Enkephalins: Endogenous Analgesics with an Emerging Role in Stress Resilience.
Ontology highlight
ABSTRACT:
SUBMITTER: Henry MS
PROVIDER: S-EPMC5525068 | biostudies-other | 2017
REPOSITORIES: biostudies-other
Similar Datasets
Project description:Pain is often associated with depression of behavior and mood, and relief of pain-related depression is a common goal of treatment. This study tested the hypothesis that pain-related behavioral depression is mediated by activation of endogenous ?-opioid systems and subsequent depression of mesolimbic dopamine release. Adult male Sprague-Dawley rats were implanted with electrodes targeting the medial forebrain bundle (for behavior studies of intracranial self-stimulation (ICSS)) or with cannulae for microdialysis measures of nucleus accumbens dopamine (NAc DA). Changes in ICSS and NAc DA were examined after treatment with a visceral noxious stimulus (intraperitoneal injection of dilute lactic acid) or an exogenous ?-agonist (U69593). Additional studies examined the sensitivity of acid and U69593 effects to blockade by two analgesics (the nonsteroidal antiinflammatory drug ketoprofen and the ?-opioid agonist morphine) or by the ?-antagonist norbinaltorphimine (norBNI). The effects of acid were also examined on mRNA expression for prodynorphin (PDYN) and ?-opioid receptors (KORs) in mesocorticolimbic brain regions. Both acid and U69593 depressed ICSS and extracellular levels of NAc DA. Pain-related acid effects were blocked by ketoprofen and morphine but not by norBNI. The U69593 effects were blocked by norBNI but not by ketoprofen, and were only attenuated by morphine. Acid did not significantly alter PDYN or KOR in NAc, but it produced a delayed increase in PDYN in prefrontal cortex. These results support a key role for the mesolimbic DA system, but a more nuanced role for endogenous ?-opioid systems, in mediating acute pain-related behavioral depression in rats.
| S-EPMC3895239 | biostudies-literature
Project description:Stress granules (SGs) are small membrane-free cytosolic liquid-phase ordered entities in which mRNAs are protected and translationally silenced during cellular adaptation to harmful conditions (e.g., hypoxia, oxidative stress). This function is achieved by structural and functional SG components such as scaffold proteins and RNA-binding proteins controlling the fate of mRNAs. Increasing evidence indicates that the capacity of cells to assemble/disassemble functional SGs may significantly impact the onset and the development of metabolic and inflammatory diseases, as well as cancers. In the liver, the abnormal expression of SG components and formation of SG occur with chronic liver diseases, hepatocellular carcinoma (HCC), and selective hepatic resistance to anti-cancer drugs. Although, the role of SG in these diseases is still debated, the modulation of SG assembly/disassembly or targeting the expression/activity of specific SG components may represent appealing strategies to treat hepatic disorders and potentially cancer. In this review, we discuss our current knowledge about pathophysiological functions of SGs in HCC as well as available molecular tools and drugs capable of modulating SG formation and functions for therapeutic purposes.
| S-EPMC8430939 | biostudies-literature
Project description:BACKGROUND:Clinical studies suggest that heightened peripheral inflammation contributes to the pathogenesis of stress-related disorders, including major depressive disorder. However, the molecular mechanisms within peripheral immune cells that mediate enhanced stress vulnerability are not well known. Because microRNAs (miRs) are important regulators of immune response, we sought to examine their role in mediating inflammatory and behavioral responses to repeated social defeat stress (RSDS), a mouse model of stress vulnerability that produces susceptible and resilient phenotypes. METHODS:We isolated Ly6chigh monocytes via fluorescence-activated cell sorting in the blood of susceptible and resilient mice following RSDS and profiled miR expression via quantitative real-time polymerase chain reaction. Bone marrow chimeric mice were generated to confirm a causal role of the miR-106b?25 cluster in bone marrow-derived leukocytes in mediating stress resilience versus susceptibility. RESULTS:We found that RSDS produces an increase in circulating Ly6chigh inflammatory monocytes in both susceptible and resilient mice. We next investigated whether intrinsic leukocyte posttranscriptional mechanisms contribute to individual differences in stress response and the resilient phenotype. Of the miRs profiled in our panel, eight were significantly regulated by RSDS within Ly6chigh monocytes, including miR-25-3p, a member of the miR-106b?25 cluster. Selective knockout of the miR-106b?25 cluster in peripheral leukocytes promoted behavioral resilience to RSDS. CONCLUSIONS:Our results identify the miR-106b?25 cluster as a key regulator of stress-induced inflammation and depression that may represent a novel therapeutic target for drug development.
| S-EPMC6717005 | biostudies-literature
Project description:BackgroundAdolescent brains are sensitive to stressors. However, under certain circumstances, developmental stress can promote an adaptive phenotype, allowing individuals to cope better with adverse situations in adulthood, thereby contributing to resilience.MethodsSprague Dawley rats (50 males, 48 females) were subjected to adolescent chronic variable stress (adol CVS) for 2 weeks at postnatal day 45. At postnatal day 85, a group was subjected to single prolonged stress (SPS). After a week, animals were evaluated in an auditory-cued fear conditioning paradigm, and neuronal recruitment during reinstatement was assessed by Fos expression. Patch clamp electrophysiology (17-35 cells/group) was performed in male rats to examine physiological changes associated with resilience.ResultsAdol CVS blocked fear potentiation evoked by SPS. We observed that SPS impaired extinction (males) and enhanced reinstatement (both sexes) of the conditioned freezing response. Prior adol CVS prevented both effects. SPS effects were associated with a reduction of infralimbic (IL) cortex neuronal recruitment after reinstatement in males and increased engagement of the central amygdala in females, both also prevented by adol CVS, suggesting different neurocircuits involved in generating resilience between sexes. We explored the mechanism behind reduced IL recruitment in males by studying the intrinsic excitability of IL pyramidal neurons. SPS reduced excitability of IL neurons, and prior adol CVS prevented this effect.ConclusionsOur data indicate that adolescent stress can impart resilience to the effects of traumatic stress on neuroplasticity and behavior. Our data provide a mechanistic link behind developmental stress-induced behavioral resilience and prefrontal (IL) cortical excitability in males.
| S-EPMC10140393 | biostudies-literature
Project description:Posttraumatic stress disorder (PTSD) has been impacting the functioning of a large number of people in military activities and victims of violence for many generations. However, investments in research aiming to understand the neurobiological aspects of the disorder started relatively late, around the last third of the 20th century. The development of neuroimaging methods has greatly supported further understanding of the structural and functional changes in the re-organization processes of brains with PTSD. This helps to better explain the severity and evolution of behavioral symptoms, and opens the possibilities for identifying individual preexisting structural characteristics that could increase symptom severity and the risk of development. Here, we review the advances in neuroanatomical research on these adaptations in PTSD and discuss how those modifications in prefrontal and anterior cingulate circuitry impact the severity and development of the disorder, detaching the research from an amygdalocentric perspective. In addition, we investigate existing and contradictory evidence regarding the preexisting neurobiological features found mostly in twin studies and voxel-based morphometry (VBM) reports.
| S-EPMC9407950 | biostudies-literature
Project description:Forest ecosystems depend on their capacity to withstand and recover from natural and anthropogenic perturbations (that is, their resilience)1. Experimental evidence of sudden increases in tree mortality is raising concerns about variation in forest resilience2, yet little is known about how it is evolving in response to climate change. Here we integrate satellite-based vegetation indices with machine learning to show how forest resilience, quantified in terms of critical slowing down indicators3-5, has changed during the period 2000-2020. We show that tropical, arid and temperate forests are experiencing a significant decline in resilience, probably related to increased water limitations and climate variability. By contrast, boreal forests show divergent local patterns with an average increasing trend in resilience, probably benefiting from warming and CO2 fertilization, which may outweigh the adverse effects of climate change. These patterns emerge consistently in both managed and intact forests, corroborating the existence of common large-scale climate drivers. Reductions in resilience are statistically linked to abrupt declines in forest primary productivity, occurring in response to slow drifting towards a critical resilience threshold. Approximately 23% of intact undisturbed forests, corresponding to 3.32 Pg C of gross primary productivity, have already reached a critical threshold and are experiencing a further degradation in resilience. Together, these signals reveal a widespread decline in the capacity of forests to withstand perturbation that should be accounted for in the design of land-based mitigation and adaptation plans.
| S-EPMC9385496 | biostudies-literature
Project description:We demonstrate that stress differentially regulates glutamate homeostasis in the dorsal and ventral hippocampus and established a previously unknown role for the glial marker xCT in the homeostatic regulation of the ventral dentate gyrus (vDG) in stress resilience and antidepressant responses. We provide RNAseq roadmap for the stress-sensitive vDG and show that the transcription factor REST binds to xCT promoter in co-occupancy with the epigenetic marker H3K27acet, to negatively regulate xCT expression. Reduced xCT was also observed in a genetic mouse model of inherent susceptibility to depression. Pharmacologically modulating histone acetylation with next-generation therapeutics, such as acetyl-N-cysteine (NAC) or acetyl-L-carnitine (LAC), rapidly increased xCT reduction and activated a network that included mGlu2 receptors to prime an enhanced glutamate homeostasis that promoted stress resilience and antidepressant-like responses. Moreover, pharmacological xCT blockage counteracted NAC prophylactic effects. Anatomical (vDG) and cell-type specific (GFAP+) virus-overexpression mimicked the effects of pharmacological treatments in increasing stress resilience. These findings establish xCT as critical regulator of the glutamate system in a network with mGlu2 receptors. These studies also point to a role of histone acetylation as mediator of stress resilience.
2017-10-11 | GSE103435 | GEO
Project description:The endoplasmic reticulum (ER) is the main cellular organelle involved in protein synthesis, assembly and secretion. Accumulating evidence shows that across several neurodegenerative and neuroprogressive diseases, ER stress ensues, which is accompanied by over-activation of the unfolded protein response (UPR). Although the UPR could initially serve adaptive purposes in conditions associated with higher cellular demands and after exposure to a range of pathophysiological insults, over time the UPR may become detrimental, thus contributing to neuroprogression. Herein, we propose that immune-inflammatory, neuro-oxidative, neuro-nitrosative, as well as mitochondrial pathways may reciprocally interact with aberrations in UPR pathways. Furthermore, ER stress may contribute to a deregulation in calcium homoeostasis. The common denominator of these pathways is a decrease in neuronal resilience, synaptic dysfunction and even cell death. This review also discusses how mechanisms related to ER stress could be explored as a source for novel therapeutic targets for neurodegenerative and neuroprogressive diseases. The design of randomised controlled trials testing compounds that target aberrant UPR-related pathways within the emerging framework of precision psychiatry is warranted.
| S-EPMC6208857 | biostudies-other
Project description:Post-traumatic stress disorder (PTSD) is a common and potentially disabling disorder that develops in 1/5 to 1/3 of people exposed to severe trauma. Twin studies indicate that genetic factors account for at least one third of the variance in the risk for developing PTSD, however, the specific role for genetic factors in the pathogenesis of PTSD is not well understood. We studied genome-wide gene expression and DNA methylation profiles in 12 participants with PTSD and 12 participants who were resilient to similar severity trauma exposure. Close to 4000 genes were differentially expressed with adjusted p<0.05, fold-change >2, with all but 3 upregulated with PTSD. Eight odorant/olfactory receptor related genes were up-regulated with PTSD as well as genes related to immune activation, the Gamma-Aminobutyric Acid A (GABAA) receptor, and vitamin D synthesis. No differences with adjusted significance for DNA methylation were found. We conclude that increased gene expression may play an important role in PTSD and this expression may not be a consequence of DNA methylation. The role of odorant receptor expression warrants independent replication.
| S-EPMC5148136 | biostudies-literature
Project description:Psychologists worldwide are becoming increasingly concerned about the negative impact of the novel coronavirus (COVID-19) pandemic on adolescents' mental health. However, compared to studies involving adults, research using a young population is limited. To further understand the mental health of older adolescents and young adults during the pandemic, the present study examined whether resilience, as a protective factor, buffers the relationship between the personality trait of environmental sensitivity and COVID-19-related distress. In total, 441 older adolescents and young adults (53.7% women, M age = 18.91 years, SD age = 0.82 years) living in urban Japan completed an online cross-sectional survey in October 2020. The results showed that sensitivity was positively, though weakly, correlated with COVID-19 stress and negatively correlated with resilience. Resilience was negatively correlated with COVID-19 stress. Mediation analysis showed that resilience buffered the negative relationship between sensitivity and COVID-19 stress, and its indirect effect was statistically significant, albeit close to zero. These results suggest that higher sensitivity is not necessarily a vulnerability factor, if resilience can be enhanced.
| S-EPMC8496909 | biostudies-literature