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Frontiers in Molecular Neuroscience 2022Recent evidence has shown that G protein-coupled receptors (GPCRs) are direct sensors of the autophagic machinery and opioid receptors regulate neuronal plasticity and...
Recent evidence has shown that G protein-coupled receptors (GPCRs) are direct sensors of the autophagic machinery and opioid receptors regulate neuronal plasticity and neurotransmission with an as yet unclarified mechanism. Using and experimental approaches, this study aims to clarify the potential role of autophagy and κ-opioid receptor (κ-OR) signaling in synaptic alterations. We hereby demonstrate that the selective κ-OR agonist U50,488H, induces autophagy in a time-and dose-dependent manner in Neuro-2A cells stably expressing the human κ-OR by upregulating microtubule-associated protein Light Chain 3-II (LC3-II), Beclin 1 and Autophagy Related Gene 5 (ATG5). Pretreatment of neuronal cells with pertussis toxin blocked the above κ-OR-mediated cellular responses. Our molecular analysis also revealed a κ-OR-driven upregulation of gene through ERK1,2-dependent activation of the transcription factor CREB in Neuro-2A cells. Moreover, our studies demonstrated that sub-chronic U50,488H administration in mice causes profound increases of specific autophagic markers in the hippocampus with a concomitant decrease of several pre-and post-synaptic proteins, such as spinophilin, postsynaptic density protein 95 (PSD-95) and synaptosomal associated protein 25 (SNAP25). Finally, using acute stress, a stimulus known to increase the levels of the endogenous κ-OR ligand dynorphin, we are demonstrating that administration of the κ-ΟR selective antagonist, nor-binaltorphimine (norBNI), blocks the induction of autophagy and the stress-evoked reduction of synaptic proteins in the hippocampus. These findings provide novel insights about the essential role of autophagic machinery into the mechanisms through which κ-OR signaling regulates brain plasticity.
PubMed: 36466809
DOI: 10.3389/fnmol.2022.1039135 -
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 -
Molecular Psychiatry Jan 2023Modulation of corticostriatal plasticity alters the information flow throughout basal ganglia circuits and represents a fundamental mechanism for motor learning, action...
Modulation of corticostriatal plasticity alters the information flow throughout basal ganglia circuits and represents a fundamental mechanism for motor learning, action selection, and reward. Synaptic plasticity in the striatal direct- and indirect-pathway spiny projection neurons (dSPNs and iSPNs) is regulated by two distinct networks of GPCR signaling cascades. While it is well-known that dopamine D2 and adenosine A2a receptors bi-directionally regulate iSPN plasticity, it remains unclear how D1 signaling modulation of synaptic plasticity is counteracted by dSPN-specific Gi signaling. Here, we show that striatal dynorphin selectively suppresses long-term potentiation (LTP) through Kappa Opioid Receptor (KOR) signaling in dSPNs. Both KOR antagonism and conditional deletion of dynorphin in dSPNs enhance LTP counterbalancing with different levels of D1 receptor activation. Behaviorally, mice lacking dynorphin in D1 neurons show comparable motor behavior and reward-based learning, but enhanced flexibility during reversal learning. These findings support a model in which D1R and KOR signaling bi-directionally modulate synaptic plasticity and behavior in the direct pathway.
Topics: Mice; Animals; Dynorphins; Corpus Striatum; Basal Ganglia; Long-Term Potentiation; Neuronal Plasticity; Receptors, Opioid, kappa; Receptors, Dopamine D1
PubMed: 36460726
DOI: 10.1038/s41380-022-01885-0 -
Endocrine Connections Jan 2023The nutritional environment during development periods induces metabolic programming, leading to metabolic disorders and detrimental influences on human reproductive...
The nutritional environment during development periods induces metabolic programming, leading to metabolic disorders and detrimental influences on human reproductive health. This study aimed to determine the long-term adverse effect of intrauterine malnutrition on the reproductive center kisspeptin-neurokinin B-dynorphin A (KNDy) neurons in the hypothalamic arcuate nucleus (ARC) of female offspring. Twelve pregnant rats were divided into ad-lib-fed (control, n = 6) and 50% undernutrition (UN, n = 6) groups. The UN group was restricted to 50% daily food intake of the control dams from gestation day 9 until term delivery. Differences between the two groups in terms of various maternal parameters, including body weight (BW), pregnancy duration, and litter size, as well as birth weight, puberty onset, estrous cyclicity, pulsatile luteinizing hormone (LH) secretion, and hypothalamic gene expression of offspring, were determined. Female offspring of UN dams exhibited low BW from birth to 3 weeks, whereas UN offspring showed signs of precocious puberty; hypothalamic Tac3 (a neurokinin B gene) expression was increased in prepubertal UN offspring, and the BW at the virginal opening was lower in UN offspring than that in the control group. Interestingly, the UN offspring showed significant decreases in the number of KNDy gene-expressing cells after 29 weeks of age, but the number of ARC kisspeptin-immunoreactive cells, pulsatile LH secretions, and estrous cyclicity were comparable between the groups. In conclusion, intrauterine undernutrition induced various changes in KNDy gene expression depending on the life stage. Thus, intrauterine undernutrition affected hypothalamic developmental programming in female rats.
PubMed: 36408965
DOI: 10.1530/EC-22-0307 -
Acta Pharmacologica Sinica May 2023
PubMed: 36400838
DOI: 10.1038/s41401-022-01016-z -
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 -
Frontiers in Systems Neuroscience 2022Decades of research advances have established a central role for endogenous opioid systems in regulating reward processing, mood, motivation, learning and memory,... (Review)
Review
Decades of research advances have established a central role for endogenous opioid systems in regulating reward processing, mood, motivation, learning and memory, gastrointestinal function, and pain relief. Endogenous opioid systems are present ubiquitously throughout the central and peripheral nervous system. They are composed of four families, namely the μ (MOPR), κ (KOPR), δ (DOPR), and nociceptin/orphanin FQ (NOPR) opioid receptors systems. These receptors signal through the action of their endogenous opioid peptides β-endorphins, dynorphins, enkephalins, and nociceptins, respectfully, to maintain homeostasis under normal physiological states. Due to their prominent role in pain regulation, exogenous opioids-primarily targeting the MOPR, have been historically used in medicine as analgesics, but their ability to produce euphoric effects also present high risks for abuse. The ability of pain and opioid use to perturb endogenous opioid system function, particularly within the central nervous system, may increase the likelihood of developing opioid use disorder (OUD). Today, the opioid crisis represents a major social, economic, and public health concern. In this review, we summarize the current state of the literature on the function, expression, pharmacology, and regulation of endogenous opioid systems in pain. Additionally, we discuss the adaptations in the endogenous opioid systems upon use of exogenous opioids which contribute to the development of OUD. Finally, we describe the intricate relationship between pain, endogenous opioid systems, and the proclivity for opioid misuse, as well as potential advances in generating safer and more efficient pain therapies.
PubMed: 36341476
DOI: 10.3389/fnsys.2022.1014768 -
Angewandte Chemie (International Ed. in... Jan 2023Electrochemical transformations provide enticing opportunities for programmable, residue-specific peptide modifications. Herein, we harness the potential of amidic...
Electrochemical transformations provide enticing opportunities for programmable, residue-specific peptide modifications. Herein, we harness the potential of amidic side-chains as underutilized handles for late-stage modification through the development of an electroauxiliary-assisted oxidation of glutamine residues within unprotected peptides. Glutamine building blocks bearing electroactive side-chain N,S-acetals are incorporated into peptides using standard Fmoc-SPPS. Anodic oxidation of the electroauxiliary in the presence of diverse alcohol nucleophiles enables the installation of high-value N,O-acetal functionalities. Proof-of-principle for an electrochemical peptide stapling protocol, as well as the functionalization of dynorphin B, an endogenous opioid peptide, demonstrates the applicability of the method to intricate peptide systems. Finally, the site-selective and tunable electrochemical modification of a peptide bearing two discretely oxidizable sites is achieved.
Topics: Glutamine; Peptides; Solid-Phase Synthesis Techniques
PubMed: 36336657
DOI: 10.1002/anie.202215470 -
Biomolecules Sep 2022The gut peptide, ghrelin, mediates energy homeostasis and reproduction by acting through its receptor, growth hormone secretagogue receptor (GHSR), expressed in...
The gut peptide, ghrelin, mediates energy homeostasis and reproduction by acting through its receptor, growth hormone secretagogue receptor (GHSR), expressed in hypothalamic neurons in the arcuate (ARC). We have shown 17β-estradiol (E2) increases expression in Kisspeptin/Neurokinin B/Dynorphin (KNDy) neurons, enhancing sensitivity to ghrelin. We hypothesized that E2-induced expression augments KNDy sensitivity in a fasting state by elevating ghrelin to disrupt energy expenditure in females. We produced a Kiss1-GHSR knockout to determine the role of GHSR in ARC KNDy neurons. We found that changes in ARC gene expression with estradiol benzoate (EB) treatment were abrogated by the deletion of GHSR and ghrelin abolished these differences. We also observed changes in metabolism and fasting glucose levels. Additionally, knockouts were resistant to body weight gain on a high fat diet (HFD). Behaviorally, we found that knockouts on HFD exhibited reduced anxiety-like behavior. Furthermore, knockouts did not refeed to the same extent as controls after a 24 h fast. Finally, in response to cold stress, knockout females had elevated metabolic parameters compared to controls. These data indicate GHSR in Kiss1 neurons modulate ARC gene expression, metabolism, glucose homeostasis, behavior, and thermoregulation, illustrating a novel mechanism for E2 and ghrelin to control Kiss1 neurons.
Topics: Animals; Female; Mice; Arcuate Nucleus of Hypothalamus; Diet, High-Fat; Dynorphins; Estradiol; Ghrelin; Glucose; Kisspeptins; Neurokinin B; Neurons; Obesity; Receptors, Ghrelin
PubMed: 36291579
DOI: 10.3390/biom12101370 -
Computational and Structural... 2022Amyloid β-peptide (Aβ) misfolding into β-sheet structures triggers neurotoxicity inducing Alzheimer's disease (AD). Molecules able to reduce or to impair Aβ...
Amyloid β-peptide (Aβ) misfolding into β-sheet structures triggers neurotoxicity inducing Alzheimer's disease (AD). Molecules able to reduce or to impair Aβ aggregation are highly relevant as possible AD treatments since they should protect against Aβ neurotoxicity. We have studied the effects of the interaction of dynorphins, a family of opioid neuropeptides, with Aβ the most abundant species of Aβ. Biophysical measurements indicate that Aβ interacts with Big Dynorphin (BigDyn), lowering the amount of hydrophobic aggregates, and slowing down the aggregation kinetics. As expected, we found that BigDyn protects against Aβ aggregates when studied in human neuroblastoma cells by cell survival assays. The cross-interaction between BigDyn and Aβ provides insight into the mechanism of amyloid pathophysiology and may open up new therapy possibilities.
PubMed: 36284704
DOI: 10.1016/j.csbj.2022.10.014