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Endocrinology Feb 2015Kisspeptin/neurokinin B/dynorphin (KNDy) neurons, which coexpress kisspeptins (Kps), neurokinin B (NKB), and dynorphin (Dyn), regulate gonadotropin secretion. The KNDy... (Comparative Study)
Comparative Study
Kisspeptin/neurokinin B/dynorphin (KNDy) neurons, which coexpress kisspeptins (Kps), neurokinin B (NKB), and dynorphin (Dyn), regulate gonadotropin secretion. The KNDy model proposes that NKB (a stimulator, through NK3R) and Dyn (an inhibitor, through κ-opioid receptor) shape Kp secretion onto GnRH neurons. However, some aspects of this paradigm remain ill defined. Here we aimed to characterize the following: 1) the effects of NKB signaling on FSH secretion and 2) the role of Dyn in gonadotropin secretion after NK3R activation; 3) additionally, we explored the roles of other tachykinin receptors, NK1R and NK2R, on gonadotropin release. Thus, the effects of the NK3R agonist, senktide, on FSH release were explored across postnatal development in male and female rats; gonadotropin responses to agonists of NK1R substance P and NK2R [neurokinin A (NKA)] were also monitored. Moreover, the effects of senktide on gonadotropin secretion were assessed after antagonizing Dyn actions by nor-binaltorphimine didydrochloride. Before puberty, rats of both sexes showed increased FSH secretion to senktide (and Kp-10). Conversely, adult female rats were irresponsive to senktide in terms of FSH, despite proven LH responses, whereas the adult males did not display FSH or LH responses to senktide, even at high doses. In turn, substance P and NKA stimulated gonadotropin secretion in prepubertal rats, whereas in adults modest gonadotropin responses to NKA were detected. By pretreatment with a Dyn antagonist, adult males became responsive to senktide in terms of LH secretion and displayed elevated basal LH and FSH levels; nor-binaltorphimine didydrochloride treatment uncovered FSH responses to senktide in adult females. Furthermore, the expression of Pdyn and Opkr1 (encoding Dyn and κ-opioid receptor, respectively) in the mediobasal hypothalamus was greater in males than in females at prepubertal ages. Overall, our data contribute to refining our understanding on how the elements of the KNDy node and related factors (ie, other tachykinins) differentially participate in the control of gonadotropins at different stages of rat postnatal maturation.
Topics: Aging; Animals; Dynorphins; Enkephalins; Female; Follicle Stimulating Hormone; Hypothalamus; Kisspeptins; Luteinizing Hormone; Male; Neurokinin B; Peptide Fragments; Protein Precursors; Rats, Wistar; Receptors, Neurokinin-1; Receptors, Neurokinin-2; Substance P
PubMed: 25490143
DOI: 10.1210/en.2014-1026 -
Handbook of Experimental Pharmacology 2018Understanding the neural systems that drive alcohol motivation and are disrupted in alcohol use disorders is of critical importance in developing novel treatments. The...
Understanding the neural systems that drive alcohol motivation and are disrupted in alcohol use disorders is of critical importance in developing novel treatments. The dynorphin and orexin/hypocretin neuropeptide systems are particularly relevant with respect to alcohol use and misuse. Both systems are strongly associated with alcohol-seeking behaviors, particularly in cases of high levels of alcohol use as seen in dependence. Furthermore, both systems also play a role in stress and anxiety, indicating that disruption of these systems may underlie long-term homeostatic dysregulation seen in alcohol use disorders. These systems are also closely interrelated with one another - dynorphin/kappa opioid receptors and orexin/hypocretin receptors are found in similar regions and hypocretin/orexin neurons also express dynorphin - suggesting that these two systems may work together in the regulation of alcohol seeking and may be mutually disrupted in alcohol use disorders. This chapter reviews studies demonstrating a role for each of these systems in motivated behavior, with a focus on their roles in regulating alcohol-seeking and self-administration behaviors. Consideration is also given to evidence indicating that these neuropeptide systems may be viable targets for the development of potential treatments for alcohol use disorders.
Topics: Alcoholism; Dynorphins; Ethanol; Humans; Motivation; Orexins
PubMed: 29526023
DOI: 10.1007/164_2018_100 -
Neuropharmacology Jan 2024Pain comorbidities include several psychological disorders, such as anxiety and anhedonia. However, the way pain affects male and female individuals and by which...
Pain comorbidities include several psychological disorders, such as anxiety and anhedonia. However, the way pain affects male and female individuals and by which mechanism is not well understood. Previous research shows that pain induces alterations in the dynorphinergic pathway within the mesocorticolimbic system (MCLS), together with a relationship between corticotropin-releasing system and dynorphin release in the MCLS. Here, we analyse the sex and time course-dependent effects of pain on negative affect. Additionally, we study the implication of dynorphinergic and corticotropin releasing factor in these pain related behaviours. We used behavioural pharmacology and biochemical tools to characterise negative affective states induced by inflammatory pain in male and female rats, and the alterations in the dynorphinergic and the corticotropin systems within the MCLS. Female rats showed persistent anxiety-like and reversible anhedonia-like behaviours derived from inflammatory pain. Additionally, we found alterations in dynorphin and corticotropin releasing factor in NAc and amygdala, which suggests sex-dependent dynamic adaptations. Finally blockade on the kappa opioid receptor in the NAc confirmed its role in pain-induced anxiety-like behaviour in female rats. Our results show sex and time-dependent anxiety- and anhedonia-like behaviours induced by the presence of pain in female rats. Furthermore, we replicated previous data, pointing to the KOR/DYN recruitment in the NAc as a key neurological substrate mediating pain-induced behavioural alterations. This research studies the mechanisms underlying these behaviours, to better understand the emotional dimension of pain.
Topics: Rats; Male; Female; Animals; Receptors, Opioid, kappa; Nucleus Accumbens; Dynorphins; Corticotropin-Releasing Hormone; Anhedonia; Pain; Adrenocorticotropic Hormone
PubMed: 37879455
DOI: 10.1016/j.neuropharm.2023.109764 -
Dynorphin and κ-Opioid Receptor Dysregulation in the Dopaminergic Reward System of Human Alcoholics.Molecular Neurobiology Aug 2018Molecular changes induced by excessive alcohol consumption may underlie formation of dysphoric state during acute and protracted alcohol withdrawal which leads to...
Molecular changes induced by excessive alcohol consumption may underlie formation of dysphoric state during acute and protracted alcohol withdrawal which leads to craving and relapse. A main molecular addiction hypothesis is that the upregulation of the dynorphin (DYN)/κ-opioid receptor (KOR) system in the nucleus accumbens (NAc) of alcohol-dependent individuals causes the imbalance in activity of D1- and D2 dopamine receptor (DR) expressing neural circuits that results in dysphoria. We here analyzed post-mortem NAc samples of human alcoholics to assess changes in prodynorphin (PDYN) and KOR (OPRK1) gene expression and co-expression (transcriptionally coordinated) patterns. To address alterations in D1- and D2-receptor circuits, we studied the regulatory interactions between these pathways and the DYN/KOR system. No significant differences in PDYN and OPRK1 gene expression levels between alcoholics and controls were evident. However, PDYN and OPRK1 showed transcriptionally coordinated pattern that was significantly different between alcoholics and controls. A downregulation of DRD1 but not DRD2 expression was seen in alcoholics. Expression of DRD1 and DRD2 strongly correlated with that of PDYN and OPRK1 suggesting high levels of transcriptional coordination between these gene clusters. The differences in expression and co-expression patterns were not due to the decline in neuronal proportion in alcoholic brain and thereby represent transcriptional phenomena. Dysregulation of DYN/KOR system and dopamine signaling through both alterations in co-expression patterns of opioid genes and decreased DRD1 gene expression may contribute to imbalance in the activity of D1- and D2-containing pathways which may lead to the negative affective state in human alcoholics.
Topics: Alcoholics; Case-Control Studies; Dopamine; Dynorphins; Gene Expression Regulation; Humans; Male; Middle Aged; Models, Biological; Nucleus Accumbens; RNA, Messenger; Receptors, Dopamine; Receptors, Opioid, kappa; Reward
PubMed: 29383684
DOI: 10.1007/s12035-017-0844-4 -
Neuropsychopharmacology : Official... Feb 2022Reward and reinforcement processes are critical for survival and propagation of genes. While numerous brain systems underlie these processes, a cardinal role is ascribed...
Optogenetic stimulation of lateral hypothalamic orexin/dynorphin inputs in the ventral tegmental area potentiates mesolimbic dopamine neurotransmission and promotes reward-seeking behaviours.
Reward and reinforcement processes are critical for survival and propagation of genes. While numerous brain systems underlie these processes, a cardinal role is ascribed to mesolimbic dopamine. However, ventral tegmental area (VTA) dopamine neurons receive complex innervation and various neuromodulatory factors, including input from lateral hypothalamic (LH) orexin/hypocretin neurons which also express and co-release the neuropeptide, dynorphin. Dynorphin in the VTA induces aversive conditioning through the Kappa opioid receptor (KOR) and decreases dopamine when administered intra-VTA. Exogenous application of orexin or orexin 1 receptor (oxR1) antagonists in the VTA bidirectionally modulates dopamine-driven motivation and reward-seeking behaviours, including the attribution of motivational value to primary rewards and associated conditioned stimuli. However, the effect of endogenous stimulation of LH orexin/dynorphin-containing projections to the VTA and the potential contribution of co-released dynorphin on mesolimbic dopamine and reward related processes remains uncharacterised. We combined optogenetic, electrochemical, and behavioural approaches to examine this. We found that optical stimulation of LH orexin/dynorphin inputs in the VTA potentiates mesolimbic dopamine neurotransmission in the nucleus accumbens (NAc) core, produces real time and conditioned place preference, and increases the food cue-directed orientation in a Pavlovian conditioning procedure. LH orexin/dynorphin potentiation of NAc dopamine release and real time place preference was blocked by an oxR1, but not KOR antagonist. Thus, rewarding effects associated with optical stimulation of LH orexin/dynorphin inputs in the VTA are predominantly driven by orexin rather than dynorphin.
Topics: Dopamine; Dopaminergic Neurons; Dynorphins; Hypothalamic Area, Lateral; Optogenetics; Orexins; Reward; Synaptic Transmission; Ventral Tegmental Area
PubMed: 34663867
DOI: 10.1038/s41386-021-01196-y -
Neuron Nov 2021Emerging evidence implicates experience-dependent myelination in learning and memory. However, the specific signals underlying this process remain unresolved. We...
Emerging evidence implicates experience-dependent myelination in learning and memory. However, the specific signals underlying this process remain unresolved. We demonstrate that the neuropeptide dynorphin, which is released from neurons upon high levels of activity, promotes experience-dependent myelination. Following forced swim stress, an experience that induces striatal dynorphin release, we observe increased striatal oligodendrocyte precursor cell (OPC) differentiation and myelination, which is abolished by deleting dynorphin or blocking its endogenous receptor, kappa opioid receptor (KOR). We find that dynorphin also promotes developmental OPC differentiation and myelination and demonstrate that this effect requires KOR expression specifically in OPCs. We characterize dynorphin-expressing neurons and use genetic sparse labeling to trace their axonal projections. Surprisingly, we find that they are unmyelinated normally and following forced swim stress. We propose a new model whereby experience-dependent and developmental myelination is mediated by unmyelinated, neuropeptide-expressing neurons that promote OPC differentiation for the myelination of neighboring axons.
Topics: Axons; Cell Differentiation; Dynorphins; Myelin Sheath; Neuropeptides; Oligodendroglia; Receptors, Opioid, kappa
PubMed: 34536353
DOI: 10.1016/j.neuron.2021.08.015 -
British Journal of Pharmacology Jan 2015Addiction is a devastating disorder that affects 15.3 million people worldwide. While prevalent, few effective treatments exist. Orexin receptors have been proposed as a... (Review)
Review
UNLABELLED
Addiction is a devastating disorder that affects 15.3 million people worldwide. While prevalent, few effective treatments exist. Orexin receptors have been proposed as a potential target for anti-craving medications. Orexins, also known as hypocretins, are neuropeptides produced in neurons of the lateral and dorsomedial hypothalamus and perifornical area, which project widely throughout the brain. The absence of orexins in rodents and humans leads to narcolepsy. However, orexins also have an established role in reward seeking. This review will discuss some of the original studies describing the roles of the orexins in reward seeking as well as specific works that were presented at the 2013 International Narcotics Research Conference. Orexin signalling can promote drug-induced plasticity of glutamatergic synapses onto dopamine neurons of the ventral tegmental area (VTA), a brain region implicated in motivated behaviour. Additional evidence suggests that orexin signalling can also promote drug seeking by initiating an endocannabinoid-mediated synaptic depression of GABAergic inputs to the VTA, and thereby disinhibiting dopaminergic neurons. Orexin neurons co-express the inhibitory opioid peptide dynorphin. It has been proposed that orexin in the VTA may not mediate reward per se, but rather occludes the 'anti-reward' effects of dynorphin. Finally, orexin signalling in the prefrontal cortex and the central amygdala is implicated in reinstatement of reward seeking. This review will highlight recent work describing the role of orexin signalling in cellular processes underlying addiction-related behaviours and propose novel hypotheses for the mechanisms by which orexin signalling may impart drug seeking.
LINKED ARTICLES
This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.
Topics: Animals; Dynorphins; Ethanol; Humans; Hypothalamus; Intracellular Signaling Peptides and Proteins; Neuropeptides; Orexin Receptors; Orexins; Reward; Substance-Related Disorders; Ventral Tegmental Area
PubMed: 24641197
DOI: 10.1111/bph.12639 -
Endocrinology May 2020Progesterone can block estrogen-induced luteinising hormone (LH) surge secretion and can be used clinically to prevent premature LH surges. The blocking effect of...
Progesterone can block estrogen-induced luteinising hormone (LH) surge secretion and can be used clinically to prevent premature LH surges. The blocking effect of progesterone on the LH surge is mediated through its receptor in the anteroventral periventricular nucleus (AVPV) of the hypothalamus. However, the underlying mechanisms are unclear. The preovulatory LH surge induced by estrogen is preceded by a significant reduction in hypothalamic dynorphin and gamma-aminobutyric acid (GABA) release. To test the detailed roles of dynorphin and GABA in an LH surge blockade by progesterone, ovariectomized and 17β-estradiol capsule-implanted (OVX/E2) mice received simultaneous injections of estradiol benzoate (EB) and progesterone (P) or vehicle for 2 consecutive days. The LH level was monitored from 2:30 pm to 8:30 pm at 30-minute intervals. Progesterone coadministration resulted in the LH surge blockade. A continuous microinfusion of the dynorphin receptor antagonist nor-BNI or GABAA receptor antagonist bicuculline into the AVPV from 3:00 pm to 7:00 pm reversed the progesterone-mediated blockade of the LH surge in 7 of 9 and 6 of 10 mice, respectively. In addition, these LH surges started much earlier than the surge induced by estrogen alone. However, 5 of 7 progesterone-treated mice did not show LH surge secretion after microinfusion with the GABAB receptor antagonist CGP-35348. Additionally, peripheral administration of kisspeptin-54 promotes LH surge-like release in progesterone treated mice. These results demonstrated that the progesterone-mediated suppression of the LH surge is mediated by an increase in dynorphin and GABAA receptor signaling acting though kisspeptin neurons in the AVPV of the hypothalamus in female mice.
Topics: Animals; Bicuculline; Dynorphins; Estradiol; Female; GABA Antagonists; Hypothalamus; Hypothalamus, Anterior; Kisspeptins; Luteinizing Hormone; Mice, Inbred C57BL; Naltrexone; Neurons; Organophosphorus Compounds; Ovariectomy; Progesterone; Receptors, GABA-A; Signal Transduction
PubMed: 32181477
DOI: 10.1210/endocr/bqaa036 -
Methods and Findings in Experimental... Sep 1998The role of kappa-opioid receptor agonists on learning and memory is controversial. In this review, the effects of dynorphin A (1-13) and U-50,488H on learning and... (Review)
Review
The role of kappa-opioid receptor agonists on learning and memory is controversial. In this review, the effects of dynorphin A (1-13) and U-50,488H on learning and memory impairments in mice and rats are summarized. Muscarinic cholinergic antagonists and a nicotinic cholinergic antagonist significantly impaired learning and memory in various behavioral tests. Administration of dynorphin A (1-13) or U-50,488H reversed the impairment of learning and memory. U-50,488H completely blocked the decrease in acetylcholine release induced by mecamylamine, while it only partially blocked the increase of acetylcholine induced by scopolamine. The antagonistic effect of U-50,488H was abolished by pretreatment with nor-binaltorphimine, a selective kappa-opioid receptor antagonist. Dynorphin A (1-13) and U-50,488H did not affect the impairment of learning and memory induced by the blockade of NMDA-receptors by dizocilpine ((+)-MK-801. These results suggest that kappa-opioid receptor antagonist reverses the impairment of learning and memory induced by the blockade of cholinergic transmission and abolishes the decrease of acetylcholine release via the kappa-opioid receptor-mediated neuronal system.
Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Dynorphins; Humans; Learning; Memory Disorders; Models, Psychological; Peptide Fragments; Receptors, Opioid, kappa
PubMed: 9819804
DOI: 10.1358/mf.1998.20.7.485724 -
The Journal of Neuroscience : the... Feb 2020Cocaine-driven changes in the modulation of neurotransmission by neuromodulators are poorly understood. The ventral pallidum (VP) is a key structure in the reward...
Cocaine-driven changes in the modulation of neurotransmission by neuromodulators are poorly understood. The ventral pallidum (VP) is a key structure in the reward system, in which GABA neurotransmission is regulated by opioid neuropeptides, including dynorphin. However, it is not known whether dynorphin acts differently on different cell types in the VP and whether its effects are altered by withdrawal from cocaine. Here, we trained wild-type, D1-Cre, A2A-Cre, or vGluT2-Cre:Ai9 male and female mice in a cocaine conditioned place preference protocol followed by 2 weeks of abstinence, and then recorded GABAergic synaptic input evoked either electrically or optogenetically onto identified VP neurons before and after applying dynorphin. We found that after cocaine CPP and abstinence dynorphin attenuated inhibitory input to VP neurons through a postsynaptic mechanism. This effect was absent in saline mice. Furthermore, this effect was seen specifically on the inputs from nucleus accumbens medium spiny neurons expressing either the D1 or the D2 dopamine receptor. Unlike its effect on VP neurons, dynorphin surprisingly potentiated the inhibitory input on VP neurons, but this effect was abolished after cocaine CPP and abstinence. Thus, dynorphin has contrasting influences on GABA input to VP and VP neurons and these influences are affected differentially by cocaine CPP and abstinence. Collectively, our data suggest a role for dynorphin in withdrawal through its actions in the VP. As VP and VP neurons have contrasting effects on drug-seeking behavior, our data may indicate a complex role for dynorphin in withdrawal from cocaine. The ventral pallidum consists mainly of GABAergic reward-promoting neurons, but it also encloses a subgroup of aversion-promoting glutamatergic neurons. Dynorphin, an opioid neuropeptide abundant in the ventral pallidum, shows differential modulation of GABA input to GABAergic and glutamatergic pallidal neurons and may therefore affect both the rewarding and aversive aspects of withdrawal. Indeed, abstinence after repeated exposure to cocaine alters dynorphin actions in a cell-type-specific manner; after abstinence dynorphin suppresses the inhibitory drive on the "rewarding" GABAergic neurons but ceases to modulate the inhibitory drive on the "aversive" glutamatergic neurons. This reflects a complex role for dynorphin in cocaine reward and abstinence.
Topics: Animals; Basal Forebrain; Cocaine; Drug-Seeking Behavior; Dynorphins; Female; Male; Mice; Mice, Inbred C57BL; Neurons; Reward; Substance Withdrawal Syndrome; Synaptic Transmission
PubMed: 31836660
DOI: 10.1523/JNEUROSCI.1262-19.2019