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

Simmons, Sarah C.; Shepard, Ryan D.; Gouty, Shawn; Langlois, Ludovic D.; Flerlage, William J; Cox, Brian M.; Nugent, Fereshteh S.

doi:10.1016/j.ynstr.2020.100267

Cited by 34 publications

(52 citation statements)

References 85 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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%

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

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

confidence: 99%

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

show abstract

“…Considering that the LHb regulates VTA DA signaling, we extended our studies to determine whether MD also perturbs LHb function. Studies from our lab using MD and others using maternal separation (MS; Tchenio et al, 2017) or the limited bedding and nesting models of ELS (Bolton et al, 2018) demonstrated that ELS can promote LHb hyperactivity (Authement et al, 2018;Shepard et al, 2018b;Simmons et al, 2020). Mechanistically, we have shown that LHb neurons in adolescent rats that underwent MD stress are hyperexcitable partly due to a shift in synaptic excitation and inhibition (E/I) balance towards excitation, as well as downregulation of small conductance (SK2) potassium channels and increased protein kinase (PKA) activity, resulting in induction of an intrinsic plasticity in LHb neurons.…”

Section: Discussionmentioning

confidence: 89%

“…Most notably, LHb hyperactivity has been consistently found in both clinical and animal models of depression (Proulx et al, 2014;Browne et al, 2018;Nuno-Perez et al, 2018;Yang et al, 2018;Cerniauskas et al, 2019;Gold and Kadriu, 2019). While LHb hyperactivity associated with depressive phenotypes have been found to occur uniformly across all LHb neuronal subpopulations (Li et al, 2013;Authement et al, 2018;Shepard et al, 2018b;Yang et al, 2018;Simmons et al, 2020), some studies suggest projection-and input-specific LHb subcircuit dysfunction in depression (Li et al, 2011;Cerniauskas et al, 2019). For example, the enhanced release of glutamate at glutamatergic synapses onto VTA-projecting LHb neurons correlates with learned helplessness behaviors in rats (Li et al, 2011) suggesting that depression-related hyperactivity in specific LHb subpopulations may arise from synaptic changes at distinct synaptic inputs to LHb subpopulations.…”

Section: Discussionmentioning

confidence: 99%

“…Maternal deprivation (MD) was carried out as described previously (Authement et al, 2018;Shepard et al, 2018aShepard et al, ,b, 2020Simmons et al, 2020). At P9, male pups (Charles River) were isolated from the dam as a group in a separate room to avoid localization from other animals in the main housing area.…”

Section: Maternal Deprivation and Lhb Microdissectionmentioning

confidence: 99%

“…Although these structures have been extensively studied, evidence now suggests that the lateral habenula (LHb), an evolutionarily conserved epithalamic structure, is a critical brain region that is involved in depression, substance use disorder, anxiety, and sleep disorders (Hu et al, 2020). Earlier studies from our lab and others have demonstrated that rodent models of ELS promote LHb dysfunction through increased LHb neuronal excitability and altered synaptic transmission (Tchenio et al, 2017;Authement et al, 2018;Langlois et al, 2020;Simmons et al, 2020). Moreover, our longitudinal studies have demonstrated that these ELS-induced alterations are potentially long-lasting and span across multiple stages of development (Shepard et al, 2018b;Langlois et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Targeting Endocannabinoid Signaling in the Lateral Habenula as an Intervention to Prevent Mental Illnesses Following Early Life Stress: A Perspective

Shepard

Nugent

2021

Front. Synaptic Neurosci.

Self Cite

View full text Add to dashboard Cite

Adverse events and childhood trauma increase the susceptibility towards developing psychiatric disorders (substance use disorder, anxiety, depression, etc.) in adulthood. Although there are treatment strategies that have utility in combating these psychiatric disorders, little attention is placed on how to therapeutically intervene in children exposed to early life stress (ELS) to prevent the development of later psychopathology. The lateral habenula (LHb) has been a topic of extensive investigation in mental health disorders due to its prominent role in emotion and mood regulation through modulation of brain reward and motivational neural circuits. Importantly, rodent models of ELS have been shown to promote LHb dysfunction. Moreover, one of the potential mechanisms contributing to LHb neuronal and synaptic dysfunction involves endocannabinoid (eCB) signaling, which has been observed to critically regulate emotion/mood and motivation. Many pre-clinical studies targeting eCB signaling suggest that this neuromodulatory system could be exploited as an intervention therapy to halt maladaptive processes that promote dysfunction in reward and motivational neural circuits involving the LHb. In this perspective article, we report what is currently known about the role of eCB signaling in LHb function and discuss our opinions on new research directions to determine whether the eCB system is a potentially attractive therapeutic intervention for the prevention and/or treatment of ELS-associated psychiatric illnesses.

show abstract

Teneurin C-terminal associated peptide (TCAP)-1 attenuates the development and expression of naloxone-precipitated morphine withdrawal in male Swiss Webster mice

Mueller,

Wexler,

Lovejoy

et al. 2024

Psychopharmacology

View full text Add to dashboard Cite

Rationale Corticotropin-releasing factor (CRF), the apical stress-inducing hormone, exacerbates stress and addictive behaviors. TCAP-1 is a peptide that directly inhibits both CRF-mediated stress and addiction-related behaviors; however, the direct action of TCAP-1 on morphine withdrawal-associated behaviors has not previously been examined. Objective To determine whether TCAP-1 administration attenuates behavioral and physiological consequences of morphine withdrawal in mice. Methods Mice were administered via subcutaneous route TCAP-1 either before or after initial morphine exposure, after which jumping behavior was quantified to assess the effects of TCAP-1 on naloxone-precipitated morphine withdrawal. As a comparison, mice were treated with nonpeptide CRF1 receptor antagonist CP-154,526. In one experiment, plasma corticosterone (CORT) was also measured as a physiological stress indicator. Results Pretreatment with TCAP-1 (10–250 nmol/kg) before morphine treatment significantly inhibited the development of naloxone-precipitated withdrawal. TCAP-1 (250–500 nmol/kg) treatment administered after morphine treatment attenuated the behavioral expression of naloxone-precipitated withdrawal. TCAP-1 (250 nmol/kg) treatment during morphine treatment was more effective than the optimal dosing of CP-154,526 (20 mg/kg) at suppressing the behavioral expression of naloxone-precipitated withdrawal, despite similar reduction of withdrawal-induced plasma CORT level increases. Conclusions These findings establish TCAP-1 as a potential therapeutic candidate for the prevention and treatment of morphine withdrawal.

show abstract

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

Cited by 34 publications

References 85 publications

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

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

Targeting Endocannabinoid Signaling in the Lateral Habenula as an Intervention to Prevent Mental Illnesses Following Early Life Stress: A Perspective

Teneurin C-terminal associated peptide (TCAP)-1 attenuates the development and expression of naloxone-precipitated morphine withdrawal in male Swiss Webster mice

Contact Info

Product

Resources

About