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Delta Opioid Receptor Signaling Promotes Resilience to Stress Under the Repeated Social Defeat Paradigm in Mice.

ABSTRACT: 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.

SUBMITTER: Henry MS

PROVIDER: S-EPMC5897549 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Delta Opioid Receptor Signaling Promotes Resilience to Stress Under the Repeated Social Defeat Paradigm in Mice.

Henry Mathilde S MS Bisht Kanchan K Vernoux Nathalie N Gendron Louis L Torres-Berrio Angélica A Drolet Guy G Tremblay Marie-Ève MÈ

Frontiers in molecular neuroscience 20180406

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 t ...[more]

PMID: 29681795

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Project description:BackgroundPost-traumatic stress disorder (PTSD) is a devastating psychological disorder. Patients with PTSD canonically demonstrate an increased risk for inflammatory diseases, as well as increased sympathetic tone and norepinephrine (NE) outflow. Yet, the exact etiology and causal nature of these physiologic changes remain unclear. Previously, we demonstrated that exogenous NE alters mitochondrial superoxide in T-lymphocytes to produce a pro-inflammatory T-helper 17 (TH17) phenotype, and observed similar TH17 polarization in a preclinical model of PTSD. Therefore, we hypothesized sympathetic-driven neuroimmune interactions could mediate psychological trauma-induced T-lymphocyte inflammation.MethodsRepeated social defeat stress (RSDS) is a preclinical murine model that recapitulates the behavioral, autonomic, and inflammatory aspects of PTSD. Targeted splenic denervation (Dnx) was performed to deduce the contribution of splenic sympathetic nerves to RSDS-induced inflammation. Eighty-five C57BL/6J mice underwent Dnx or sham-operation, followed by RSDS or control paradigms. Animals were assessed for behavioral, autonomic, inflammatory, and redox profiles.ResultsDnx did not alter the antisocial or anxiety-like behavior induced by RSDS. In circulation, RSDS Dnx animals exhibited diminished levels of T-lymphocyte-specific cytokines (IL-2, IL-17A, and IL-22) compared to intact animals, whereas other non-specific inflammatory cytokines (e.g., IL-6, TNF-α, and IL-10) were unaffected by Dnx. Importantly, Dnx specifically ameliorated the increases in RSDS-induced T-lymphocyte mitochondrial superoxide, TH17 polarization, and pro-inflammatory gene expression with minimal impact to non-T-lymphocyte immune populations.ConclusionsOverall, our data suggest that sympathetic nerves regulate RSDS-induced splenic T-lymphocyte inflammation, but play less of a role in the behavioral and non-T-lymphocyte inflammatory phenotypes induced by this psychological trauma paradigm.

Dataset Information

Delta Opioid Receptor Signaling Promotes Resilience to Stress Under the Repeated Social Defeat Paradigm in Mice.

Publications

Delta Opioid Receptor Signaling Promotes Resilience to Stress Under the Repeated Social Defeat Paradigm in Mice.

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