Changes in opioid receptors, opioid peptides and morphine antinociception in mice subjected to early life stress

Nakamoto, Kazuo; Taniguchi, Ayaka; Tokuyama, Shogo

doi:10.1016/j.ejphar.2020.173173

Cited by 19 publications

(16 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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

View full text Add to dashboard Cite

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.

show abstract

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

View full text Add to dashboard Cite

show abstract

“…The deleterious impact of ELS can be observed as far back as gestational exposure, wherein pups whose mothers were exposed to stress during gestation were more likely to acquire morphine CPP during their adolescence [ 61 ]. Converging evidence indicates that ELS in animals reduces opioid (particularly mu) receptor availability [ 62 , 63 , 64 ] and decreases downstream dopamine signaling [ 63 , 65 ] in a way that may bolster the reinforcing effects of opioids. Such an effect is also evident in behavioral tests where young animals exposed to stress display more CPP for µ- versus κ-opioid agonists [ 66 ].…”

Section: Individual Differences Confer Differential Risk For Oudmentioning

confidence: 99%

“…Conformational changes that have been specifically associated with ELS in preclinical studies include changes in opioid peptide levels [ 63 , 261 ], kappa receptor signaling [ 262 ], and variations in mu- and kappa-receptor (KOR) gene expression [ 62 , 64 , 65 , 263 , 264 ] in brain regions that include the hypothalamus, PFC, periaqueductal gray (PAG), AMG, NAc, rostral ventromedial medulla, and lateral habenula. Nylander and Roman [ 251 ] concluded that the most pronounced effect of ELS on opioid peptides is on Met-inkephalinArg6Phe7 (MEAP) levels, which are reduced in ELS-exposed animals.…”

Section: Role Of Endogenous Opioid Neurotransmitter System In Els and Oudmentioning

confidence: 99%

“…Vazquez et al [ 273 ] showed that maternal deprivation in rat pups was associated with hypersensitivity to the reinforcing effects of morphine and development of morphine dependence in adulthood, which was likely a result of basal hypoactivity of the nucleus accumbens (NAc) enkephalinergic system. Nakamoto et al [ 64 ] found that ELS-exposed mice displayed decreased µ- and k-opioid receptor messenger mRNA expression in the PAG and increased k-opioid receptor expression in the AMG. A lack of morphine antinociception was observed in stressed mice in adulthood but not immediately after ELS exposure.…”

Section: Role Of Endogenous Opioid Neurotransmitter System In Els and Oudmentioning

confidence: 99%

See 1 more Smart Citation

Early Life Stress and Risks for Opioid Misuse: Review of Data Supporting Neurobiological Underpinnings

Oswald

Dunn

Seminowicz

et al. 2021

JPM

View full text Add to dashboard Cite

A robust body of research has shown that traumatic experiences occurring during critical developmental periods of childhood when neuronal plasticity is high increase risks for a spectrum of physical and mental health problems in adulthood, including substance use disorders. However, until recently, relatively few studies had specifically examined the relationships between early life stress (ELS) and opioid use disorder (OUD). Associations with opioid use initiation, injection drug use, overdose, and poor treatment outcome have now been demonstrated. In rodents, ELS has also been shown to increase the euphoric and decrease antinociceptive effects of opioids, but little is known about these processes in humans or about the neurobiological mechanisms that may underlie these relationships. This review aims to establish a theoretical model that highlights the mechanisms by which ELS may alter opioid sensitivity, thereby contributing to future risks for OUD. Alterations induced by ELS in mesocorticolimbic brain circuits, and endogenous opioid and dopamine neurotransmitter systems are described. The limited but provocative evidence linking these alterations with opioid sensitivity and risks for OUD is presented. Overall, the findings suggest that better understanding of these mechanisms holds promise for reducing vulnerability, improving prevention strategies, and prescribing guidelines for high-risk individuals.

show abstract

“…The relationship between susceptibility to alcohol addiction, depression, and the level of opioid system functioning emerges from opioids’ involvement in nociception and mood-balancing or in support of survival by the induction of attraction to reward or aversion avoidance in response to external stimuli. The endogenous opioid system is altered by environmental factors starting at a very early stage of life [ 14 ]. The nucleus accumbens and ventral tegmental area are less susceptible to stress in the early postnatal phase, while the endogenous opioids in the amygdala are more reactive [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

The Influence of Cross-Fostering on Alcohol Consumption and Depressive-Like Behaviors in HA and LA Mice: The Role of the Endogenous Opioid System

et al. 2021

View full text Add to dashboard Cite

The development of alcohol dependence and depression is determined by various genetic and environmental factors. In the presented study, we used high analgesia (HA) and low analgesia (LA) mouse lines, characterized by different endogenous opioid system activity and divergent blood–brain barrier permeability, to determine the influence of cross-fostering of these lines raised by surrogate mothers on ethanol consumption and development of depressive-like behaviors. We also investigated ethanol drinking by biological parents or surrogate mothers. Furthermore, we investigated whether these parental changes would alter the effect of naloxone on ethanol intake and depressive-like behaviors in offspring. Our results reveal that cross-fostering of HA and LA raised by surrogate mothers has a greater impact on depressive-like behaviors than ethanol consumption. Ethanol intake by biological parents substantially affected depressive-like behaviors and ethanol consumption in offspring. Moreover, ethanol intake by biological parents or an adoptive mother modified the effect of naloxone on ethanol consumption and preference and depressive-like behaviors in the HA offspring only. Together, these results indicate that cross-fostering differentially affects the effect of naloxone on alcohol consumption and the development of depression.

show abstract

Changes in opioid receptors, opioid peptides and morphine antinociception in mice subjected to early life stress

Cited by 19 publications

References 47 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

Early Life Stress and Risks for Opioid Misuse: Review of Data Supporting Neurobiological Underpinnings

The Influence of Cross-Fostering on Alcohol Consumption and Depressive-Like Behaviors in HA and LA Mice: The Role of the Endogenous Opioid System

Contact Info

Product

Resources

About