11 research outputs found
Table_4.PDF
<p>The adaptation to chronic stress is highly variable across individuals. Resilience to stress is a complex process recruiting various brain regions and neurotransmitter systems. The aim of this study was to investigate the involvement of endogenous opioid enkephalin (ENK) signaling in the development of stress resilience in mice. The translational model of repeated social defeat (RSD) stress was selected to mimic the unpredictable disruptions of daily life and induce resilience or vulnerability to stress. As in humans, adult C57BL/6J mice demonstrated a great variability in their response to stress under this paradigm. A social interaction (SI) test was used to discriminate between the phenotypes of resilience or vulnerability to stress. After social defeat, the expression levels of ENK mRNA and their delta opioid receptors (DOPr) were quantified in the basolateral amygdala (BLA) and BLA-target areas by in situ hybridization. In this manner, ENK mRNA levels were found to decrease in the BLA and those of DOPr in the ventral hippocampus (HPC) CA1 of vulnerable mice only. Stimulating the DOPr pathway during social defeat by pharmacological treatment with the nonpeptide, selective DOPr agonist SNC80 further induced a resilient phenotype in a majority of stressed animals, with the proportion of resilient ones increasing from 33% to 58% of the total population. Ultrastructural analyses additionally revealed a reduction of oxidative stress markers in the pyramidal cells and interneurons of the ventral HPC CA1 upon SNC80 treatment, thus proposing a mechanism by which ENK-DOPr signaling may prevent the deleterious effects of chronic social stress.</p
Data_Sheet_1.docx
<p>The adaptation to chronic stress is highly variable across individuals. Resilience to stress is a complex process recruiting various brain regions and neurotransmitter systems. The aim of this study was to investigate the involvement of endogenous opioid enkephalin (ENK) signaling in the development of stress resilience in mice. The translational model of repeated social defeat (RSD) stress was selected to mimic the unpredictable disruptions of daily life and induce resilience or vulnerability to stress. As in humans, adult C57BL/6J mice demonstrated a great variability in their response to stress under this paradigm. A social interaction (SI) test was used to discriminate between the phenotypes of resilience or vulnerability to stress. After social defeat, the expression levels of ENK mRNA and their delta opioid receptors (DOPr) were quantified in the basolateral amygdala (BLA) and BLA-target areas by in situ hybridization. In this manner, ENK mRNA levels were found to decrease in the BLA and those of DOPr in the ventral hippocampus (HPC) CA1 of vulnerable mice only. Stimulating the DOPr pathway during social defeat by pharmacological treatment with the nonpeptide, selective DOPr agonist SNC80 further induced a resilient phenotype in a majority of stressed animals, with the proportion of resilient ones increasing from 33% to 58% of the total population. Ultrastructural analyses additionally revealed a reduction of oxidative stress markers in the pyramidal cells and interneurons of the ventral HPC CA1 upon SNC80 treatment, thus proposing a mechanism by which ENK-DOPr signaling may prevent the deleterious effects of chronic social stress.</p
Table_2.PDF
<p>The adaptation to chronic stress is highly variable across individuals. Resilience to stress is a complex process recruiting various brain regions and neurotransmitter systems. The aim of this study was to investigate the involvement of endogenous opioid enkephalin (ENK) signaling in the development of stress resilience in mice. The translational model of repeated social defeat (RSD) stress was selected to mimic the unpredictable disruptions of daily life and induce resilience or vulnerability to stress. As in humans, adult C57BL/6J mice demonstrated a great variability in their response to stress under this paradigm. A social interaction (SI) test was used to discriminate between the phenotypes of resilience or vulnerability to stress. After social defeat, the expression levels of ENK mRNA and their delta opioid receptors (DOPr) were quantified in the basolateral amygdala (BLA) and BLA-target areas by in situ hybridization. In this manner, ENK mRNA levels were found to decrease in the BLA and those of DOPr in the ventral hippocampus (HPC) CA1 of vulnerable mice only. Stimulating the DOPr pathway during social defeat by pharmacological treatment with the nonpeptide, selective DOPr agonist SNC80 further induced a resilient phenotype in a majority of stressed animals, with the proportion of resilient ones increasing from 33% to 58% of the total population. Ultrastructural analyses additionally revealed a reduction of oxidative stress markers in the pyramidal cells and interneurons of the ventral HPC CA1 upon SNC80 treatment, thus proposing a mechanism by which ENK-DOPr signaling may prevent the deleterious effects of chronic social stress.</p
Image_2.TIF
<p>The adaptation to chronic stress is highly variable across individuals. Resilience to stress is a complex process recruiting various brain regions and neurotransmitter systems. The aim of this study was to investigate the involvement of endogenous opioid enkephalin (ENK) signaling in the development of stress resilience in mice. The translational model of repeated social defeat (RSD) stress was selected to mimic the unpredictable disruptions of daily life and induce resilience or vulnerability to stress. As in humans, adult C57BL/6J mice demonstrated a great variability in their response to stress under this paradigm. A social interaction (SI) test was used to discriminate between the phenotypes of resilience or vulnerability to stress. After social defeat, the expression levels of ENK mRNA and their delta opioid receptors (DOPr) were quantified in the basolateral amygdala (BLA) and BLA-target areas by in situ hybridization. In this manner, ENK mRNA levels were found to decrease in the BLA and those of DOPr in the ventral hippocampus (HPC) CA1 of vulnerable mice only. Stimulating the DOPr pathway during social defeat by pharmacological treatment with the nonpeptide, selective DOPr agonist SNC80 further induced a resilient phenotype in a majority of stressed animals, with the proportion of resilient ones increasing from 33% to 58% of the total population. Ultrastructural analyses additionally revealed a reduction of oxidative stress markers in the pyramidal cells and interneurons of the ventral HPC CA1 upon SNC80 treatment, thus proposing a mechanism by which ENK-DOPr signaling may prevent the deleterious effects of chronic social stress.</p
Table_1.pdf
<p>The adaptation to chronic stress is highly variable across individuals. Resilience to stress is a complex process recruiting various brain regions and neurotransmitter systems. The aim of this study was to investigate the involvement of endogenous opioid enkephalin (ENK) signaling in the development of stress resilience in mice. The translational model of repeated social defeat (RSD) stress was selected to mimic the unpredictable disruptions of daily life and induce resilience or vulnerability to stress. As in humans, adult C57BL/6J mice demonstrated a great variability in their response to stress under this paradigm. A social interaction (SI) test was used to discriminate between the phenotypes of resilience or vulnerability to stress. After social defeat, the expression levels of ENK mRNA and their delta opioid receptors (DOPr) were quantified in the basolateral amygdala (BLA) and BLA-target areas by in situ hybridization. In this manner, ENK mRNA levels were found to decrease in the BLA and those of DOPr in the ventral hippocampus (HPC) CA1 of vulnerable mice only. Stimulating the DOPr pathway during social defeat by pharmacological treatment with the nonpeptide, selective DOPr agonist SNC80 further induced a resilient phenotype in a majority of stressed animals, with the proportion of resilient ones increasing from 33% to 58% of the total population. Ultrastructural analyses additionally revealed a reduction of oxidative stress markers in the pyramidal cells and interneurons of the ventral HPC CA1 upon SNC80 treatment, thus proposing a mechanism by which ENK-DOPr signaling may prevent the deleterious effects of chronic social stress.</p
Image_1.TIF
<p>The adaptation to chronic stress is highly variable across individuals. Resilience to stress is a complex process recruiting various brain regions and neurotransmitter systems. The aim of this study was to investigate the involvement of endogenous opioid enkephalin (ENK) signaling in the development of stress resilience in mice. The translational model of repeated social defeat (RSD) stress was selected to mimic the unpredictable disruptions of daily life and induce resilience or vulnerability to stress. As in humans, adult C57BL/6J mice demonstrated a great variability in their response to stress under this paradigm. A social interaction (SI) test was used to discriminate between the phenotypes of resilience or vulnerability to stress. After social defeat, the expression levels of ENK mRNA and their delta opioid receptors (DOPr) were quantified in the basolateral amygdala (BLA) and BLA-target areas by in situ hybridization. In this manner, ENK mRNA levels were found to decrease in the BLA and those of DOPr in the ventral hippocampus (HPC) CA1 of vulnerable mice only. Stimulating the DOPr pathway during social defeat by pharmacological treatment with the nonpeptide, selective DOPr agonist SNC80 further induced a resilient phenotype in a majority of stressed animals, with the proportion of resilient ones increasing from 33% to 58% of the total population. Ultrastructural analyses additionally revealed a reduction of oxidative stress markers in the pyramidal cells and interneurons of the ventral HPC CA1 upon SNC80 treatment, thus proposing a mechanism by which ENK-DOPr signaling may prevent the deleterious effects of chronic social stress.</p
Synthesis of Gly-ψ[(<i>Z</i>)CFCH]-Phe, a Fluoroalkene Dipeptide Isostere, and Its Incorporation into a Leu-enkephalin Peptidomimetic
A new
Leu-enkephalin peptidomimetic designed to explore the hydrogen
bond acceptor ability of the third peptide bond has been prepared
and studied. This new analog is produced by replacing the third amide
of Leu-enkephalin with a fluoroalkene. An efficient and innovative
synthesis of the corresponding dipeptide surrogate Fmoc-Gly-ψ[(<i>Z</i>)CFCH]-Phe-OH is described. The key step involves
the alkylation of a tin dienolate from the less hindered face of its
chiral sulfonamide auxiliary derived from camphor. Once its synthesis
was complete, its incorporation into the peptidomimetic sequence was
achieved on a solid support with chlorotrityl resin following the
Fmoc strategy. The peptidomimetic was characterized using competition
binding with [<sup>125</sup>I]-deltorphin I on membrane extracts of
HEK293 cells expressing the mouse delta opioid receptor (DOPr) and
based on its abilities to inhibit the electrically induced contractions
of the mouse <i>vas deferens</i> and to activate the ERK1/2
signaling pathway in DRGF11/DOPr-GFP cells. Together with our previous
observations, our findings strongly suggest that the third amide bond
of Leu-enkephalin primarily acts as a hydrogen bond acceptor in DOPr.
Consequently, this amide bond can be successfully replaced by an ester,
a thioamide, or a fluoroalkene without greatly impacting the binding
or biological activity of the corresponding analogs. The lipophilicity
(LogD<sub>7.4</sub>) of the active analog was also measured. It appears
that fluoroalkenes are almost as efficient at increasing the lipophilicity
as normal alkenes
Synthesis and Evaluation of a <sup>64</sup>Cu-Conjugate, a Selective δ‑Opioid Receptor Positron Emission Tomography Imaging Agent
Given the putative
selectivity of the antagonist TIPP (Tyr-Tic-Phe-Phe)
for δ-opioid receptors (DOP), this compound was selected for
the design of a novel <sup>64</sup>Cu-radiolabeled potent and selective
DOP positron emission tomography (PET) imaging agent. <i>Ex vivo</i> autoradiography of TIPPD-PEG-K(NOTA/<sup>64</sup>Cu)-NH<sub>2</sub> on rat brain sections produced a distribution pattern consistent
with the known expression of DOP. Taken together, the <i>in vitro</i> and <i>ex vivo</i> data indicate that this <sup>64</sup>Cu-tracer holds promise for studying the DOP by means of PET
Preparation and Evaluation at the Delta Opioid Receptor of a Series of Linear Leu-Enkephalin Analogues Obtained by Systematic Replacement of the Amides
Leu-enkephalin
analogues, in which the amide bonds were sequentially and systematically
replaced either by ester or <i>N</i>-methyl amide bonds,
were prepared using classical organic chemistry as well as solid phase
peptide synthesis (SPPS). The peptidomimetics were characterized using
competition binding, ERK1/2 phosphorylation, receptor internalization,
and contractility assays to evaluate their pharmacological profile
over the delta opioid receptor (DOPr). The lipophilicity (LogD<sub>7.4</sub>) and plasma stability of the active analogues were also
measured. Our results revealed that the last amide bond can be successfully
replaced by either an ester or an <i>N</i>-methyl amide
bond without significantly decreasing the biological activity of the
corresponding analogues when compared to Leu-enkephalin. The peptidomimetics
with an <i>N</i>-methyl amide function between residues
Phe and Leu were found to be more lipophilic and more stable than
Leu-enkephalin. Findings from the present study further revealed that
the hydrogen-bond donor properties of the fourth amide of Leu-enkephalin
are not important for its biological activity on DOPr. Our results
show that the systematic replacement of amide bonds by isosteric functions
represents an efficient way to design and synthesize novel peptide
analogues with enhanced stability. Our findings further suggest that
such a strategy can also be useful to study the biological roles of
amide bonds
Identification of 1‑({[1-(4-Fluorophenyl)-5-(2-methoxyphenyl)‑1<i>H</i>‑pyrazol-3-yl]carbonyl}amino)cyclohexane Carboxylic Acid as a Selective Nonpeptide Neurotensin Receptor Type 2 Compound
Compounds
active at neurotensin receptors (NTS1 and NTS2) exert analgesic effects
on different types of nociceptive modalities, including thermal, mechanical,
and chemical stimuli. The NTS2 preferring peptide JMV-431 (<b>2</b>) and the NTS2 selective nonpeptide compound levocabastine (<b>6</b>) have been shown to be effective in relieving the pain associated
with peripheral neuropathies. With the aim of identifying novel nonpeptide
compounds selective for NTS2, we examined analogues of SR48692 (<b>5a</b>) using a FLIPR calcium assay in CHO cells stably expressing
rat NTS2. This led to the discovery of the NTS2 selective nonpeptide
compound 1-({[1-(4-fluorophenyl)-5-(2-methoxyphenyl)-1<i>H</i>-pyrazol-3-yl]carbonyl}amino)cyclohexane carboxylic acid (NTRC-739, <b>7b</b>) starting from the nonselective compound <b>5a</b>