteins; Brain; Dynorphins; Cell Nucleus
PubMed: 37298129
DOI: 10.3390/ijms24119177 -
Neuropsychopharmacology : Official... Jan 2016
Review
Topics: Animals; Behavior, Addictive; Benzamides; Depressive Disorder, Major; Dynorphins; Humans; Pyrrolidines; Receptors, Opioid, kappa; Stress, Psychological
PubMed: 26657953
DOI: 10.1038/npp.2015.258 -
Current Neuropharmacology 2016Opioids are traditionally associated with pain, analgesia and drug abuse. It is now clear, however, that the opioids are central players in mood. The implications for... (Review)
Review
Opioids are traditionally associated with pain, analgesia and drug abuse. It is now clear, however, that the opioids are central players in mood. The implications for mood disorders, particularly clinical depression, suggest a paradigm shift from the monoamine neurotransmitters to the opioids either alone or in interaction with monoamine neurons. We have a special interest in dynorphin, the last of the major endogenous opioids to be isolated and identified. Dynorphin is derived from the Greek word for power, dynamis, which hints at the expectation that the neuropeptide held for its discoverers. Yet, dynorphin and its opioid receptor subtype, kappa, has always taken a backseat to the endogenous b-endorphin and the exogenous morphine that both bind the mu opioid receptor subtype. That may be changing as the dynorphin/ kappa system has been shown to have different, often opposite, neurophysiological and behavioral influences. This includes major depressive disorder (MDD). Here, we have undertaken a review of dynorphin/ kappa neurobiology as related to behaviors, especially MDD. Highlights include the unique features of dynorphin and kappa receptors and the special relation of a plant-based agonist of the kappa receptor salvinorin A. In addition to acting as a kappa opioid agonist, we conclude that salvinorin A has a complex pharmacologic profile, with potential additional mechanisms of action. Its unique neurophysiological effects make Salvinorina A an ideal candidate for MDD treatment research.
Topics: Anhedonia; Animals; Brain; Depressive Disorder, Major; Diterpenes, Clerodane; Dynorphins; Humans; Receptors, Opioid, kappa
PubMed: 26903446
DOI: 10.2174/1570159x13666150727220944 -
Cellular and Molecular Life Sciences :... Mar 2012The dynorphin/κ-opioid receptor system has been implicated in the pathogenesis and pathophysiology of several psychiatric disorders. In the present review, we present... (Review)
Review
The dynorphin/κ-opioid receptor system has been implicated in the pathogenesis and pathophysiology of several psychiatric disorders. In the present review, we present evidence indicating a key role for this system in modulating neurotransmission in brain circuits that subserve mood, motivation, and cognitive function. We overview the pharmacology, signaling, post-translational, post-transcriptional, transcriptional, epigenetic and cis regulation of the dynorphin/κ-opioid receptor system, and critically review functional neuroanatomical, neurochemical, and pharmacological evidence, suggesting that alterations in this system may contribute to affective disorders, drug addiction, and schizophrenia. We also overview the dynorphin/κ-opioid receptor system in the genetics of psychiatric disorders and discuss implications of the reviewed material for therapeutics development.
Topics: Brain; Central Nervous System Stimulants; Cyclic AMP Response Element-Binding Protein; Dynorphins; Enkephalins; Epigenesis, Genetic; Gene Expression Regulation; Humans; Mental Disorders; Models, Animal; Protein Precursors; Receptors, Opioid, kappa; Self Stimulation; Signal Transduction
PubMed: 22002579
DOI: 10.1007/s00018-011-0844-x -
Frontiers in Bioscience (Scholar... Jan 2011Reproductive function, as essential for the survival of species, is under the control of a vast array of regulatory factors that ultimately modulate the release of GnRH.... (Review)
Review
Reproductive function, as essential for the survival of species, is under the control of a vast array of regulatory factors that ultimately modulate the release of GnRH. However, GnRH neurons lack the ability to directly sense most of these signals; hence, intermediate pathways are required. Kisspeptins have recently emerged as a pivotal piece in the reproductive brain, serving primarily as conduits for central and peripheral regulatory cues of GnRH release. Different populations of hypothalamic Kiss1 neurons have been described, which mediate either the positive or negative feedback of sex steroids in the sexually differentiated brain of rodents. Kisspeptins, however, are not the only recently-appointed contributors to this integrative process. Indeed, neurokinin B (NKB) and dynorphin have been described to co-localize within Kiss1 neurons at the arcuate nucleus in different species, and may contribute to the regulation of kisspeptin release. In this work, we provide a concise overview of the major reproductive headlines of kisspeptins, focusing on their role as mediators of sex steroid feedback and their interaction with key neurotransmitters, such as NKB and dynorphin.
Topics: Animals; Arcuate Nucleus of Hypothalamus; Dynorphins; Gonadal Steroid Hormones; Gonadotropin-Releasing Hormone; Humans; Kisspeptins; Neurokinin B; Neurosecretory Systems; Neurotransmitter Agents; Reproduction; Tumor Suppressor Proteins
PubMed: 21196375
DOI: 10.2741/s150 -
Biological Psychiatry Oct 2019Schizophrenia is a debilitating mental illness that affects approximately 1% of the world's population. Despite much research in its neurobiology to aid in developing... (Review)
Review
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.
Topics: Animals; Antipsychotic Agents; Dynorphins; Humans; Narcotic Antagonists; Receptors, Opioid, kappa; Schizophrenia
PubMed: 31376930
DOI: 10.1016/j.biopsych.2019.05.012