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Neurochemistry International Oct 2019Neural circuits that enable an organism to protect itself by promoting escape from immediate threat and avoidance of future injury are conceptualized to carry an... (Review)
Review
Neural circuits that enable an organism to protect itself by promoting escape from immediate threat and avoidance of future injury are conceptualized to carry an "aversive" signal. One of the key molecular elements of these circuits is the kappa opioid receptor (KOR) and its endogenous peptide agonist, dynorphin. In many cases, the aversive response to an experimental manipulation can be eliminated by selective blockade of KOR function, indicating its necessity in transmitting this signal. The dopamine system, through its contributions to reinforcement learning, is also involved in processing of aversive stimuli, and KOR control of dopamine in the context of aversive behavioral states has been intensely studied. In this review, we have discussed the multiple ways in which the KORs regulate dopamine dynamics with a central focus on dopamine neurons and projections from the ventral tegmental area. At the neuronal level, KOR agonists inhibit dopamine neurons both in the somatodendritic region as well as at terminal release sites, through various signaling pathways and ion channels, and these effects are specific to different synaptic sites. While the dominant hypotheses are that aversive states are driven by decreases in dopamine and increases in dynorphin, reported exceptions to these patterns indicate these ideas require refinement. This is critical given that KOR is being considered as a target for development of new therapeutics for anxiety, depression, pain, and other psychiatric disorders.
Topics: Amygdala; Animals; Avoidance Learning; Dopamine; Dopaminergic Neurons; Dynorphins; Forecasting; Learning; Nucleus Accumbens; Punishment; Receptors, Opioid, kappa; Reinforcement, Psychology; Signal Transduction; Ventral Tegmental Area
PubMed: 31301327
DOI: 10.1016/j.neuint.2019.104504 -
Neuron Nov 2021Accumulating evidence supports the prevalence of experience-dependent oligodendrocyte precursor cell (OPC) differentiation and myelination in learning and memory....
Accumulating evidence supports the prevalence of experience-dependent oligodendrocyte precursor cell (OPC) differentiation and myelination in learning and memory. However, the mechanisms remain unknown. In this issue of Neuron, Osso et al., (2021) report that stress causes the secretion of dynorphin by unmyelinated axons, which induces OPC differentiation and myelination of neighboring axons.
Topics: Axons; Cell Differentiation; Dynorphins; Oligodendrocyte Precursor Cells; Oligodendroglia
PubMed: 34793703
DOI: 10.1016/j.neuron.2021.10.027 -
Cold Spring Harbor Perspectives in... Feb 2013Psychostimulants such as amphetamine and cocaine are believed to produce dependence by causing rapid, supraphysiological elevations in synaptic dopamine (DA) within the... (Review)
Review
Psychostimulants such as amphetamine and cocaine are believed to produce dependence by causing rapid, supraphysiological elevations in synaptic dopamine (DA) within the nucleus accumbens (NAc) (Volkow et al. 2009, Neuropharmacology 56: 3-8). These changes in forebrain DA transmission are similar to those evoked by natural reinforcers (Louilot et al. 1991, Brain Res 553: 313-317; Roitman et al. 2004, J Neurosci 24: 1265-1271), but are of greater magnitude and longer duration. Repeated drug exposure causes compensatory neuroadaptations in neurons of the NAc, some of which may modulate excess DA in a homeostatic fashion. One such adaptation is the activation of the transcription factor CREB (cAMP response element-binding protein) within neurons of the NAc. Although elevated levels of transcriptionally active CREB appear to attenuate DA transmission by increasing expression of the endogenous κ opioid receptor (KOR) ligand dynorphin, increased dynorphin transmission may ultimately have undesirable effects that contribute to drug withdrawal states as well as comorbid psychiatric illnesses such as depression. This state may prompt a return to drug use to mitigate the adverse effects of withdrawal. This article summarizes our current understanding of how CREB and dynorphin contribute to the dysregulation of motivation and describes novel therapeutic strategies that derive from preclinical research in this area.
Topics: Animals; Cocaine; Cyclic AMP Response Element-Binding Protein; Dopamine Uptake Inhibitors; Dynorphins; Gene Expression Regulation; Humans; Mammals; Morphine; Motivation; Narcotics; Nucleus Accumbens; Receptors, Neurotransmitter; Reward; Signal Transduction; Substance-Related Disorders; Transcriptional Activation
PubMed: 23293139
DOI: 10.1101/cshperspect.a012005 -
Brain Research Reviews Dec 2009The dynorphin-like peptides have profound effects on the state of the brain reward system and human and animal behavior. The dynorphin-like peptides affect locomotor... (Review)
Review
The dynorphin-like peptides have profound effects on the state of the brain reward system and human and animal behavior. The dynorphin-like peptides affect locomotor activity, food intake, sexual behavior, anxiety-like behavior, and drug intake. Stimulation of kappa-opioid receptors, the endogenous receptor for the dynorphin-like peptides, inhibits dopamine release in the striatum (nucleus accumbens and caudate putamen) and induces a negative mood state in humans and animals. The administration of drugs of abuse increases the release of dopamine in the striatum and mediates the concomitant release of dynorphin-like peptides in this brain region. The reviewed studies suggest that chronic drug intake leads to an upregulation of the brain dynorphin system in the striatum and in particular in the dorsal part of the striatum/caudate putamen. This might inhibit drug-induced dopamine release and provide protection against the neurotoxic effects of high dopamine levels. After the discontinuation of chronic drug intake these neuroadaptations remain unopposed which has been suggested to contribute to the negative emotional state associated with drug withdrawal and increased drug intake. kappa-Opioid receptor agonists have also been shown to inhibit calcium channels. Calcium channel inhibitors have antidepressant-like effects and inhibit the release of norepinephrine. This might explain that in some studies kappa-opioid receptor agonists attenuate nicotine and opioid withdrawal symptomatology. A better understanding of the role of dynorphins in the regulation of brain reward function might contribute to the development of novel treatments for mood disorders and other disorders that stem from a dysregulation of the brain reward system.
Topics: Animals; Brain; Dynorphins; Humans; Receptors, Opioid, kappa; Reward; Substance Withdrawal Syndrome; Substance-Related Disorders
PubMed: 19804796
DOI: 10.1016/j.brainresrev.2009.09.008 -
Journal of Neuroendocrinology Oct 2022The reproductive neuropeptide kisspeptin has emerged as the master regulator of mammalian reproduction due to its key roles in the initiation of puberty and the control... (Review)
Review
The reproductive neuropeptide kisspeptin has emerged as the master regulator of mammalian reproduction due to its key roles in the initiation of puberty and the control of fertility. Alongside the tachykinin neurokinin B and the endogenous opioid dynorphin, these peptides are central to the hormonal control of reproduction. Building on the expanding body of experimental animal models, interest has flourished with human studies revealing that kisspeptin administration stimulates physiological reproductive hormone secretion in both healthy men and women, as well as patients with common reproductive disorders. In addition, emerging therapeutic roles based on neurokinin B for the management of menopausal flushing, endometriosis and uterine fibroids are increasingly recognised. In this review, we focus on kisspeptin and neurokinin B and their potential application as novel clinical strategies for the management of reproductive disorders.
Topics: Male; Animals; Humans; Female; Neurokinin B; Kisspeptins; Reproductive Health; Dynorphins; Reproduction; Biology; Gonadotropin-Releasing Hormone; Mammals
PubMed: 36262016
DOI: 10.1111/jne.13201 -
Neuroendocrinology 2014The KNDy neuropeptides, kisspeptin, neurokinin B (NKB) and dynorphin A (Dyn), have been implicated in regulating pulsatile luteinising hormone (LH) secretion. Studies of... (Review)
Review
The KNDy neuropeptides, kisspeptin, neurokinin B (NKB) and dynorphin A (Dyn), have been implicated in regulating pulsatile luteinising hormone (LH) secretion. Studies of the interactions between KNDy signalling systems, however, are currently few. Although the stimulatory effect of kisspeptin and the inhibitory effect of Dyn on the gonadotropin-releasing hormone pulse generator are widely accepted, the effects of NKB in rodents are variable and sometimes controversial. Literature describing increased LH secretion in response to NKB receptor agonism predominates and is in line with human physiology, as well as the pathophysiology of pubertal failure associated with disruption of NKB signalling. However, the robust suppression of the LH pulse, induced by the same treatment under hypoestrogenic conditions, may hold clues as to the mechanisms of reproductive inhibition under pathological conditions. This review discusses the recent evidence for this paradox and outlines a revised working model incorporating the mechanisms by which KNDy neuropeptides modulate the reproductive axis.
Topics: Animals; Arcuate Nucleus of Hypothalamus; Dynorphins; Gonadotropin-Releasing Hormone; Humans; Hypothalamo-Hypophyseal System; Kisspeptins; Luteinizing Hormone; Male; Mice; Neuroendocrinology; Neurokinin B; Pituitary-Adrenal System; Rats; Reproduction; Signal Transduction
PubMed: 24356581
DOI: 10.1159/000357734 -
Acta Pharmacologica Sinica Jul 2015Anxiety disorders are the most common and prevalent forms of psychiatric disease, although the biological basis of anxiety is not well understood. The dynorphin/κ... (Review)
Review
Anxiety disorders are the most common and prevalent forms of psychiatric disease, although the biological basis of anxiety is not well understood. The dynorphin/κ opioid receptor system is widely distributed in the central nervous system and has been shown to play a critical role in modulating mood and emotional behaviors. In the present review, we summarize current literature relating to the role played by the dynorphin/κ opioid receptor system in anxiety and κ opioid receptor antagonists as potential therapeutic agents for the treatment of anxiety disorders.
Topics: Animals; Anxiety; Dynorphins; Humans; Narcotic Antagonists; Receptors, Opioid, kappa
PubMed: 25982631
DOI: 10.1038/aps.2015.32 -
Journal of Neuroinflammation Dec 2022Adverse pathophysiological and behavioral outcomes related to mild traumatic brain injury (mTBI), posttraumatic stress disorder (PTSD), and chronic pain are common...
BACKGROUND
Adverse pathophysiological and behavioral outcomes related to mild traumatic brain injury (mTBI), posttraumatic stress disorder (PTSD), and chronic pain are common following blast exposure and contribute to decreased quality of life, but underlying mechanisms and prophylactic/treatment options remain limited. The dynorphin/kappa opioid receptor (KOR) system helps regulate behavioral and inflammatory responses to stress and injury; however, it has yet to be investigated as a potential mechanism in either humans or animals exposed to blast. We hypothesized that blast-induced KOR activation mediates adverse outcomes related to inflammation and affective behavioral response.
METHODS
C57Bl/6 adult male mice were singly or repeatedly exposed to either sham (anesthesia only) or blast delivered by a pneumatic shock tube. The selective KOR antagonist norBNI or vehicle (saline) was administered 72 h prior to repetitive blast or sham exposure. Serum and brain were collected 10 min or 4 h post-exposure for dynorphin A-like immunoreactivity and cytokine measurements, respectively. At 1-month post-exposure, mice were tested in a series of behavioral assays related to adverse outcomes reported by humans with blast trauma.
RESULTS
Repetitive but not single blast exposure resulted in increased brain dynorphin A-like immunoreactivity. norBNI pretreatment blocked or significantly reduced blast-induced increase in serum and brain cytokines, including IL-6, at 4 h post exposure and aversive/anxiety-like behavioral dysfunction at 1-month post-exposure.
CONCLUSIONS
Our findings demonstrate a previously unreported role for the dynorphin/KOR system as a mediator of biochemical and behavioral dysfunction following repetitive blast exposure and highlight this system as a potential prophylactic/therapeutic treatment target.
Topics: Animals; Male; Mice; Blast Injuries; Brain; Dynorphins; Quality of Life; Receptors, Opioid, kappa
PubMed: 36463243
DOI: 10.1186/s12974-022-02643-3 -
Depression and Anxiety Oct 2016Kappa-opioid receptor (KOR) antagonists are currently being considered for the treatment of a variety of neuropsychiatric conditions, including depressive, anxiety, and... (Review)
Review
Kappa-opioid receptor (KOR) antagonists are currently being considered for the treatment of a variety of neuropsychiatric conditions, including depressive, anxiety, and substance abuse disorders. A general ability to mitigate the effects of stress, which can trigger or exacerbate these conditions, may explain their putative efficacy across such a broad array of conditions. The discovery of their potentially therapeutic effects evolved from preclinical research designed to characterize the molecular mechanisms by which experience causes neuroadaptations in the nucleus accumbens (NAc), a key element of brain reward circuitry. This research established that exposure to drugs of abuse or stress increases the activity of the transcription factor CREB (cAMP response element binding protein) in the NAc, which leads to elevated expression of the opioid peptide dynorphin that in turn causes core signs of depressive- and anxiety-related disorders. Disruption of KORs-the endogenous receptors for dynorphin-produces antidepressant- and anxiolytic-like actions in screening procedures that identify standard drugs of these classes, and reduces stress effects in tests used to study addiction and stress-related disorders. Although interest in this target is high, prototypical KOR antagonists have extraordinarily persistent pharmacodynamic effects that complicate clinical trials. The development of shorter acting KOR antagonists together with more rapid designs for clinical trials may soon provide insight on whether these drugs are efficacious as would be predicted by preclinical work. If successful, KOR antagonists would represent a unique example in psychiatry where the therapeutic mechanism of a drug class is understood before it is shown to be efficacious in humans.
Topics: Animals; Anti-Anxiety Agents; Antidepressive Agents; Anxiety Disorders; Brain; CREB-Binding Protein; Disease Models, Animal; Dynorphins; Gene Expression Regulation; Humans; Narcotic Antagonists; Nucleus Accumbens; Receptors, Opioid, kappa; Reward; Stress, Psychological; Substance-Related Disorders; Translational Research, Biomedical
PubMed: 27699938
DOI: 10.1002/da.22500 -
Alcoholism, Clinical and Experimental... Aug 2017Evidence has demonstrated that dynorphin (DYN) and the kappa opioid receptor (KOR) system contribute to various psychiatric disorders, including anxiety, depression, and... (Review)
Review
Evidence has demonstrated that dynorphin (DYN) and the kappa opioid receptor (KOR) system contribute to various psychiatric disorders, including anxiety, depression, and addiction. More recently, this endogenous opioid system has received increased attention as a potential therapeutic target for treating alcohol use disorders. In this review, we provide an overview and synthesis of preclinical studies examining the influence of alcohol (ethanol [EtOH]) exposure on DYN/KOR expression and function, as well as studies examining the effects of DYN/KOR manipulation on EtOH's rewarding and aversive properties. We then describe work that has characterized effects of KOR activation and blockade on EtOH self-administration and EtOH dependence/withdrawal-related behaviors. Finally, we address how the DYN/KOR system may contribute to stress-EtOH interactions. Despite an apparent role for the DYN/KOR system in motivational effects of EtOH, support comes from relatively few studies. Nevertheless, review of this literature reveals several common themes: (i) rodent strains genetically predisposed to consume more EtOH generally appear to have reduced DYN/KOR tone in brain reward circuitry; (ii) acute and chronic EtOH exposure typically up-regulate the DYN/KOR system; (iii) KOR antagonists reduce behavioral indices of negative affect associated with stress and chronic EtOH exposure/withdrawal; and (iv) KOR antagonists are effective in reducing EtOH consumption, but are often more efficacious under conditions that engender high levels of consumption, such as dependence or stress exposure. These results support the contention that the DYN/KOR system plays a significant role in contributing to dependence- and stress-induced elevation in EtOH consumption. Overall, more comprehensive analyses (on both behavioral and mechanistic levels) are needed to provide additional insight into how the DYN/KOR system is engaged and adapts to influence the motivation effects of EtOH. This information will be critical for the development of new pharmacological agents targeting KORs as promising novel therapeutics for alcohol use disorders and comorbid affective disorders.
Topics: Alcohol Drinking; Animals; Dynorphins; Ethanol; Humans; Motivation; Receptors, Opioid, kappa
PubMed: 28425121
DOI: 10.1111/acer.13406