Epigenetic Regulation of the Kappa Opioid Receptor by Child Abuse

Lutz, Pierre-Eric; Gross, J.; Dhir, Sabine K.; Maussion, Gilles; Yang, Jennie; Bramoullé, Alexandre; Meaney, Michael J.; Turecki, Gustavo

doi:10.1016/j.biopsych.2017.07.012

Cited by 69 publications

(45 citation statements)

References 81 publications

(77 reference statements)

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“…Due to increased expression of p38 by MD, the sensitivity of the kinase to KOR stimulation to U50,488 remains intact. Therefore, MD appears to dysregulate Dyn/KOR signaling at multiple levels that involve projections from Dyn-containing brain areas to the LHb as well as the KOR expression/availability on synaptic terminals within the LHb, consistent with earlier studies of ELS [28,76,[81][82][83][84][85][86].…”

Section: Dysregulated Dyn/kor Signaling Within the Lhbsupporting

confidence: 86%

Early life stress dysregulates kappa opioid receptor signaling within the lateral habenula

Simmons

Shepard

Gouty

et al. 2020

Preprint

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The lateral habenula (LHb) is an epithalamic brain region associated with value-based decision making and stress evasion through its modulation of dopamine (DA)-mediated reward circuitry. Specifically, increased activity of the LHb is associated with drug addiction, schizophrenia and stress-related disorders such as depression, anxiety and posttraumatic stress disorder. Dynorphin (Dyn)/Kappa opioid receptor (KOR) signaling is a mediator of stress response in reward circuitry. Previously, we have shown that maternal deprivation (MD), a severe early life stress, increases LHb intrinsic excitability while blunting the response of LHb neurons to extra hypothalamic corticotropin-releasing factor (CRF) signaling, another stress mediator. CRF pathways also interact with Dyn/KOR signaling. Surprisingly, there has been little study of direct KOR regulation of the LHb despite its distinct role in stress, reward and aversion processing. To test the functional role of Dyn-KOR signaling in the LHb, we utilized ex-vivo electrophysiology combined with pharmacological tools in rat LHb slices. We show that activation of KORs by a KOR agonist (U50,488) exerts differential effects on the excitability of two distinct subpopulations of LHb neurons that differ in their expression of hyperpolarization-activated cation currents (HCN, Ih). Specifically, KOR stimulation increases neuronal excitability in LHb neurons with large Ih currents (Ih+) while decreases neuronal excitability in small/negative Ih (Ih-) neurons. Additionally, we found that an intact fast-synaptic transmission is required for the effects of U50,488 on the excitability of both Ih- and Ih+ LHb neuronal subpopulations. Consistently, KOR activation also altered both glutamatergic and GABAergic synaptic transmission. While stimulation of presynaptic KORs uniformly suppressed glutamate release onto LHb neurons, we found that U50, 488 either increased or decreased GABA release. We also found that MD significantly increased immunolabeled Dyn (the endogenous KOR agonist) labeling in neuronal fibers in LHb while significantly decreased mRNA levels of KORs in LHb tissues compared to those from non-maternally deprived (non-MD) control rats. While total p38 MAPK (a downstream signaling pathway driven by KOR activation) expression was elevated in the LHb of MD rats compared to non-MD controls, we found that application of KOR-specific agonist, U50,488, onto LHb slices was still able to alter phosphorylated p38 MAPK (ph-p38) expression in MD rats similar to non-MD controls. Moreover, we found that the U50,488-mediated increase in LHb neuronal firing observed in non-MD rats was absent following MD. Altogether, this is the first demonstration of the existence of the functional Dyn/KOR signaling in the LHb that can be modulated in response to severe early life stressors such as MD.

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Section: Dysregulated Dyn/kor Signaling Within the Lhbsupporting

confidence: 86%

Early life stress dysregulates kappa opioid receptor signaling within the lateral habenula

Simmons

Shepard

Gouty

et al. 2020

Preprint

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“…While these animal data mostly establish a link between attachment to parental figures and the MOR, a recent post‐mortem investigation points towards the implication of another receptor, the KOR (Lutz et al ). In this study a history of child abuse, which represents a severe disruption of attachment patterns, specifically associated in suicide completers with lower KOR expression in the anterior insular cortex, where opioid receptors are known to regulate social pain (see below), and where KOR may significantly contribute to trauma‐related psychopathology (Pietrzak et al ).…”

Section: Opioid Receptors and Social Behaviors During Neuro‐developmementioning

confidence: 99%

“…Regarding social pain, it has been associated by brain imaging with the activation of a large network of structures under tight regulation by MOR (see main text), and the understanding of the role of MOR signaling in these regions in relationship to various psychological dimensions and psychiatric phenotypes is only beginning. In comparison, there is only limited evidence pointing toward the implication of KOR (Lutz et al ). In the context of depressive disorders and suicidal behaviors, decreased sensitivity to socially rewarding experiences, and over‐reactivity to social pain and distress are considered as critical factors contributing to disease onset, progression, and prognosis.…”

Section: Introductionmentioning

confidence: 99%

The opioid system and the social brain: implications for depression and suicide

Lutz

Courtet

Calati

2018

J of Neuroscience Research

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In the past decade, considerable attention has been drawn to social interactions and behaviors as sources of pleasurable (social reward) and painful (social pain) emotional states. While the role of the opioid system in the regulation of reward and pain processes has long been recognized, it has more recently been investigated and characterized in the specific context of social experiences across several mammalian species. Accordingly, the present narrative review provides a comprehensive summary of studies detailing how the opioid system controls social reward and social pain. From a translational and pathophysiological perspective, we further discuss how opioid-dependent regulation of social behaviors may contribute to depressive illness and suicidal behaviors, and ultimately provide innovative therapeutic opportunities.

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“…Epigenetik spielt nicht nur eine zentrale Rolle in der Zelldifferenzierung und Entwicklung, sondern ist auch ein Mechanismus, der es Umweltfaktoren erlaubt, eine "Gedächtnisspur" in der DNA zu hinterlassen. [22][23][24].…”

Section: Epigenetik Und Umweltunclassified

Umwelt und Epigenetik

Binder

2019

Nervenarzt

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Epigenetic Regulation of the Kappa Opioid Receptor by Child Abuse

Abstract: Altogether, our findings uncover new facets of Kappa physiology, whereby this receptor may be epigenetically regulated by stressful experiences, in particular as a function of early social life.

Cited by 69 publications

References 81 publications

Early life stress dysregulates kappa opioid receptor signaling within the lateral habenula

Early life stress dysregulates kappa opioid receptor signaling within the lateral habenula

The opioid system and the social brain: implications for depression and suicide

Umwelt und Epigenetik

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