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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 -
Addiction Biology Sep 2023Chronic exposure to methamphetamine (METH) causes severe and persistent cognitive impairment. The present study aimed to investigate the role of dynorphin/κ opioid...
Chronic exposure to methamphetamine (METH) causes severe and persistent cognitive impairment. The present study aimed to investigate the role of dynorphin/κ opioid receptor (KOR) system in the development of METH-induced cognitive impairment. We found that mice showed significant cognitive impairment in the novel object recognition test (NOR) following daily injections of METH (10 mg/kg) for seven consecutive days. Systemic blockade of KOR prevented METH-induced cognitive impairment by pretreatment of the selective KOR antagonist norBNI (10 mg/kg, i.p.) or KOR deletion. Then, significant increased dynorphin and KOR mRNA were observed exclusively in prelimbic cortex (PL) other than infralimbic cortex. Finally, microinjection with norBNI into PL also improved cognitive memory in METH-treated mice using NOR and spontaneous alternation behaviour test. Our results demonstrated that dynorphin/KOR system activation in PL may be a possible mechanism for METH-induced cognitive impairment and shed light on KOR antagonists as a potential neuroprotective agent against the cognitive deficits induced by drug abuse.
Topics: Animals; Mice; Dynorphins; Receptors, Opioid, kappa; Cognitive Dysfunction; Cognition Disorders; Methamphetamine; Narcotic Antagonists
PubMed: 37644896
DOI: 10.1111/adb.13323 -
Current Opinion in Pharmacology Dec 2022Gonadotropin-releasing hormone (GnRH) is the final output of the central nervous system that drives fertility. A characteristic of GnRH secretion is its pulsatility,... (Review)
Review
Gonadotropin-releasing hormone (GnRH) is the final output of the central nervous system that drives fertility. A characteristic of GnRH secretion is its pulsatility, which is driven by a pulse generator. Each GnRH pulse triggers a luteinizing hormone (LH) pulse. However, the puzzle has been to reconcile the synchronicity of GnRH neurons with the scattered hypothalamic distribution of their cell bodies. A leap toward understanding GnRH pulses was the discovery of kisspeptin neurons near the distal processes of GnRH neurons, which secrete kisspeptins, potent excitatory neuropeptides on GnRH neurons, and equipped with dual, but opposite, self-modulatory neuropeptides, neurokinin B and dynorphin. Over the last decade, this cell-to-cell communication has been dissected in animal models. Today the 50-year quest for the basic mechanism of GnRH pulse generation may be over, but questions about its physiological tuning remain. Here is an overview of recent basic research that frames translational research.
Topics: Animals; Gonadotropin-Releasing Hormone; Arcuate Nucleus of Hypothalamus; Neurokinin B; Kisspeptins; Neurons
PubMed: 36347163
DOI: 10.1016/j.coph.2022.102316 -
Journal of Neuroendocrinology May 2022The concept that different systems control episodic and surge secretion of gonadotropin-releasing hormone (GnRH) was well established by the time that GnRH was... (Review)
Review
The concept that different systems control episodic and surge secretion of gonadotropin-releasing hormone (GnRH) was well established by the time that GnRH was identified and formed the framework for studies of the physiological roles of GnRH, and later kisspeptin. Here, we focus on recent studies identifying the neural mechanisms underlying these two modes of secretion, with an emphasis on their core components. There is now compelling data that kisspeptin neurons in the arcuate nucleus that also contain neurokinin B (NKB) and dynorphin (i.e., KNDy cells) and their projections to GnRH dendrons constitute the GnRH pulse generator in mice and rats. There is also strong evidence for a similar role for KNDy neurons in sheep and goats, and weaker data in monkeys and humans. However, whether KNDy neurons act on GnRH dendrons and/or GnRH soma and dendrites that are found in the mediobasal hypothalamus (MBH) of these species remains unclear. The core components of the GnRH/luteinising hormone surge consist of an endocrine signal that initiates the process and a neural trigger that drives GnRH secretion during the surge. In all spontaneous ovulators, the core endocrine signal is a rise in estradiol secretion from the maturing follicle(s), with the site of estrogen positive feedback being the rostral periventricular kisspeptin neurons in rodents and neurons in the MBH of sheep and primates. There is considerable species variations in the neural trigger, with three major classes. First, in reflex ovulators, this trigger is initiated by coitus and carried to the hypothalamus by neural or vascular pathways. Second, in rodents, there is a time of day signal that originates in the suprachiasmatic nucleus and activates rostral periventricular kisspeptin neurons and GnRH soma and dendrites. Finally, in sheep nitric oxide-producing neurons in the ventromedial nucleus, KNDy neurons and rostral kisspeptin neurons all appear to participate in driving GnRH release during the surge.
Topics: Animals; Arcuate Nucleus of Hypothalamus; Dendrimers; Dynorphins; Gonadotropin-Releasing Hormone; Kisspeptins; Mice; Neurokinin B; Rats; Sheep
PubMed: 35107859
DOI: 10.1111/jne.13094 -
International Journal of Molecular... Jan 2024Tobacco smoking is the leading cause of preventable death and disease. Although there are some FAD-approved medicines for controlling smoking, the relapse rate remains... (Review)
Review
Tobacco smoking is the leading cause of preventable death and disease. Although there are some FAD-approved medicines for controlling smoking, the relapse rate remains very high. Among the factors that could induce nicotine relapse, stress might be the most important one. In the last decades, preclinical studies have generated many new findings that lead to a better understanding of stress-induced relapse of nicotine-seeking. Several molecules such as α3β4 nicotinic acetylcholine receptor, α2-adrenergic receptors, cannabinoid receptor 1, trace amine-associated receptor 1, and neuropeptide systems (corticotropin-releasing factor and its receptors, dynorphine and kappa opioid receptor) have been linked to stress-induced nicotine relapse. In this review, we discuss recent advances in the neurobiology, treatment targets, and potential therapeutics of stress-induced nicotine relapse. We also discuss some factors that may influence stress-induced nicotine relapse and that should be considered in future studies. In the final section, a perspective on some research directions is provided. Further investigation on the neurobiology of stress-induced nicotine relapse will shed light on the development of new medicines for controlling smoking and will help us understand the interactions between the stress and reward systems in the brain.
Topics: Humans; Nicotine; Tobacco Use Disorder; Reward; Corticotropin-Releasing Hormone; Recurrence; Receptors, Nicotinic
PubMed: 38338760
DOI: 10.3390/ijms25031482 -
Frontiers in Neurology 2023A lack of treatment options for temporal lobe epilepsy (TLE) demands an urgent quest for new therapies to recover neuronal damage and reduce seizures, potentially... (Review)
Review
A lack of treatment options for temporal lobe epilepsy (TLE) demands an urgent quest for new therapies to recover neuronal damage and reduce seizures, potentially interrupting the neurotoxic cascades that fuel hyper-excitability. Endogenous opioids, along with their respective receptors, particularly dynorphin and kappa-opioid-receptor, present as attractive candidates for controlling neuronal excitability and therapeutics in epilepsy. We perform a critical review of the literature to evaluate the role of opioids in modulating microglial function and morphology in epilepsy. We find that, in accordance with anticonvulsant effects, acute opioid receptor activation has unique abilities to modulate microglial activation through toll-like 4 receptors, regulating downstream secretion of cytokines. Abnormal activation of microglia is a dominant feature of neuroinflammation, and inflammatory cytokines are found to aggravate TLE, inspiring the challenge to alter microglial activation by opioids to suppress seizures. We further evaluate how opioids can modulate microglial activation in epilepsy to enhance neuroprotection and reduce seizures. With controlled application, opioids may interrupt inflammatory cycles in epilepsy, to protect neuronal function and reduce seizures. Research on opioid-microglia interactions has important implications for epilepsy and healthcare approaches. However, preclinical research on opioid modulation of microglia supports a new therapeutic pathway for TLE.
PubMed: 38249734
DOI: 10.3389/fneur.2023.1298489 -
Handbook of Experimental Pharmacology 2022Cortical circuits control a plethora of behaviors, from sensation to cognition. The cortex is enriched with neuropeptides and receptors that play a role in information... (Review)
Review
Cortical circuits control a plethora of behaviors, from sensation to cognition. The cortex is enriched with neuropeptides and receptors that play a role in information processing, including opioid peptides and their cognate receptors. The dynorphin (DYN)/kappa-opioid receptor (KOR) system has been implicated in the processing of sensory and motivationally-charged emotional information and is highly expressed in cortical circuits. This is important as dysregulation of DYN/KOR signaling in limbic and cortical circuits has been implicated in promoting negative affect and cognitive deficits in various neuropsychiatric disorders. However, research investigating the role of this system in controlling cortical circuits and computations therein is limited. Here, we review the (1) basic anatomy of cortical circuits, (2) anatomical architecture of the cortical DYN/KOR system, (3) functional regulation of cortical synaptic transmission and microcircuit function by the DYN/KOR system, (4) regulation of behavior by the cortical DYN/KOR system, (5) implications for the DYN/KOR system for human health and disease, and (6) future directions and unanswered questions for the field. Further work elucidating the role of the DYN/KOR system in controlling cortical information processing and associated behaviors will be of importance to increasing our understanding of principles underlying neuropeptide modulation of cortical circuits, mechanisms underlying sensation and perception, motivated and emotional behavior, and cognition. Increased emphasis in this area of study will also aid in the identification of novel ways to target the DYN/KOR system to treat neuropsychiatric disorders.
Topics: Dynorphins; Humans; Opioid Peptides; Receptors, Opioid, kappa; Synaptic Transmission
PubMed: 33580392
DOI: 10.1007/164_2021_440 -
Problemy Endokrinologii Aug 2020Endomorphins – endogenous tetrapeptides with the highest affinity for the µ-opioid receptor. Currently, two tetrapeptides that differ in one amino acid... (Review)
Review
Endomorphins – endogenous tetrapeptides with the highest affinity for the µ-opioid receptor. Currently, two tetrapeptides that differ in one amino acid residue have been isolated and characterized. The structure of endomorphins differs from the structure of members of three main families of opioid peptides: endorphins, enkephalins, and dynorphins, which contain the same N-terminal sequence. In the central nervous system, endomorphins are distributed everywhere, where they are primarily responsible for antinociception. Distribution of endomorphins in the immune system, similar to that of other opioid peptides, has allowed to suggest their active participation in the processes of immune regulation. This review summarizes modern views on the structure of endomorphins, their localization, possible intracellular mechanisms of signal transmission and their effects on the processes of activation, proliferation and differentiation of cells of innate and adaptive immunity. Endomorphins actively modulate the functions of the cells of the immune system. Peptides predominantly suppress adaptive immunity reactions. There effects on the functions of innate immunity cells (granulocytes, macrophages, monocytes, dendritic cells) depending on the conditions and can have either an inhibitory or stimulating orientation. Thus, endomorphins can be promising compounds that can effectively regulate both nociceptive signals and processes in the immune system.
Topics: Endorphins; Oligopeptides; Opioid Peptides; Receptors, Opioid; Receptors, Opioid, mu
PubMed: 33351316
DOI: 10.14341/probl10364 -
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