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The Journal of Neuroscience : the... Sep 2000The nonopioid actions of spinal dynorphin may promote aspects of abnormal pain after nerve injury. Mechanistic similarities have been suggested between opioid tolerance...
The nonopioid actions of spinal dynorphin may promote aspects of abnormal pain after nerve injury. Mechanistic similarities have been suggested between opioid tolerance and neuropathic pain. Here, the hypothesis that spinal dynorphin might mediate effects of sustained spinal opioids was explored. Possible abnormal pain and spinal antinociceptive tolerance were evaluated after intrathecal administration of [D-Ala(2), N-Me-Phe(4), Gly-ol(5)]enkephalin (DAMGO), an opioid mu agonist. Rats infused with DAMGO, but not saline, demonstrated tactile allodynia and thermal hyperalgesia of the hindpaws (during the DAMGO infusion) and a decrease in antinociceptive potency and efficacy of spinal opioids (tolerance), signs also characteristic of nerve injury. Spinal DAMGO elicited an increase in lumbar dynorphin content and a decrease in the mu receptor immunoreactivity in the spinal dorsal horn, signs also seen in the postnerve-injury state. Intrathecal administration of dynorphin A(1-17) antiserum blocked tactile allodynia and reversed thermal hyperalgesia to above baseline levels (i.e., antinociception). Spinal dynorphin antiserum, but not control serum, also reestablished the antinociceptive potency and efficacy of spinal morphine. Neither dynorphin antiserum nor control serum administration altered baseline non-noxious or noxious thresholds or affected the intrathecal morphine antinociceptive response in saline-infused rats. These data suggest that spinal dynorphin promotes abnormal pain and acts to reduce the antinociceptive efficacy of spinal opioids (i.e., tolerance). The data also identify a possible mechanism for previously unexplained clinical observations and offer a novel approach for the development of strategies that could improve the long-term use of opioids for pain.
Topics: Analgesics; Analgesics, Opioid; Animals; Drug Tolerance; Dynorphins; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Hindlimb; Hot Temperature; Hyperalgesia; Immune Sera; Immunohistochemistry; Injections, Spinal; Male; Morphine; Pain Measurement; Precipitin Tests; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, Opioid, mu; Sensory Thresholds; Spinal Cord; Touch
PubMed: 10995854
DOI: 10.1523/JNEUROSCI.20-18-07074.2000 -
ENeuro 2021Neuropeptides within the central nucleus of the amygdala (CeA) potently modulate neuronal excitability and have been shown to regulate conditioned threat discrimination...
Neuropeptides within the central nucleus of the amygdala (CeA) potently modulate neuronal excitability and have been shown to regulate conditioned threat discrimination and anxiety. Here, we investigated the role of κ opioid receptor (KOR) and its endogenous ligand dynorphin in the CeA for regulation of conditioned threat discrimination and anxiety-like behavior in mice. We demonstrate that reduced KOR expression through genetic inactivation of the KOR encoding gene, , in the CeA results in increased anxiety-like behavior and impaired conditioned threat discrimination. In contrast, reduction of dynorphin through genetic inactivation of the dynorphin encoding gene, , in the CeA has no effect on anxiety or conditioned threat discrimination. However, inactivation of from multiple sources, intrinsic and extrinsic to the CeA phenocopies inactivation. These findings suggest that dynorphin inputs to the CeA signal through KOR to promote threat discrimination and dampen anxiety.
Topics: Animals; Anxiety; Central Amygdaloid Nucleus; Dynorphins; Mice; Receptors, Opioid, kappa; Signal Transduction
PubMed: 33323398
DOI: 10.1523/ENEURO.0370-20.2020 -
Proceedings of the National Academy of... Feb 1983A specific antiserum was prepared against dynorphin B, an endogenous opioid peptide contained in a recently isolated 4,000-dalton dynorphin. The antiserum did not...
A specific antiserum was prepared against dynorphin B, an endogenous opioid peptide contained in a recently isolated 4,000-dalton dynorphin. The antiserum did not crossreact with dynorphin A, alpha-neo-endorphin, beta-neo-endorphin, dynorphin-(1-8), or [Leu]enkephalin. In immunohistochemical staining experiments on frozen sections through rat brains from normal and colchicine-treated animals, the antiserum labeled the same neuronal fiber systems previously described as containing both dynorphin A and alpha-neo-endorphin immunoreactive material. The alpha-neo-endorphin/dynorphin A immunoreactive perikarya in the hypothalamic magnocellular nuclei also were labeled by the dynorphin B antiserum. In addition, the dynorphin B antiserum revealed groups of immunoreactive neuronal cell bodies in several other hypothalamic and extrahypothalamic areas, including brain-stem, midbrain, central nucleus of amygdala, and in the dorsomedial, lateral, and anterior nuclei of hypothalamus. These perikarya had not been detected in previous studies that used dynorphin A and alpha-neo-endorphin antisera. The findings are in agreement with recent studies demonstrating a common precursor for dynorphin A, dynorphin B, and alpha-neo-endorphin. The apparently wider distribution of dynorphin B immunoreactive cell bodies compared to alpha-neo-endorphin/dynorphin A immunoreactive perikarya may be a reflection of differential processing of the precursor in different brain regions.
Topics: Animals; Brain; Brain Chemistry; Brain Mapping; Dynorphins; Endorphins; Fluorescent Antibody Technique; Neurons; Rats
PubMed: 6133279
DOI: 10.1073/pnas.80.4.1125 -
The Journal of Neuroscience : the... Nov 2015We employ transgenic mice with selective expression of tdTomato or cre recombinase together with optogenetics to investigate whether hypothalamic arcuate (ARC)...
Dopamine/Tyrosine Hydroxylase Neurons of the Hypothalamic Arcuate Nucleus Release GABA, Communicate with Dopaminergic and Other Arcuate Neurons, and Respond to Dynorphin, Met-Enkephalin, and Oxytocin.
UNLABELLED
We employ transgenic mice with selective expression of tdTomato or cre recombinase together with optogenetics to investigate whether hypothalamic arcuate (ARC) dopamine/tyrosine hydroxylase (TH) neurons interact with other ARC neurons, how they respond to hypothalamic neuropeptides, and to test whether these cells constitute a single homogeneous population. Immunostaining with dopamine and TH antisera was used to corroborate targeted transgene expression. Using whole-cell recording on a large number of neurons (n = 483), two types of neurons with different electrophysiological properties were identified in the dorsomedial ARC where 94% of TH neurons contained immunoreactive dopamine: bursting and nonbursting neurons. In contrast to rat, the regular oscillations of mouse bursting neurons depend on a mechanism involving both T-type calcium and A-type potassium channel activation, but are independent of gap junction coupling. Optogenetic stimulation using cre recombinase-dependent ChIEF-AAV-DJ expressed in ARC TH neurons evoked postsynaptic GABA currents in the majority of neighboring dopamine and nondopamine neurons, suggesting for the first time substantial synaptic projections from ARC TH cells to other ARC neurons. Numerous met-enkephalin (mENK) and dynorphin-immunoreactive boutons appeared to contact ARC TH neurons. mENK inhibited both types of TH neuron through G-protein coupled inwardly rectifying potassium currents mediated by δ and μ opioid receptors. Dynorphin-A inhibited both bursting and nonbursting TH neurons by activating κ receptors. Oxytocin excited both bursting and nonbursting neurons. These results reveal a complexity of TH neurons that communicate extensively with neurons within the ARC.
SIGNIFICANCE STATEMENT
Here, we show that the great majority of mouse hypothalamic arcuate nucleus (ARC) neurons that synthesize TH in the dorsomedial ARC also contain immunoreactive dopamine, and show either bursting or nonbursting electrical activity. Unlike rats, the mechanism underlying bursting was not dependent on gap junctions but required T-type calcium and A-type potassium channel activation. Neuropeptides dynorphin and met-enkephalin inhibited dopamine neurons, whereas oxytocin excited them. Most ventrolateral ARC TH cells did not contain dopamine and did not show bursting electrical activity. TH-containing neurons appeared to release synaptic GABA within the ARC onto dopamine neurons and unidentified neurons, suggesting that the cells not only control pituitary hormones but also may modulate nearby neurons.
Topics: Animals; Arcuate Nucleus of Hypothalamus; Cell Communication; Dopaminergic Neurons; Dynorphins; Enkephalin, Methionine; Female; Humans; Male; Mice; Mice, Transgenic; Organ Culture Techniques; Oxytocin; Rats; Swine; Tyrosine 3-Monooxygenase; gamma-Aminobutyric Acid
PubMed: 26558770
DOI: 10.1523/JNEUROSCI.0293-15.2015 -
Proceedings of the National Academy of... Apr 2014
Topics: Animals; Dynorphins; Intracellular Signaling Peptides and Proteins; Male; Neuropeptides; Neurotransmitter Agents; Orexins; Reward; Ventral Tegmental Area
PubMed: 24706899
DOI: 10.1073/pnas.1403603111 -
Neuropharmacology Jul 2008Interest in development of therapeutics targeting brain neuropeptide systems for treatment of cocaine addiction (e.g., kappa opioid agonists) is based on animal data...
Interest in development of therapeutics targeting brain neuropeptide systems for treatment of cocaine addiction (e.g., kappa opioid agonists) is based on animal data showing interactions between the neuropeptides, brain dopamine, and cocaine. In this autopsied brain study, our major objective was to establish by radioimmunoassay whether levels of dynorphin and other neuropeptides (e.g., metenkephalin, neurotensin and substance P) are increased in the dopamine-rich caudate, putamen, and nucleus accumbens of human chronic cocaine users (n=12) vs. matched control subjects (n=17) as predicted by animal findings. Changes were limited to markedly increased dynorphin immunoreactivity in caudate (+92%), decreased caudate neurotensin (-49%), and a trend for increased dynorphin (+75%) in putamen. In other examined subcortical/cerebral cortical areas dynorphin levels were normal with the striking exception of the ventral pallidum (+346%), whereas cerebral cortical metenkephalin levels were generally decreased and neurotensin variably changed. Our finding that, in contradistinction to animal data, the other striatal neuropeptides were not increased in human cocaine users could be explained by differences in pattern and contingency between human drug users and the animal models. However, the human dynorphin observations parallel well animal findings and suggest that the dynorphin system is upregulated, manifested as elevated neuropeptide levels, after chronic drug exposure in striatum and ventral pallidum. Our postmortem brain data suggest involvement of striatal dynorphin systems in human cocaine users and should add to the interest in the testing of new dynorphin-related therapeutics for the treatment of cocaine addiction.
Topics: Adult; Case-Control Studies; Cocaine-Related Disorders; Corpus Striatum; Dynorphins; Female; Globus Pallidus; Humans; Male; Postmortem Changes; Statistics as Topic
PubMed: 18538358
DOI: 10.1016/j.neuropharm.2008.04.019 -
Nature Communications Jan 2024The hippocampus is pivotal in integrating emotional processing, learning, memory, and reward-related behaviors. The dorsal hippocampus (dHPC) is particularly crucial for...
The hippocampus is pivotal in integrating emotional processing, learning, memory, and reward-related behaviors. The dorsal hippocampus (dHPC) is particularly crucial for episodic, spatial, and associative memory, and has been shown to be necessary for context- and cue-associated reward behaviors. The nucleus accumbens (NAc), a central structure in the mesolimbic reward pathway, integrates the salience of aversive and rewarding stimuli. Despite extensive research on dHPC→NAc direct projections, their sufficiency in driving reinforcement and reward-related behavior remains to be determined. Our study establishes that activating excitatory neurons in the dHPC is sufficient to induce reinforcing behaviors through its direct projections to the dorso-medial subregion of the NAc shell (dmNAcSh). Notably, dynorphin-containing neurons specifically contribute to dHPC-driven reinforcing behavior, even though both dmNAcSh dynorphin- and enkephalin-containing neurons are activated with dHPC stimulation. Our findings unveil a pathway governing reinforcement, advancing our understanding of the hippocampal circuity's role in reward-seeking behaviors.
Topics: Nucleus Accumbens; Dynorphins; Hippocampus; Reward; Neurons; Phospholipid Ethers
PubMed: 38286800
DOI: 10.1038/s41467-024-44836-9 -
International Journal of Molecular... Jun 2024The physiology of reproduction has been of interest to researchers for centuries. The purpose of this work is to review the development of our knowledge on the... (Review)
Review
The physiology of reproduction has been of interest to researchers for centuries. The purpose of this work is to review the development of our knowledge on the neuroendocrine background of the regulation of ovulation. We first describe the development of the pituitary gland, the structure of the median eminence (ME), the connection between the hypothalamus and the pituitary gland, the ovarian and pituitary hormones involved in ovulation, and the pituitary cell composition. We recall the pioneer physiological and morphological investigations that drove development forward. The description of the supraoptic-paraventricular magnocellular and tuberoinfundibular parvocellular systems and recognizing the role of the hypophysiotropic area were major milestones in understanding the anatomical and physiological basis of reproduction. The discovery of releasing and inhibiting hormones, the significance of pulse and surge generators, the pulsatile secretion of the gonadotropin-releasing hormone (GnRH), and the subsequent pulsatility of luteinizing (LH) and follicle-stimulating hormones (FSH) in the human reproductive physiology were truly transformative. The roles of three critical neuropeptides, kisspeptin (KP), neurokinin B (NKB), and dynorphin (Dy), were also identified. This review also touches on the endocrine background of human infertility and assisted fertilization.
Topics: Humans; Ovulation; Female; Neurosecretory Systems; Animals; Pituitary Gland; Kisspeptins; Neurokinin B; Luteinizing Hormone; Gonadotropin-Releasing Hormone; Dynorphins; Hypothalamus
PubMed: 38928237
DOI: 10.3390/ijms25126531 -
Central non-opioid physiological and pathophysiological effects of dynorphin A and related peptides.Journal of Psychiatry & Neuroscience :... Sep 1992Dynorphin A (Dyn A) and related opioid peptides derived from prodynorphin possess a high affinity for kappa opioid receptors, but they also bind to other opioid... (Review)
Review
Dynorphin A (Dyn A) and related opioid peptides derived from prodynorphin possess a high affinity for kappa opioid receptors, but they also bind to other opioid receptors (mu and delta) as well as to some non-opioid receptor sites. Although the physiological role of these peptides is not well established, recent experimental data pinpoint their particular involvement in physiological and pathophysiological conditions that relate to algesia, spinal cord injury and epilepsy. In this paper, we review data which support the concept that the non-opioid behavioral effects of Dyn A and related endogenous peptides which are observed under these conditions are physiologically and pathophysiologically relevant.
Topics: Brain; Dynorphins; Epilepsy; Humans; Neuropeptides; Nociceptors; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid; Spinal Cord; Spinal Cord Injuries
PubMed: 1356430
DOI: No ID Found -
Endocrine Journal 2012The role of Neurokinin B (NKB) and Dynorphin A (Dyn) in the regulation of the hypothalamic pituitary axis is an important area of recent investigation. These peptides...
The role of Neurokinin B (NKB) and Dynorphin A (Dyn) in the regulation of the hypothalamic pituitary axis is an important area of recent investigation. These peptides are critical for the rhythmic release of GnRH, which subsequently stimulates the secretion of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). The present study utilized the gonadotroph cell line LβT2 and the somatolactotroph GH3 cell line to examine the possible role of these peptides in pituitary hormone secretion. The NKB receptor (NK3R) and the Dyn receptor (the κ-opiate receptor (KOR)) were both detected in LβT2 cells and GH3 cells. NKB, by itself, failed to increase gonadotropin LHβ and FSHβ promoter activities and did not modulate the effects of GnRH on gonadotropin promoter activity. In GH3 cells, NKB significantly increased TRH-induced PRL promoter activity although NKB alone did not have an effect on basal PRL promoter activity. Dyn had no effect on gonadotropin promoters alone or in combination with GnRH stimulation. PRL promoters stimulated by TRH were not significantly changed by Dyn. TRH-induced PRL promoter activity was further increased in the presence of higher concentrations of NKB, whereas Dyn did not have a significant effect on the PRL promoter even at a high concentration. In addition, TRH-induced ERK (Extracelluar signal-regulated kinase) activation was enhanced in the presence of NKB. Our current study demonstrated that NKB had a stimulatory effect on PRL expression in a PRL-producing cell, but had no effect on gonadotropin secretion from a gonadotroph cell line.
Topics: Animals; Cell Line; Dynorphins; Gonadotrophs; Gonadotropins; Lactotrophs; Neurokinin B; Pituitary Gland; Prolactin; Promoter Regions, Genetic; Rats; Receptors, Opioid; Receptors, Tachykinin; Somatotrophs; Transfection; Nociceptin Receptor
PubMed: 22641014
DOI: 10.1507/endocrj.ej11-0401